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Food Increases the Bioavailability of Isotretinoin
Abstract
Twenty healthy male subjects received 80 mg (2 X 40 mg SEG capsules) oral isotretinoin separated by two-week washout periods in an open randomized crossover design. Isotretinoin was administered during a complete fast, 1 hour after a standard breakfast, with a standard breakfast, or 1 hour before a standard breakfast. Blood samples were obtained at specific times over a 72-hour period. Isotretinoin blood concentrations were determined by a specific HPLC method. The relative bioavailability (AUC) of isotretinoin was found to be approximately 1.5 to 2 times greater when the dose was administered 1 hour before, concomitantly with, or 1 hour after a meal than when it was given during a complete fast. In addition, because the Cmax value is lower when the dose is administered with food rather than 1 hour after a meal, coadministration of isotretinoin with food may be the best method of administration.
... However, inadequate attention has been given to the 63 % decrease in gastrointestinal (GI) absorption of isotretinoin that occurs when OI is administered on an empty stomach as compared to with a high calorie-high fat meal [17••, 23]. As there is evidence that cumulative systemic exposure to OI directly affects the duration of remission, the variability in GI absorption of isotretinoin with and without an adequate meal has been raised as a potential cause for recurrence of AV that warrants aggressive retreatment [12••, 13-17••, [18][19][20][21][22][23][24][25]. ...
... Among the cases of recurrence of AV after use of OI, the onset of recurrence was as early as 6 months, and usually within 2 to 3 years after completion of OI. The subset of patients who needed at least one additional course of OI usually completed this within 2 to 3 years, of their initial course [1, 4, 12••, 13-17••, [18][19][20][21][22][23][24][25]. Given the same duration of OI therapy which was usually 16 to 20 weeks, a consistent trend for recurrence of AV has been observed in several studies, with a lower daily dose (0.1 -0.2 mg/kg/day) associated with a higher recurrence rate and often an earlier onset of recurrent AV as compared to higher daily doses (0.5mg/kg/day; 1 mg/ kg/day) [12••, 13-17••, [18][19][20][21][22][23][24][25]. ...
... The subset of patients who needed at least one additional course of OI usually completed this within 2 to 3 years, of their initial course [1, 4, 12••, 13-17••, [18][19][20][21][22][23][24][25]. Given the same duration of OI therapy which was usually 16 to 20 weeks, a consistent trend for recurrence of AV has been observed in several studies, with a lower daily dose (0.1 -0.2 mg/kg/day) associated with a higher recurrence rate and often an earlier onset of recurrent AV as compared to higher daily doses (0.5mg/kg/day; 1 mg/ kg/day) [12••, 13-17••, [18][19][20][21][22][23][24][25]. The culmination of data analysis supports that a course of OI achieves a total dose of 120 -50 mg/kg to reduce the potential for recurrence of AV (Table 1) [17••, 18-22]. ...
Oral isotretinoin is a highly successful therapy for severe, refractory inflammatory acne vulgaris (AV) that is indicated especially for patients with multiple nodulocystic lesions. After over 30 years of clinical use, it is apparent that the majority of patients experience clearing of AV with prolonged remission after a course of oral isotretinoin therapy is completed. Multiple reports have shown that recurrence of AV occurs in some patients and is more likely in those who had not achieved adequate cumulative exposure to a total dose of drug, which has been defined as 120 – 150 mg/kg. As the pharmacokinetic profile of orally administered isotretinoin shows that gastrointestinal absorption is highly dependent on administration with a high calorie-high fat meal, it is has been considered that patients who ingest a conventional formulation of oral isotretinoin without an adequate meal or without food at all may be predisposed to a higher rate and earlier onset of recurrence of AV as their cumulative systemic exposure is effectively reduced by up to 60 %. A new formulation of oral isotretinoin uses a technology where isotretinoin is pre-solubilized in a lipid matrix so absorption is not markedly diminished if the patient does not ingest the drug with an adequate meal. As the data analysis on recurrence of AV in patients treated with conventional formulations of oral isotretinoin are retrospective, additional research and vigilant observation are needed to determine if the new formulation will provide better long term outcomes.
... 3 As a result, isotretinoin improves patients' QoL. 4 However, due to the highly lipophilic nature of traditional forms of isotretinoin, historically Accutane® (Roche Laboratories Inc., Nutley, New Jersey), it is recommended that oral traditional isotretinoin is administered with a high-fat/ high-calorie meal to optimize bioavailability and efficacy. 5,6 The bioavailability of traditional isotretinoin taken in fasted conditions is nearly 60 percent lower than when traditional isotretinoin is taken under fed conditions. 6 Nonadherence to isotretinoin food intake requirements, to any degree, could compromise long-term efficacy and might affect patient QoL. ...
... 5,6 The bioavailability of traditional isotretinoin taken in fasted conditions is nearly 60 percent lower than when traditional isotretinoin is taken under fed conditions. 6 Nonadherence to isotretinoin food intake requirements, to any degree, could compromise long-term efficacy and might affect patient QoL. 7 The patient QoL benefits associated with traditional isotretinoin therapy might be achievable without specific dietary requirements through treatment with Lidose-isotretinoin (Absorica®; Sun Pharmaceutical Industries, Inc., Princeton, New Jersey). ...
OBJECTIVE: We sought to assess the impact of Lidose-isotretinoin taken without food on patient quality of life (QoL) at baseline, monthly intervals, and end of study in patients with severe recalcitrant nodular acne. DESIGN: In this open-label, single-arm, multicenter study, 197 patients took twice-daily Lidose-isotretinoin without food for 20 weeks (120-150mg/kg cumulative dosage). Patient visits occurred at Weeks 2, 4, 8, 12, 16, and 20. At baseline and Weeks 4, 8, 12, 16, and 20, patients underwent QoL and acne severity assessments and lesion counts. SETTING: Participants were enrolled from 21 sites across the United States. PARTICIPANTS: Eligible participants were 12 to 45 years of age, weighing 40 to 110kg, and with e;5 facial nodules and no prior exposure to systemic retinoids, including isotretinoin. Female participants were nonpregnant and nonlactating. MEASUREMENTS: An acne-specific QoL questionnaire (Acne-QoL) was used to assess QoL. Efficacy endpoints were lesion counts and Investigator Global Assessment (IGA) of acne severity. Safety assessments included reported adverse events. RESULTS: Lidose-isotretinoin taken without food significantly improved mean (standard deviation) overall Acne-QoL score from baseline (61.6 [28.7]) to end of treatment (101.8 [16.9]; P<0.0001). Improvements were shown in both male and female patients. Significant improvements in patient QoL (overall and by questionnaire domain), lesion counts, and IGA scores were observed as early as Week 4 and continued to improve throughout treatment. CONCLUSION: Twice-daily Lidose-isotretinoin taken without food for 20 weeks significantly improved patient QoL from Week 4.
... 3 These properties require that isotretinoin be ingested with a high-fat/high-calorie (HF/HC) meal (50g of fat, 1,000 calories) to achieve optimal gastrointestinal absorption. 4,5 Other than lidoseisotretinoin (Absorica®; Sun Pharmaceutical Industries, Inc., Princeton, New Jersey), all currently available isotretinoin formulations are based on bioequivalence to pharmacokinetic data achieved with the original brand of isotretinoin (Accutane®; Roche Laboratories Inc., Nutley, New Jersey), referred to here as traditional isotretinoin. 5 Traditional isotretinoin administered under fasted conditions results in plasma isotretinoin levels that are about 60-percent lower than those achieved along with the administration of an HF/HC meal. 4 Relapse rates have been correlated directly with decreased total systemic exposure to isotretinoin, meaning that nonadherence or inconsistent adherence with food intake can increase the risk of post-treatment relapse and compromise long-term efficacy. ...
... 5 Traditional isotretinoin administered under fasted conditions results in plasma isotretinoin levels that are about 60-percent lower than those achieved along with the administration of an HF/HC meal. 4 Relapse rates have been correlated directly with decreased total systemic exposure to isotretinoin, meaning that nonadherence or inconsistent adherence with food intake can increase the risk of post-treatment relapse and compromise long-term efficacy. 6 The term relapse in acne treatment refers to the appearance of new acne lesions after apparent clearance; however, in some publications, relapse may only include patients who require retreatment after acne therapy has ceased. ...
Objective: We sought to evaluate long-term relapse rates following lidose-isotretinoin taken without food in patients with severe recalcitrant acne. Design: In this single-arm, open-label study, 197 patients received twice-daily lidose-isotretinoin without food for up to 20 weeks. Patients with a 75-percent or higher adherence rate with the protocol-designated dosage and end-of-treatment lesion counts were predefined as the per-protocol (PP) population and evaluated in a 104-week post-treatment period (PTP) to determine the proportion of patients requiring retreatment. Setting: Participants were enrolled from 21 sites across the United States. Participants: Eligible participants were male or nonpregnant, nonlactating female, aged between 12 to 45 years, weighing 40 to 110 kg, and with no prior exposure to systemic isotretinoin or systemic retinoids. Acne was considered severe enough for treatment if the patient had five or more facial nodule lesions. Measurements: Patients were observed to determine whether they required retreatment with isotretinoin or any acne therapy during the PTP. Lesion counts and assessments of acne severity, quality of life, and adverse events were completed. Results: Of the 166 patients in the PP population, seven (4.2%; 95% confidence interval [CI]: 1.7%-8.5%) were retreated with isotretinoin, 25 (15.1%; 95% CI: 10.0%-21.4%) were treated with topical and/or oral nonisotretinoin therapies including over-the-counter therapies or intralesional injections, and 137 (82.5%; 95% CI: 75.8%-88.0%) required no retreatment. Isotretinoin retreatment was most common in male patients aged 14 to 18 years. Conclusion: Long-term relapse rates for lidose-isotretinoin taken without food for 20 weeks were at the low end of those published for traditional isotretinoin taken with a high-fat/high-calorie meal. ClinicalTrials.gov Registration: NCT02457520.
... In general, most a lipophilic drug such as diazepam [15], spironolactoe [16][17], propranolol and metoprolol [18], isotretinoin [19] and amiodarone [20] had been shown to be solubilized in this way, and the apparent of absorption rate was increased. However, a similar mechanism may be explaining the observed increased absorption of simvastatin in this study after intake with the 30.70 gm fat-containing food. ...
... The results from the current study indicate that systemic exposure (Cmax and AUC) to simvastatin is higher when administered with food rather than under fasting conditions. The difference in mean AUC values between fed and fasting conditions in this study is similar to the findings of studies conducted by ; Colburn et al (1983); Overdiek and Merkus, (1986); Fabre and Timmer, (2003) when they concluded that food increase drugs absorption when drugs are immediately taken after food due to change in hepatic blood flow during the first passage through the liver and suggest that the amount of unchanged drug reaching systemic circulation is enhanced in the presence of food, possibly because the resultant increase in hepatic blood flow could lead to a reduction in first pass metabolism of drugs that have a high hepatic extraction ratio, such as spironolactone, propranolol, metoprolol, isotretinoin and gepirone. ...
Simvastatin 40 mg tablet was evaluated with Malaysian food in 9 healthy Malaysian male volunteers in a randomized, single dose, two-way crossover study. Simvastatin with Malaysian food produced higher AUC0-24, Cmax and Tmax values, as compared with fasting condition. The Ke, t1/2 and Cl did not show any significant difference between fasting and food conditions. However, food delayed gastric emptying and gastrointestinal transit, the longer gastric residence time of the simvastatin is offset by the rise in the pH of gastrointestinal tract. Food may be did not affect the increase of splanchnic hepatic blood flow by decreasing first pass metabolism of simvastatin. Food may be had the effect on the increasing of pH of gastrointestinal tract which lead to increase the stability of simvastatin in gastrointestinal fluid and its absorption into blood circulation.
... The decision to designate twicedaily (BID) dosing as the FDA-approved daily dosing frequency was based on early limited PK data collected in a small number of subjects, and may be more rational with ≥60 mg/day. 2,[66][67][68] Studies showed the PK of isotretinoin can be adequately described using a simple linear model for doses up to 240mg/day. [66][67][68] The decision to designate BID dosing when Acc-ISO was initially FDA-approved in 1982 was at least partially a desire to achieve a steady state plasma level with repetitive ISO dosing that avoided marked fluctuations in peak and trough concentrations ( Table 2). ...
... 2,[66][67][68] Studies showed the PK of isotretinoin can be adequately described using a simple linear model for doses up to 240mg/day. [66][67][68] The decision to designate BID dosing when Acc-ISO was initially FDA-approved in 1982 was at least partially a desire to achieve a steady state plasma level with repetitive ISO dosing that avoided marked fluctuations in peak and trough concentrations ( Table 2). [67][68] The maximum plasma concentration (Cmax) is higher with a single dose compared to a twice-daily divided dose, and Cmax may potentially affect the side effect profile of ISO. ...
... 35 The bioavailability of isotretinoin increased 1.5 to 2 times more significantly when the dose was administered 1 hour before, concomitantly with, or 1 hour after a meal than when it was taken during a complete fast. 36 This recommendation cannot be followed in many patients, which may result in poor treatment efficacy. ...
In 1982, the Food and Drug Administration (FDA) of the United States of America approved isotretinoin (13-cis-retinoic acid), a retinoid derivative of vitamin A, to treat severe recalcitrant acne vulgaris. Apart from its prescribed use for severe acne, evidence suggests that isotretinoin is commonly used off-label to treat mild-to-moderate acne, inflammatory skin conditions, genodermatoses, skin cancer, and other skin disorders. This is due to its anti-inflammatory, immunomodulatory, and antineoplastic properties. Some "off-label" use is successful, while others are ineffective. Therefore, this information is essential to clinicians for deciding on the appropriate use of isotretinoin. In this article, we aim to review the most updated evidence-based data about the use of oral isotretinoin in dermatology.
... 11 Oral isotretinoin is highly lipophilic and taking the medication with a fatty meal can enhance absorption by 60%. 12 It is associated with adverse effects including increased serum triglycerides, deranged liver function tests (LFTs), xerosis of the skin and mucous membranes and teratenogenicity. [13][14][15] Although it remains controversial and no causal relationship has been firmly established, a range of neuropsychiatric effects have been described, and isotretinoin may induce changes in brain functioning. ...
... 11 Oral isotretinoin is highly lipophilic and taking the medication with a fatty meal can enhance absorption by 60%. 12 It is associated with adverse effects including increased serum triglycerides, deranged liver function tests (LFTs), xerosis of the skin and mucous membranes and teratenogenicity. [13][14][15] Although it remains controversial and no causal relationship has been firmly established, a range of neuropsychiatric effects have been described, and isotretinoin may induce changes in brain functioning. ...
How does low‐dose oral isotretinoin compare with recommended and high‐dose oral isotretinoin in terms of efficacy, adverse effect profile, duration of remission, economic profile and rate and severity of relapse? A systematic literature search of EMBASE, MEDLINE, PubMed and The Cochrane Library from 1983 to July 2022 was conducted to identify randomised control trials (RCTs), cohort studies and cross‐sectional studies investigating the treatment of acne vulgaris with oral isotretinoin. This systematic review of the literature sought to explore and compare the use of different isotretinoin dosing regimens. Primary outcomes were efficacy, relapse, and safety profiles of oral isotretinoin of varying doses. Secondary outcomes included adverse events and economic considerations. The quality of studies, including risk of bias was assessed using GRADE (Grading of Recommendations, Assessment, Development and Evaluations). A total of 32 studies were included. Severe acne responds better to conventional or high fixed daily doses of isotretinoin. In cases of mild to moderate acne, where oral isotretinoin was prescribed, clearance rates were comparable with low, conventional or high dosage regimens. Despite this, relapse was more frequent in those treated with a lower dose. The severity of mucocutaneous adverse effects worsens as the dose of isotretinoin is increased. Comparison between studies was challenging due to differing methods of assessment, outcome measures and duration of follow‐up. This review highlights the need for an adequately powered RCT comparing low, conventional and high doses of oral isotretinoin to establish optimal dosing for treatment and prevention of relapse in acne vulgaris.
... Приверженность пациента к совместному приему данного лекарственного препарата с продуктами питания с высоким содержанием жиров является очень важным фактором с точки зрения эффективности терапии. В этой связи противоречивые пищевые привычки во время курса терапии системными ретиноидами могут в конечном счете привести к неустойчивости плазменных концентраций изотретиноина и оказать неблагоприятное влияние на результаты терапии [15][16][17][18]. ...
The article presents current data on the application of a systemic retinoid, isotretinoin, on the basis of the Lidose system for the treatment of patients with severe forms of acne. It also discusses issues of optimization of the daily dose of isotretinoin taking into consideration long-term clinical efficacy and safety of the therapy. The article presents the results of the authors’ study demonstrating the possibility to select mainly large or small doses of systemic isotretinoin depending on the treatment duration.
... прием пищи повышает содержание жирных кислот и увеличивает биодоступность препарата (25% -в состоянии натощак и 40% -после еды). при этом чем выше уровень растворенной фракции изотретиноина в наполнителях, тем больше биодоступность изотретиноина [16]. ...
... Isotretinoin (13-cis-retinoic acid), a naturally occurring retinoid in human serum, 4,5 is readily produced after the consumption of oral vitamin A. 5 Following oral administration, the bioavailability of isotretinoin is approximately 25%. 6 As it is highly lipophilic, the relative bioavailability is 1.5 to 2 times greater when isotretinoin is taken with food, compared with a complete fast. 7 A novel formulation of isotretinoin, isotretinoin-lidose, uses lipid agents to encase the lipophilic isotretinoin and can be taken without regard for meals. 8 In one study, mean plasma levels of the isotretinoin-lidose formulation during fasting conditions were 67% when taken with a fatty meal, compared with 40% for the innovator formulation. ...
Since it was first approved for use in 1982, isotretinoin has revolutionized the management of acne vulgaris. Despite almost four decades of widespread use, uncertainty still exists regarding the manner in which it is best prescribed. In this review, we provide an update on the pharmacokinetics, mechanism of action, contraindications, interactions, and appropriate dosing schedule of isotretinoin in the treatment of acne. We also discuss the safety of performing concurrent dermatological procedures in patients taking isotretinoin.
... 28 Oral isotretinoin is highly lipophilic, and its bioavailability can be increased 1.5-2 times by intaking with fat components (milk, butter, cheese, oil) during or after a meal. 29,30 Clinical question 4: Is a cumulative dose necessary? ...
Guidelines and consensus on the management of patients with acne aim to give evidence‐based, expert‐group recommendations. This review compares current guidelines and consensus articles to provide a compilation of recommendations on the treatment of acne with oral isotretinoin. Ten common, relevant, clinical questions are addressed, based on published recommendations, including the indications of isotretinoin, the proposed daily dose, the cumulative isotretinoin dose and the laboratory monitoring needed. Recommendations on special considerations are also addressed, including the timing of procedures and the question of an association of depression or inflammatory bowel disease with isotretinoin. A major limitation is the use of different classification systems for acne across guidelines. The recommended daily dose ranges from 0.3‐0.5 mg/kg in the European guidelines to up to 1 mg/kg in the US guidelines. A specific duration of treatment of at least 6 months is only recommended in the European guidelines. All guidelines report the need of strict pregnancy prevention measures. The European, French and US guidelines recommend to monitor for symptoms of depression. Important clinical questions that are inconsistently addressed in guidelines include the age indication, the recommendation for a cumulative dose, the timing of procedures, the association of isotretinoin with IBD, the recommendation for preventing acne flares and for appropriate laboratory monitoring. These topics should be clearly included in the recommendations of guidelines as they are often raised in everyday clinical practice.
... I sotretinoin (13-cis retinoic acid) is the gold standard therapy for the treatment of severe nodular acne (1). It is recommended that isotretinoin is administered with a high-fat/high-calorie meal to optimize its bioavailability and efficacy (2,3). Lidose-isotretinoin (Absorica ® ; Sun Pharmaceutical Industries, Inc., Princeton, NJ, USA) is a formulation of isotretinoin that is pre-solubilized in a lipid matrix to improve bioavailability via enhanced gastrointestinal absorption (4,5). ...
Two open-label, crossover studies compared the bioavailability of micronized-isotretinoin 32 mg and Lidose-isotretinoin 40 mg in healthy adults. In the fed bioequivalence/food-effect study, participants (n = 71) received single doses of fed-state micronized-isotretinoin 32 mg, fed-state Lidose-isotretinoin 40 mg and fasted-state micronized-isotretinoin 32 mg. In the fasting study, participants (n = 8) received single doses of fasted-state micronized-isotretinoin 32 mg and fasted-state Lidose-isotretinoin 40 mg. Bioavailability was assessed by isotretinoin LnAUC0-t, LnAUC0-∞ and LnCmax in blood samples taken pre-dosing and over 96 h post-dosing. The 90% confidence intervals for baseline-adjusted least squares geometric mean ratios for LnAUC0-t, LnAUC0-∞ and LnCmax fell within the 80-125% range for bioequivalence for fed-state micronized-isotretinoin 32 mg vs. fed-state Lidose-isotretinoin 40 mg. Fasted-state micronized-isotretinoin 32 mg had ~2 times higher bioavailability than fasted-state Lidose-isotretinoin 40 mg. Food had no effect on the rate and a marginal effect on the extent of absorption of micronized-isotretinoin 32 mg.
... Isotretinoin, etretinate,acitretin are orally active retinoids increased bioavailability with fatty meals (Fleckman, 2003;Digiovanna et al., 2013). The enormity of the increase of absorption varies with different stage as like from medium to high increase of fat meal, absorption of retinoids does not enhance for the higher value (Colburn et al., 1983). ...
In bio-pharmaceutical viewpoint, absorption of drugs and their subsequent actions are influenced by various factors, including dietary components. In this paper, we have discussed the influence of dietary lipids on the absorption of drugs (mainly orally administered drugs) on the basis of database-based scientific reports. For this, we did a search in the PubMed, MedLine, ScienceDirect, and GoogleScholar databases for the up-to-date published evidences. Findings suggest that through several mechanisms dietary lipids affect in the pharmacokinetics of drug absorption processes. The absorption of fat soluble vitamins, and their analogues are dependent on the solubilisation of the drug in bile salt. Lipophilic drugs absorb better than the hydrophilic drugs with the dietary lipids. Some drugs are more absorbed with high fatty meals, while some are with medium or low and even no fatty meals .Here we mainly show the mechanism of drug absorption that interfere by the dietary lipids.
... Так, после 6 недель перорального приема препарата липидный состав комедонов изменился в сторону 36%-ного снижения фракции глицеридов, 34%-ного увеличения содержания свободных стеролов и 19-ного увеличения содержания керамидов. Этот изотретиноининдуцированный липидный состав соответствует данному показателю в нормальной коже с неизмененной десквамацией и коррелирует со снижением комедоногенеза [13]. Таким образом, можно ожидать минимального положительного эффекта от приема препарата уже к 6-8 недели терапии. ...
The article deals with the modern concepts of the pathogenesis of acne, describes the impact of this pathology on the psychoemotional state of patients and the compliance to therapy. The article considers approaches to the treatment of moderate to severe forms of acne using the systemic retinoid - isotretinoin. It presents the results of our own observations and the prospects for eliminating undesirable phenomena during administration of this retinoid.
... [6,7]. Die Bioverfügbarkeit von Isotretinoin, also der Anteil einer peroral verabreichten Dosis, der intakt in die Blutzirkulation gelangt, ist relativ gering und hängt unter anderem davon ab, ob Isotretinoin-Kapseln nüchtern oder zusammen mit einer Mahlzeit eingenommen werden [8]. ...
... Si l'on compare les différents isomères en ce qui concerne leur activité sébostatique, un effet n'a été démontré, après administration orale, que pour l'acide 13cis-rétinique [6,7]. La biodisponibilité de l'isotrétinoïne, c'est-à-dire de la proportion d'une dose administrée par voie orale arrivant intacte dans la circulation sanguine, est relativement faible et dépend entre autres de la prise des capsules d'isotrétinoïne à jeun ou avec un repas [8]. La concentration plasmatique de l'isotrétinoïne et de son métabolite principal, le 4-oxoisotrétinoïne, est dose-dépendante, mais elle varie cependant fortement entre les individus. ...
... Increased drug exposure, relative to the fasted state, following postprandial administration of poorly water-soluble drugs in conventional solid formulations is well documented in the literature [e.g., isotretinoin [17] ; danazol (43, 52, and 53); L-683,453 ...
Oral route has always been preferred route for formulators and has dominated over other routes of administrations. However this preferred route is limited to those drugs molecule that are permeable across the gastric mucosa and are at least sparingly soluble. Approximately 40%of new chemical entities exhibit poor aqueous solubility and present a major challenge to modern drug delivery system, because of their low bioavailability. The oral bioavailability of poorly water soluble drugs may be enhanced when co-administered with meal rich in fat has led to increasing recent interest in the formulation of poorly water soluble drugs in lipids. Also nowadays much attention has been paid to the lipid based formulations. Some examples of marketed lipid based formulations are Sandimmune Neoral (Cyclosporine A), Novartis Pvt. Ltd. and Fortovase (Saquinavir), Roche Laboratories Inc. with much attention focused on self micro-emulsifying drug delivery systems (SMEDDS). Self micro emulsifying drug delivery systems are isotropic mixtures of oil, surfactant, co-surfactant and drug with a unique ability to form fine oil in water microemulsion upon mild agitation following dilution with aqueous phase. The hypothesis behind dissolution rate enhancement with SMEDDS is the spontaneous formation of the emulsion in the gastrointestinal tract which presents the drug in solubilized form, and the small size of the formed droplet provides a large interfacial surface area for drug absorption. This article gives a complete overview of SMEDDS as a promising approach to effectively tackle the problem of poorly soluble molecules. Keywords: Self micro emulsifying drug delivery system, oral bioavailability, lipid based formulations, poorly water soluble drugs.
... Increased drug exposure, relative to the fasted state, following postprandial administration of poorly watersoluble drugs in conventional solid formulations is well documented in the literature [e.g., isotretinoin 17 ; danazol (43, 52, and 53); L-683,453 (54); DPC 961 18 ; halofantrine 19 . It has been postulated that the magnitude of the exposure increase may indicate the maximum extent of absorption possible when the drug is administered in a lipid-based formulation 20 . ...
Oral route has always been preferred route for formulators and has dominated over other routes of administrations. This route is limited to those drugs molecule that are permeable across the gastric mucosa and are at least sparingly soluble. Approximately 40% of new chemical entities exhibit poor aqueous solubility and present a major challenge to modern drug delivery system, because of their low bioavailability. Some examples of marketed lipid based formulations are Sand immune Neoral (Cyclosporine A), Novartis Pvt. Ltd. and Fortovase (Saquinavir), Roche Laboratories Inc. with much attention focused on self micro-emulsifying drug delivery systems (SMEDDS). Self microemulsifying drug delivery systems are isotropic mixtures of oil, surfactant, co-surfactant and drug with a unique ability to form fine oil in water microemulsion upon mild agitation following dilution with aqueous phase. This article gives a complete overview of SMEDDS as a promising approach to effectively tackle the problem of poorly soluble molecules.
... The particle size of the formulated drug can affect oral absorption. For example, the co-administration of food with a standard isotretinoin formulation increased the absorption significantly [117]; however, the micronized isotretinoin formulation further improved the bioavailability compared to the standard formulation and was minimally affected by food [118,119]. The improved bioavailability was apparently due to enhanced drug dissolution as a result of reduced particle size and the corresponding increase in surface area of the micronized drug. ...
This article reviews the major physiological and physicochemical principles of the effect of food and gastrointestinal (GI) pH on the absorption and bioavailability of oral drugs, and the various absorption models that are used to describe/predict oral drug absorption. The rate and extent of oral drug absorption is determined by a complex interaction between a drug’s physicochemical properties, GI physiologic factors, and the nature of the formulation administered. GI pH is an important factor that can markedly affect oral drug absorption and bioavailability as it may have significant influence on drug dissolution & solubility, drug release, drug stability, and intestinal permeability. Different regions of the GI tract have different drug absorptive properties. Thus, the transit time in each GI region and its variability between subjects may contribute to the variability in the rate and/or extent of drug absorption. Food-drug interactions can result in delayed, decreased, increased, and sometimes un-altered drug absorption. Food effects on oral absorption can be achieved by direct and indirect mechanisms. Various models have been proposed to describe oral absorption ranging from empirical models to the more sophisticated “mechanism-based” models. Through understanding of the physicochemical and physiological rate-limiting factors affecting oral absorption, modellers can implement simplified population-based modelling approaches that are less complex than whole-body physiologically-based models but still capture the essential elements in a physiological way and hence will be more suited for population modelling of large clinical data sets. It will also help formulation scientists to better predict formulation performance and to develop formulations that maximize oral bioavailability.
... The dermatologist should advise the patient to take isotretinoin with a fat-containing meal as this optimizes its bioavailability. 84 In addition, the type of oral isotretinoin being taken should be checked as the pharmaceutical quality of generic versions can be questionable resulting in variable activity. 71,85 Early acne scarring in patients with papulopustular or conglobate acne indicates that the therapeutic regimen is ineffective and needs to be rapidly changed (Tables 3-4). ...
Background:
Many current guidelines provide detailed evidence-based recommendations for acne treatment.
Objective:
To create consensus-based, simple, easy-to-use algorithms for clinical acne treatment in daily office-based practice and to provide checklists to assist in determining why a patient may not have responded to treatment and what action to take.
Methods:
Existing treatment guidelines and consensus papers were reviewed. The information in them was extracted and simplified according to daily clinical practice needs using a consensus-based approach and based on the authors' clinical expertise.
Results:
As outcomes, separate simple algorithms are presented for the treatment of predominant comedonal, predominant papulopustular and nodular/conglobate acne. Patients with predominant comedonal acne should initially be treated with a topical retinoid, azelaic acid or salicylic acid. Fixed combination topicals are recommended for patients with predominant papulopustular acne with treatment tailored according to the severity of disease. Treatment recommendations for nodular/conglobate acne include oral isotretinoin or fixed combinations plus oral antibiotics in men, and these options may be supplemented with oral anti-androgenic hormonal therapy in women. Further decisions regarding treatment responses should be evaluated 8 weeks after treatment initiation in patients with predominant comedonal or papulopustular acne and 12 weeks after in those with nodular/conglobate acne. Maintenance therapy with a topical retinoid or azelaic acid should be commenced once a patient is clear or almost clear of their acne to prevent the disease from recurring. The principal explanations for lack of treatment response fall into 5 main categories: disease progression, non-drug-related reasons, drug-related reasons, poor adherence, and adverse events.
Conclusion:
This practical guide provides dermatologists with treatment algorithms adapted to different clinical features of acne which are simple and easy to use in daily clinical practice. The checklists to establish the causes for a lack of treatment response and subsequent action to take will facilitate successful acne management.
... In the absence of food the larger accessibility of the mucosa surface may allow the establishment of additional interactions with glucosamine butyrate amplifying its enhancement effect on permeation and drug absorption. Without enhancer, on the contrary, the presence of food is well known to favour the gastrointestinal absorption of fenretinide and other retinoids [16][17][18][19]. High-fat meals, in particular, strongly increase their absorption and reduce variability. ...
Fenretinide (4-HPR) is the most promising retinoid derivative with anticancer activity and low toxicity profile. Despite its excellent tolerability, the formulations of 4-HPR that have been clinically evaluated until now have not provided drug plasma concentrations suitable to elicit a therapeutic response. Therefore innovative formulations able to improve the drug bioavailability would be of considerable interest. In this work we describe the preparation and functional evaluation of novel nanocapsules designed to enhance fenretinide bioavailability by oral route through the use of glucosamine butyrate as bioavailability enhancer and gelatin as a matrix forming agent. The anti-tumour activity of the nanocapsules has been tested in in vitro and in vivo models either in feeding and fasting conditions. Our data indicated that after oral administration the nanocapsules provide 4-HPR plasma concentrations in the range compatible with the antitumor activity as assessed in vitro expecially in fasting conditions. Moreover these novel nanocapsules have proved to be effective in tumor xenografts after oral administration
... A recent European Directive on isotretinoin prescribing has recommended a starting dose for all patients of 0.5 mg/kg/day, with the dose titrated to obtain a maximal early response off set against the development and tolerance of side eff ects (12). Being lipophilic, it should be administered with food, which has been shown by pharmacokinetic studies to double absorption (13). A heavy alcohol intake should be avoided while on treatment as isotretinoin is metabolized by cytochrome P450 enzymes, which are induced by ethanol, resulting in reduced effi cacy (14). ...
The efficacy of isotretinoin at 0.5 to 1.0 mg/kg per day in the treatment of acne is well established and considered safe, although it is sometimes not easily tolerated because of its cutaneous side effects.
The purpose of this study was to determine the efficacy of low-dose isotretinoin in the treatment of acne.
In this prospective, non comparative, open-label study, 50 patients, both male and female, with moderate acne were enrolled and treated with isotretinoin at 20 mg/d (approximately 0.3-0.4 mg/kg per day) for 3 months. The patients were divided into two age groups: 12 to 20 and 21 to 35 years old. Patients were evaluated at 2-month intervals by means of clinical and laboratory examinations. A 4-year follow-up was also carried out.
At the end of the treatment phase, good results were observed in 90.8% of the patients aged 12 to 20 years, and in 89.6% of the patients aged 21 to 35 years. Failure of the treatment occurred in 5.2% and 7.4% of the two groups, respectively. Three patients dropped out of the study because of lack of compliance, and another patient discontinued participation because of a laboratory side effect. During the 2-year follow-up period, relapses of the acne occurred in 3.9% of the patients aged 12 to 20 years and in 5.9% of the patients aged 21 to 35 years. Elevated serum lipid levels (up to 20% higher than the upper limit of normal value) were found in 4.2% of the patients and abnormal (<twice the upper limit of normal values) liver tests were observed in 4.8%.
This was a non comparative, open-label study.
Three months of treatment with low-dose isotretinoin (20 mg/d) was found to be effective in the treatment of moderate acne, with a low incidence of severe side effects and at a lower cost than higher doses.
Acne vulgaris is one of the commonest inflammatory skin diseases seen worldwide, affecting all ethnicities and races, with a peak prevalence between age 15 years and 20 years. The burden of this condition, and the resulting clinical and psychological sequelae, is substantial. The visual appearance of acne and its sequelae, including scarring and pigment changes, frequently results in psychological and social morbidity because of concerns about appearance. As understanding of the pathophysiology has evolved, approaches to achieving the optimal outcomes with effective treatment regimens continue to emerge. In the past few years, several novel therapeutics have been developed, including new agents aimed at reducing antimicrobial resistance and products with specific actions targeting retinoid receptors and androgen receptors. This Review considers the management approaches of an adolescent with acne vulgaris and reviews treatment options from the evidence base and international expert opinion. Approaches to selecting current treatments and novel and emerging treatment regimens are discussed.
Introduction:
Acne is one of the most common and widespread skin conditions, affecting the health as much as patients' quality of life. A wide variety of treatments for acne, topical and systemics, could be prescribed, depending on its degree of severity. Isotretinoin, a derivative of retinol, has been widely used for the treatment of severe forms of acne and those forms not responding to conventional treatments. In literature, there are several studies describing its efficacy, also reporting side-effects related to the drug; therefore, this has led the scientific community to request further studies qualifying its characteristics and comparing its efficacy and safety with other classic acne treatments, as well as with different treatment regimes, in order to find the dose with the best efficacy/safety ratio.
Areas covered:
The aim of this article is to provide a complete overview on the use of oral isotretinoin for the treatment of acne describing the efficacy, safety, and tolerability of the drug.
Expert opinion:
Oral isotretinoin represents a valid therapeutic alternative in treating severe and mild-to-moderate acne lesions, also reducing scarring damage. There are no standardized protocols regarding the use of oral isotretinoin and its association with other therapies; however, the correct patient selection and a tailored treatment protocol according to acne lesions severity and type should be considered in order to obtain optimal results.
Acne vulgaris and hidradenitis suppurativa are chronic inflammatory, multifactorial skin disorders that often develop in adolescence and young adulthood. Both acne vulgaris and hidradenitis suppurativa can cause significant morbidity and psychologic distress, with a negative impact on the quality of life. The relationship between diet, acne, and hidradenitis suppurativa remains somewhat controversial; however, there is increasing evidence that high-glycemic diets, and consumption of milk and dairy products promote acne. Studies suggest that weight loss through dietary interventions or bariatric surgery and Brewer's yeast exclusion diets have the potential to ameliorate the signs of hidradenitis suppurativa. We review h the role of diet in the pathogenesis, prevention, and treatment of hidradenitis suppurativa and acne vulgaris.
Background:
Isotretinoin is a widely used and effective drug in the treatment of severe, recalcitrant, nodular acne. However, its poor aqueous solubility limits oral bioavailability and requires administration with a high-fat, high-calorie meal (HF/HC) for optimal absorption; poor patient adherence may decrease effective dosing and treatment efficacy.
Objective:
This review covers the properties of the lidose isotretinoin and micronized isotretinoin formulations and their use in acne therapy.
Method of literature search:
PubMed was searched using the terms acne, isotretinoin, formulations, isotretinoin efficacy, and safety. Additional articles were searched using reference lists from the obtained results.
Results:
Our review discusses pathology and approved treatment options for acne; provides mechanism of action of isotretinoin; presents clinical challenges associated with isotretinoin safety; and summarizes implications in clinical practice. Newer formulations show enhanced bioavailability in both fed and fasting states.
Limitations:
Few published studies of real-world use of the identified formulations were available.
Conclusion:
Newer drug delivery technologies can simplify isotretinoin use while maximizing bioavailability and efficacy. Based on our analysis, lidose isotretinoin and micronized isotretinoin improve oral bioavailability, pharmacological bioactivity, and increase therapeutic efficacy in patients who are unwilling or unable to consistently take the medication with an HF/HC meal. Healthcare providers should consider these formulations as tools to optimize treatment based on each patient's individual needs.
Aim
The aim of the present study was to evaluate the effect of izotretinoin (ISO) on peripheral vestibular system using vHIT.
Material and method
This is a prospective study in which 30 patients administered ISO treatment with the diagnosis of acne vulgaris was evaluated. Following ear nose and throat, examination, audiological and vestibular evaluations were carried out. vHIT tests were conducted before and three months after the use of ISO (0.5–0.75 mg/kg/day). In addition, all participants underwent perceptual vertigo and dizziness tests before and three months after the use of ISO.
Results
In vHIT evaluation of all patients, no overt saccade, covert saccade and spontaneous nystagmus finding was observed. Gain and asymmetry were compared before and after the use of ISO: No significant difference was found between lateral semicircular canal, anterior, and posterior semi-circular and symmetry measurements made before ISO use and those made three months after it (p = 1.00; p = 0.99; p = 0.66). Similarly, there was no significant difference in asymmetry values of vertical semicircular canals measured before ISO and three months after it (p = 0.90; p = 0.76). No statistically significant difference was found in vertigo, nausea and dizziness in terms of responses before and 3 months after ISO use (p = 0.063; p = 0.031; p = 0.063).
Conclusion
Although the studies demonstrating the effect of ISO on cochlea and symptoms occurring during treatment such as nausea, vomiting and vertigo suggest that it may exert effects on peripheral vestibular system, the present study indicates that it has no short terms effects on structures in peripheral vestibular system and vestibuloocular reflex pathways.
Background:
Acne vulgaris, a chronic inflammatory disease of the pilosebaceous unit associated with socialisation and mental health problems, may affect more than 80% of teenagers. Isotretinoin is the only drug that targets all primary causal factors of acne; however, it may cause adverse effects.
Objectives:
To assess efficacy and safety of oral isotretinoin for acne vulgaris.
Search methods:
We searched the following databases up to July 2017: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and LILACS. We updated this search in March 2018, but these results have not yet been incorporated in the review. We also searched five trial registries, checked the reference lists of retrieved studies for further references to relevant trials, and handsearched dermatology conference proceedings. A separate search for adverse effects of oral isotretinoin was undertaken in MEDLINE and Embase up to September 2013.
Selection criteria:
Randomised clinical trials (RCTs) of oral isotretinoin in participants with clinically diagnosed acne compared against placebo, any other systemic or topical active therapy, and itself in different formulation, doses, regimens, or course duration.
Data collection and analysis:
We used standard methodological procedures expected by Cochrane.
Main results:
We included 31 RCTs, involving 3836 participants (12 to 55 years) with mild to severe acne. There were twice as many male participants as females.Most studies were undertaken in Asia, Europe, and North America. Outcomes were generally measured between eight to 32 weeks (mean 19.7 weeks) of therapy.Assessed comparisons included oral isotretinoin versus placebo or other treatments such as antibiotics. In addition, different doses, regimens, or formulations of oral isotretinoin were assessed, as well as oral isotretinoin with the addition of topical agents.Pharmaceutical companies funded 12 included trials. All, except three studies, had high risk of bias in at least one domain.Oral isotretinoin compared with oral antibiotics plus topical agentsThese studies included participants with moderate or severe acne and assessed outcomes immediately after 20 to 24 weeks of treatment (short-term). Three studies (400 participants) showed isotretinoin makes no difference in terms of decreasing trial investigator-assessed inflammatory lesion count (RR 1.01 95% CI 0.96 to 1.06), with only one serious adverse effect found, which was Stevens-Johnson syndrome in the isotretinoin group (RR 3.00, 95% CI 0.12 to 72.98). However, we are uncertain about these results as they were based on very low-quality evidence.Isotretinoin may slightly improve (by 15%) acne severity, assessed by physician's global evaluation (RR 1.15, 95% CI 1.00 to 1.32; 351 participants; 2 studies), but resulted in more less serious adverse effects (67% higher risk) (RR 1.67, 95% CI 1.42 to 1.98; 351 participants; 2 studies), such as dry lips/skin, cheilitis, vomiting, nausea (both outcomes, low-quality evidence).Different doses/therapeutic regimens of oral isotretinoinFor our primary efficacy outcome, we found three RCTs, but heterogeneity precluded meta-analysis. One study (154 participants) reported 79%, 80% and 84% decrease in total inflammatory lesion count after 20 weeks of 0.05, 0.1, or 0.2 mg/kg/d of oral isotretinoin for severe acne (low-quality evidence). Another trial (150 participants, severe acne) compared 0.1, 0.5, and 1 mg/kg/d oral isotretinoin for 20 weeks and, respectively, 58%, 80% and 90% of participants achieved 95% decrease in total inflammatory lesion count. One RCT, of participants with moderate acne, compared isotretinoin for 24 weeks at (a) continuous low dose (0.25 to 0.4 mg/kg/day), (b) continuous conventional dose (0.5 to 0.7 mg/kg/day), and (c) intermittent regimen (0.5 to 0.7 mg/kg/day, for one week in a month). Continuous low dose (MD 3.72 lesions; 95% CI 2.13 to 5.31; 40 participants; one study) and conventional dose (MD 3.87 lesions; 95% CI 2.31 to 5.43; 40 participants; one study) had a greater decrease in inflammatory lesion counts compared to intermittent treatment (all outcomes, low-quality evidence).Fourteen RCTs (906 participants, severe and moderate acne) reported that no serious adverse events were observed when comparing different doses/therapeutic regimens of oral isotretinoin during treatment (from 12 to 32 weeks) or follow-up after end of treatment (up to 48 weeks). Thirteen RCTs (858 participants) analysed frequency of less serious adverse effects, which included skin dryness, hair loss, and itching, but heterogeneity regarding the assessment of the outcome precluded data pooling; hence, there is uncertainty about the results (low- to very-low quality evidence, where assessed).Improvement in acne severity, assessed by physician's global evaluation, was not measured for this comparison.None of the included RCTs reported birth defects.
Authors' conclusions:
Evidence was low-quality for most assessed outcomes.We are unsure if isotretinoin improves acne severity compared with standard oral antibiotic and topical treatment when assessed by a decrease in total inflammatory lesion count, but it may slightly improve physician-assessed acne severity. Only one serious adverse event was reported in the isotretinoin group, which means we are uncertain of the risk of serious adverse effects; however, isotretinoin may result in more minor adverse effects.Heterogeneity in the studies comparing different regimens, doses, or formulations of oral isotretinoin meant we were unable to undertake meta-analysis. Daily treatment may be more effective than treatment for one week each month. None of the studies in this comparison reported serious adverse effects, or measured improvement in acne severity assessed by physician's global evaluation. We are uncertain if there is a difference in number of minor adverse effects, such as skin dryness, between doses/regimens.Evidence quality was lessened due to imprecision and attrition bias. Further studies should ensure clearly reported long- and short-term standardised assessment of improvement in total inflammatory lesion counts, participant-reported outcomes, and full safety accounts. Oral isotretinoin for acne that has not responded to oral antibiotics plus topical agents needs further assessment, as well as different dose/regimens of oral isotretinoin in acne of all severities.
Systemic therapy for acne is limited to antibiotics, hormonal manipulation, and isotretinoin. This chapter will consider the latter two. Oral contraceptives and spironolactone are valuable hormonal agents whose use will be reviewed. Isotretinoin usage and new findings regarding mechanism and safety will be discussed.
The distribution of the holocrine sebaceous glands in the skin is variable. These glands are associated with hair follicles, with the exception of the so-called free or ectopic sebaceous glands, e.g., on the vermilion of the lips, on the mucosa of the lips and cheeks, and on the genitals (Fordyce’s glands or spots).
Major obstacles to develop effective immunotherapy are the ability of tumors to escape the immune system and the toxicity associated with systemic administration. To overcome these challenges, a gene delivery platform technology, RheoSwitch Therapeutic System(®) (RTS(®) ), has been developed to enable the regulated expression of a target gene, Ad-RTS-IL-12 administered intratumorally, where IL-12 expression is controlled via the administration of an oral activator ligand, veledimex. Pharmacokinetics in healthy human subjects indicated that veledimex plasma exposure increased with increasing dose after single- and multiple-dose administration in Labrasol(®) slurry and F-22 capsule formulations. No apparent formulation or gender-related difference in veledimex PK was observed. Minimal or no plasma accumulation of veledimex was observed after once daily oral administration for 14 days. Veledimex steady state in plasma was reached after 5 daily doses. Food consumption prior to veledimex administration prolonged and enhanced absorption with no impact on the elimination rate and extent of metabolism of veledimex, resulting in significantly increased systemic exposure to veledimex and its two major circulating metabolites. Overall, veledimex was well tolerated and exhibited a PK profile supportive of once daily dosing. For enhanced efficacy, veledimex should be taken under fed conditions to ensure optimal absorption and sufficient systemic exposure. This article is protected by copyright. All rights reserved.
13-cis-Retinsäure (Isotretinoin, Roaccutan), ein Retinoid der ersten Generation [l, 2], ist derzeit das wirksamste Medikament zur Behandlung schwerer Akneformen. Seit der ersten Veröffentlichung von Peck et al. [25] im Jahr 1979 über den eindrucksvollen Erfolg bei Acne conglobata und den ersten Arbeiten im deutschen Schrifttum im Jahr 1980 [16, 26, 32, 39, 40], die diese Beobachtung nicht nur bestätigte, sondern als weitere Indikation auch die intertriginöse Akne (Aknetetrade) nannte sowie umfangreiche laborchemische Studien vorlegte, folgten weitere Publikationen über mögliche Wirkungsmechanismen dieses Medikamentes [6, 13, 23, 30–31]. Ab 1981 nahm die Zahl der Veröffentlichungen zu diesem Thema sprunghaft zu [12], wobei besonders die Bemühungen der Deutschen Multizentrischen Studiengruppe zu erwähnen sind, die anhand großer Patientenkollektive Indikation, Dosierung, Behandlungserfolge, Remissionsdauer und Nebenwirkungen darstellten [10, 18, 19, 29, 42]. Das Medikament ist seit 1982 in USA im Handel (Accutane); es folgten die Schweiz, England, die Bundesrepublik sowie andere europäische Länder; das Medikament wird in Form von 2-, 5-, 10- und 20 mg-Kapseln angeboten.
In the first half of this century, vitamin A and its natural derivatives: retinol, retinal (vitamin A aldehyde), and vitamin A acid, were recognized as playing an essential role in general growth, in the regulation of proliferation and differentiation of epithelial and non-epithelial tissues, in visual processes, and in the capacity of vertebrates to propagate (Wolbach and Howe 1925, 1933).
Oral isotretinoin is unrivalled in efficacy and remission capability for treatment of acne. In addition to appropriate monitoring and continued vigilance for safety concerns, appropriate dosing to mitigate avoidable dose-dependent adverse effects is the responsibility of prescribers. Low-dose regimens are better tolerated and effective in inducing acne clearance. Although much progress has been made since the advent of isotretinoin, there remain many unanswered questions regarding optimization to maximize response while minimizing the potential for avoidable adverse events. The ongoing availability of isotretinoin is imperative to patients with acne, their caregivers, and physicians.
Acne represents the most common inflammatory dermatosis seen worldwide and is the leading reason for seeing a dermatologist. This article provides some tips for managing acne in a safe and effective manner to minimize the physical and psychological scars that can result from acne. Tips include how to optimize available treatment regimens according to the evidence base and target therapy to pathophysiologic factors, while also tailoring treatments to patient expectation and needs. Attention is given to minimizing the emergence of antimicrobial resistance in acne patients and beyond.
Since its approval by the US Food and Drug Administration (FDA) in 1982, isotretinoin has been considered a breakthrough treatment against severe forms of acne. Systemic isotretinoin remains the most efficacious treatment for severe acne as well as many cases of more moderate disease that are unresponsive to other treatment modalities. Regardless of presence for approximately three decades on the market, there is still the question: which dosage? Moreover, isotretinoin is the only drug producing long-term remission, as well influencing scarring tendency. The current manuscript outlines the most appropriate dosage regimens for achieving the excellent efficacy, describes how to optimize treatment, reviews the recommended guidelines for treatment and monitoring, and summarizes interactions and adverse effects linked to oral isotretinoin usage.
Isotretinoin is the strongest, most effective oral treatment for patients with severe acne vulgaris, with remission rates of 89% and higher. Because of its potency, isotretinoin causes many adverse reactions. This article reviews common and severe adverse reactions to isotretinoin and how providers can best manage these reactions. Because of inconclusive research on the correlation between isotretinoin and depression and irritable bowel syndrome, providers should ask patients about symptoms monthly. Prescribing micronized isotretinoin and starting at the lowest dose with gradual upward titration also can help reduce the incidence of adverse reactions.
Pharmacokinetic interactions between food and orally administered drugs involve changes mainly in the absorption and metabolism of a drug, and may have clinical implications. Such interactions, in particular, may be of major clinical significance for cancer chemotherapy since the majority of anticancer agents are toxic, have a low therapeutic index and are administered long term, most often in combination with other cytotoxic agents. The purpose of this review is to compare the pharmacokinetic profiles of various anticancer drugs, including chemopreventive agents that have been examined previously in fasted and fed conditions, and to discuss the underlying basis/mechanisms of food effect in light of a drug’s physicochemical and pharmacokinetic properties. Clinical pharmacokinetic parameters such as maximum concentration, area under the concentration-time curve, time to maximum concentration and half-life for each drug are compared in fasted and fed states, and specific dietary recommendations are summarised accordingly. In addition, the effects of food on the metabolite kinetics and pharmacodynamic responses, and the potential role of food effect in the modulation of oral biovariability and multidrug resistance have been extensively discussed. Overall, this comprehensive pharmacokinetic analysis indicates that a broad spectrum of food effects is seen among anticancer agents because of diverse factors regulating each drug’s oral bioavailability and its interactions with food. The consideration of such effects is important, as it could lead to more rational pharmacological monitoring and possibly improve the oral chemotherapy of cancer in children, adults and the elderly.
Acne vulgaris is a chronic inflammatory disease of pilosebaceous follicles commonly affecting adolescents and young adults. This disease has a profound psychological impact on affected individuals and treatment has been shown to significantly improve both self-esteem and quality of life. Isotretinoin is an effective medication used primarily in severe cystic acne patients. Over the past 30 years, this medication has revolutionized the treatment of acne. However, despite its popularity there are numerous side effects associated with its use. Most of its side effects are predictable and dose dependent, which has led to the development of variable dose regimens. Unfortunately, rare but significant side effects (e.g., depression, inflammatory bowel disease) do occur and necessitate careful monitoring to improve clinical outcomes and minimize potential adverse events.
A high-fat meal is needed for optimal absorption of isotretinoin. A new formulation of isotretinoin, which enhances absorption of isotretinoin in the absence of dietary fat, has recently been approved by the Food and Drug Administration (FDA).
We sought to compare the pharmacokinetic profiles of a new formulation of isotretinoin (isotretinoin-Lidose) with the innovator isotretinoin formulation.
This study was an open-label, single-dose, randomized, 4-treatment, crossover comparative trial between a new and innovator formulation of isotretinoin in the fasting and fed states.
Both formulations were bioequivalent under fed conditions. As expected in a fasting state, absorption of both formulations was reduced. A considerable difference between the 2 drugs occurred under fasted conditions-there was a marked improvement in overall bioavailability of the isotretinoin-Lidose formulation. Mean plasma levels of the isotretinoin-Lidose formulation during fasting reached 66.8% of that observed with a fatty meal, and those of the isotretinoin formulation only reached 39.6% of that observed with a fatty meal.
Only the FDA-stipulated standard high-fat, high-calorie meal of 50-g fat was studied in the fed state.
Isotretinoin-Lidose formulation is bioequivalent to the innovator formulation under fed conditions with regard to its pharmacokinetic profile but delivers twice as much isotretinoin and 4-oxo-isotretinoin when administered after an overnight fast.
The US FDA’s mission is to ensure that safe and effective drugs are approved for use by American consumers. Among the many
factors that the FDA examines to ensure that drug products are safe and effective is the effect of food on the bioavailability
of the active drug from the drug product. Thus, the FDA asks applicants seeking marketing approval of new or generic drug
products to conduct human pharmacokinetic studies examining the effects of food on drug absorption and bioavailability. The
objectives of this chapter are to (1) describe several mechanisms by which food affects drug bioavailability; (2) present
examples from FDA-approved drug product labeling to show how food effects are considered in optimizing therapy; (3) distinguish
between food effects on drug substance versus drug product; and (4) explain the role of food-effect studies in new and generic
drug development.
Food intake exerts a complex influence on the bioavailability of drugs. It may interfere not only with tablet disintegration, drug dissolution and drug transit through the gastrointestinal tract, but may also affect the metabolic transformation of drugs in the gastrointestinal wall and in the liver. Different food components can have different effects, and food may interact in opposite ways, even with drugs that are chemically related. Therefore, the net effect of food on drug bioavailability can be predicted only by direct clinical studies of the drug in question. As judged mainly from single meal, single dose studies, food intake enhances the bioavailability of several different drugs, such as propranolol, metoprolol, hydrallazine, hydrochlorothiazide, canrenone (from spironolactone), nitrofurantoin, erythromycin (stearate), dicoumarol, phenytoin and carbamazepine, but reduces that of drugs such as isoniazid, rifampicin, tetracycline, penicillin and ampicillin, while having no consistent effect on the bioavailability of metronidazole, oxazepam, melperone, propylthiouracil, sulphasomidine and sulphonylureas. For some drugs such as digoxin and paracetamol, the rate but not the extent of absorption is reduced. Food may enhance bioavailability even though, or rather because, the rate of gastric emptying is reduced; this is apparently the case with hydrochlorothiazide and nitrofurantoin. The food induced enhancement of bioavailability of propranolol, metoprolol and hydrallazine is probably due to reduced first pass metabolism of these drugs, while food induced improvement of drug dissolution may explain the enhanced bioavailability of carbamazepine, canrenone, dicoumarol and phenytoin. An increased gastrointestinal pH may be in part the cause of the food induced reduction of the bioavailability of drugs such as isoniazid and tetracycline. In addition to single meal effects, repeated intake of protein-rich meals enhance, while carbohydrate-rich meals reduce, the rate of oxidation of antipyrine and theophylline. Moreover, intake of charcoal broiled meat markedly accelerates the oxidation of phenacetin and variably accelerates elimination of theophylline. Thus, food and its components and contaminants may have both short and long term effects on both the absorptive and biotransformation processes influencing systemic availability of drugs.
81 patients with Darier's disease (DD), lamellar ichthyosis (LI), pityriasis rubra pilaris (PRP), and other keratinizing dermatoses, cystic acne, and basal cell carcinoma were treated with an oral synthetic retinoid Ro 4-3780 (13-cis-retinoic acid). A good to excellent response has been observed in 8 of 9 patients with LI, 3 of 3 with nonbullous congenital ichthyosiform erythroderma, 1 of 1 with ichthyosis vulgaris, 8 of 9 with DD, 3 of 5 with PRO, 2 of 6 with psoriasis, and 14 of 15 with cystic acne. Partial responses were observed in epidermolytic hyperkeratosis (4 patients), PRP (2), psoriasis (1), DD (1), and keratosis palmaris et plantaris (1). 3 patients with psoriasis, 2 with X-linked ichthyosis and 1 with Netherton's syndrome worsened during therapy. Of the 14 patients with cystic or conglobate acne who completed a 4-month course of therapy with 13-cis-retinoic acid, 10 had complete resolution (100%) of all cystic lesions, 2 had a response greater than 90%, 1 above 80%, and 1 above 70%.
Fourteen patients with treatment-resistant cystic and conglobate acne were treated for four months with oral 13-cis-retinoic acid, a synthetic isomer of naturally occurring all-trans-retinoic acid. The average dose was 2.0 mg per kilogram per day. Thirteen patients experienced complete clearing of their disease; the other had 75 per cent improvement, as determined by the number of acne nodules and cysts present before and after therapy. Prolonged remissions, currently lasting as long as 20 months after discontinuation of therapy, have been observed in all 14 patients. Clinical toxicity was limited to the skin and mucous membranes in most patients and was dose dependent and rapidly reversible upon discontinuation of therapy. The mechanism of action of 13-cis-retinoic acid in the therapy of acne probably involves a direct inhibitory effect of the drug on the sebaceous gland.
The literature concerning the influence of food, and also fluid volumes, on drug absorption is reviewed. In most cases, the absorption of drugs from the gastrointestinal tract is reduced or delayed by food. However, some drugs are unaffected by food, while the absorption of a small number of drugs is increased. Observed effects of food on drug absorption are the net result of various factors, including the influence of food on gastrointestinal physiology and also physicochemical interactions between drugs, drug dosage forms, and dietary components. The intensity of food-drug interactions may be influenced by the type of food and by the time interval between eating and drug administration. Large coadministered fluid volumes tend to promote drug absorption. The clinical significance of changes in drug bioavailability due to these factors is discussed.
A high-performance liquid chromatography (HPLC) method for the quantitation of 13-cis-retinoic acid (13-cis-RA) and its major metabolite, 4-oxo-13-cis-RA, in human blood has been developed. The method includes extraction of 1 ml of blood with diethyl ether at pH 6 and the analysis of the extract by reversed-phase HPLC with solvent programming and detection at 365 nm. The quantitation ranges for 13-cis-RA and 4-oxo-13-cis-RA are 10--2000 and 50--2000 ng/ml of blood, respectively. The method also provides estimates of the concentrations of all-trans-RA and 4-oxo-all-trans-RA. The mean intra- and inter-assay variabilities for all four compounds were 6% or less. The method separates 13-cis-RA and 4-oxo-13-cis-RA from 9-cis-RA, all-trans-RA, 4-oxo-all-trans-RA, and some other possible metabolites, such as hydroxy and epoxy retinoic acids. The method has been successfully applied to the analyses of over 1200 blood samples from four 13-cis-RA clinical studies.
A pharmacokinetic profile of isotretinoin and its major dermatologically active blood metabolite, 4-oxo-isotretinoin, was developed following a single 80 mg oral suspension dose of isotretinoin to 15 normal male subjects. Blood samples were assayed for isotretinoin and 4-oxo-isotretinoin using a newly developed reverse-phase HPLC method. Following rapid absorption from the suspension formulation, isotretinoin is distributed and eliminated with harmonic mean half-lives of 1.3 and 17.4 h, respectively. Maximum concentrations of isotretinoin in blood were observed at 1 to 4 h after dosing. Maximum concentrations of the major blood metabolite of isotretinoin, 4-oxo-isotretinoin, are approximately one-half those of isotretinoin and occur at 6 to 16 h after isotretinoin dosing. The ratio of areas under the curve for metabolite and parent drug following the single dose suggests that average steady-state ratios of metabolite to parent drug during a dosing interval will be approximately 2.5. Both isotretinoin and its metabolite can be adequately described using a single linear pharmacokinetic model.
A pharmacokinetic profile was developed following oral administration of a single 100-mg oral dose of isotretinoin to 12 normal male volunteers. Concentrations of isotretinoin and its isomer, tretinoin, were measured in blood samples from 12 subjects and in urine and fecal samples from three of the 12 subjects. Blood concentration-time data during a 72-hour sampling interval were variable and, in five of the 12 cases, showed pronounced secondary and tertiary concentration maxima which were consistent with the theory of enterohepatic circulation (EHC) of isotretinoin in man. In five of the 12 subjects, adequate fits of the data could not be obtained using classical bi- or triexponential equations but were successfully fitted using a recently developed recycling model. Maximum blood concentrations of isotretinoin ranged from 74 to 511 ng/ml and occurred between 1 and 4 hours after dosing. Secondary maxima generally occurred between 6 and 24 hours after dosing. The harmonic mean elimination half-life was approximately 20 hours. These findings suggest that steady-state blood concentrations should be observed within one week. Negligible amounts of unchanged isotretinoin were excreted in urine, whereas 53 to 74 per cent of the dose was recovered as intact isotretinoin in the feces. The amount of intact drug in the feces could reflect biliary excretion of the conjugate of isotretinoin that is deconjugated beyond the site where absorption may occur, as well as unabsorbed drug.