Clinical Drug Investigation (CLIN DRUG INVEST)

Publisher: Springer Verlag

Journal description

Clinical Drug Investigation gives you rapid access to the best designed, peer reviewed clinical and pharmacoeconomic studies worldwide, allowing you to keep up to date with the latest original research in this exciting area. The Journal's aim is rapid publication of original research covering all phases of clinical drug development and therapeutic use of drugs. This includes clinical trials, outcomes research, clinical pharmacoeconomic studies, pharmacoepidemiology studies with a strong link to optimum prescribing practice for a drug or group of drugs, clinical pharmacodynamic and clinical pharmacokinetic studies with a strong link to clinical practice and, in some instances, pharmacodynamic or pharmacokinetic studies in healthy volunteers, but in which some established or purported implications for clinical prescribing are discussed. In addition, short communications and case study reports that meet these criteria are also encouraged, as are letters to the editor.

Current impact factor: 1.70

Impact Factor Rankings

2015 Impact Factor Available summer 2015
2013 / 2014 Impact Factor 1.704
2012 Impact Factor 1.915
2011 Impact Factor 1.822
2010 Impact Factor 1.622
2009 Impact Factor 1.414
2008 Impact Factor 1.301
2007 Impact Factor 0.602
2006 Impact Factor 0.559
2005 Impact Factor 0.707
2004 Impact Factor 0.77
2003 Impact Factor 0.709
2002 Impact Factor 0.914
2001 Impact Factor 0.846
2000 Impact Factor 0.888
1999 Impact Factor 0.651
1998 Impact Factor 0.71
1997 Impact Factor 0.913

Impact factor over time

Impact factor

Additional details

5-year impact 1.64
Cited half-life 4.90
Immediacy index 0.36
Eigenfactor 0.00
Article influence 0.43
Website Clinical Drug Investigation website
ISSN 1179-1918
OCLC 31920475
Material type Periodical, Internet resource
Document type Journal / Magazine / Newspaper, Internet Resource

Publisher details

Springer Verlag

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    • Articles in some journals can be made Open Access on payment of additional charge
  • Classification
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Publications in this journal

  • Eros Yamel Moreno Morales, Manuel Fernandez Peleteiro, Ernesto Carlo Bondy Peña, Jose Maria Domínguez Lorenzo, Elva Pardellas Santiago, Anxo Fernández
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    ABSTRACT: Status epilepticus (SE) is an important emergency situation associated with high morbidity and mortality. The goal of pharmacological therapy-rapid seizure termination-is only achieved in just over half of patients with first-line anti-epileptic drug (AED) therapy and many patients require second and higher lines of AEDs to achieve seizure termination; therefore, there is a clear need for more effective treatment options. Lacosamide is a relatively new AED and the intravenous formulation has shown promise for treatment of SE. The aim of the current study was to compare electroencephalographic (EEG) response and seizure termination with intravenous lacosamide (±other AEDs) in patients with convulsive versus non-convulsive SE, in a Spanish intensive care setting. In this prospective, observational study, patients with convulsive or non-convulsive SE who received intravenous lacosamide 400 mg/day for 8 days were compared in terms of EEG response and seizure termination. Adverse events were not specifically assessed. Fifty-three patients (69.8 % male; mean age 55.2 years) were treated with lacosamide (mean dose 390.6 mg) as first- (20.8 %), second- (34 %), third (22.6 %) or fourth-line (22.6 %) treatment for convulsive (n = 23, 43.4 %) or non-convulsive (n = 30, 56.6 %) SE. The majority of patients (73.6 %) had a comorbid condition, predominantly hypertension (35.8 %), and most (79.2 %) received at least one concomitant AED, including midazolam (54.7 %), valproic acid (52.8 %), and levetiracetam (30.2 %). Patient characteristics and treatment received did not differ significantly between the convulsive and non-convulsive SE groups. EEG recordings following lacosamide treatment demonstrated the elimination of paroxysmal activity (disappearance and/or attenuation of epileptiform activity in >60 % of recording time) in 56.6 % of patients; 69.6 % of convulsive and 46.7 % of non-convulsive SE groups. Among all patients, 90.6 % showed some EEG improvement (disappearance of epileptiform activity in <30 % total recording time or disappearance and/or attenuation of epileptiform activity in 30-60 % total recording time); and there was no significant between-group difference for achievement of seizure termination (90.0 vs. 91.3 % for non-convulsive vs. convulsive SE). Intravenous lacosamide (±other AEDs) was similarly effective in patients with convulsive or non-convulsive SE. Further investigation into the use of lacosamide in the treatment of SE is warranted.
    Clinical Drug Investigation 06/2015; DOI:10.1007/s40261-015-0295-5
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    ABSTRACT: Hereditary angioedema (HAE), a rare autosomal dominant genetic disorder, is caused by a deficiency in functional C1 esterase inhibitor (C1-INH). This potentially life-threatening condition manifests as recurrent attacks of subcutaneous and submucosal swelling of the skin, gastrointestinal tract and larynx. The management of HAE includes treatment of acute episodes, short-term prophylaxis in preparation for exposure to known triggers and long-term prophylaxis to decrease the incidence and severity of HAE attacks. Four products are approved in the USA for the treatment of acute attacks of HAE, including one human plasma-derived C1-INH therapy, a recombinant human C1-INH product (rhC1-INH), a plasma kallikrein inhibitor and a bradykinin B2 receptor antagonist. In addition, one human plasma-derived C1-INH therapy and danazol are approved for prophylaxis of HAE attacks. rhC1-INH, extracted from the milk of transgenic rabbits, is a glycoprotein of 478 amino acids with an identical amino acid sequence to the endogenous human C1-INH protein. Population pharmacokinetic analysis of rhC1-INH supports an intravenous dosing strategy of 50 U/kg (maximum 4200 U). The safety and efficacy of rhC1-INH in the treatment of acute attacks in patients with HAE were demonstrated in three randomized, double-blind, placebo-controlled studies and two open-label extension studies. In a pilot prophylaxis study, weekly administration of rhC1-INH 50 U/kg for 8 weeks reduced the incidence of HAE attacks and was well tolerated. Administration of rhC1-INH has not been associated with the development of anti-drug antibodies or antibodies to anti-host-related impurities.
    Clinical Drug Investigation 06/2015; DOI:10.1007/s40261-015-0300-z
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    ABSTRACT: The oral direct factor Xa inhibitor edoxaban is a P-glycoprotein (P-gp) substrate metabolized via carboxylesterase-1 and cytochrome P450 (CYP) 3A4/5. The effect of rifampin-induced induction of P-gp and CYP3A4/5 on transport and metabolism of edoxaban through the CYP3A4/5 pathway was investigated in a single-dose edoxaban study. This was a phase 1, open-label, two-treatment, two-period, single-sequence drug interaction study in healthy adults. All subjects received a single oral 60 mg edoxaban dose in period 1, and 7 days of 600 mg rifampin (2 × 300 mg capsules once daily) with a single oral edoxaban 60 mg dose administered concomitantly on day 7 in period 2. A 6-day washout period separated the treatments. Plasma concentrations of edoxaban and its metabolites M4 and M6 were measured, and limited assessments of pharmacodynamic markers of coagulation were performed. In total, 34 healthy subjects were enrolled; 32 completed the study. Coadministration of rifampin with edoxaban decreased edoxaban exposure but increased active metabolite exposure. Rifampin increased apparent oral clearance of edoxaban by 33 % and decreased its half-life by 50 %. Anticoagulant effects based on the prothrombin time (PT) and the activated partial thromboplastin time (aPTT) with and without rifampin at early time points were maintained to a greater-than-expected degree than with edoxaban exposure alone, presumably because of an increased contribution from the active metabolites. Edoxaban was well tolerated in this healthy adult population. Rifampin reduced exposure to edoxaban while increasing exposure to its active metabolites M4 and M6. PT and aPTT at early time points did not change appreciably; however, the data should be interpreted with caution.
    Clinical Drug Investigation 06/2015; DOI:10.1007/s40261-015-0298-2
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    ABSTRACT: Lenalidomide is an oral immunomodulatory drug used to treat multiple myeloma and some other hematological malignancies. Warfarin is often used concomitantly as prophylaxis against potential venous thromboembolism associated with lenalidomide treatment. The objective of this study was to evaluate the pharmacokinetic and pharmacodynamic drug interactions between lenalidomide and warfarin in healthy volunteers. This was a double-blind, placebo-controlled, randomized, two-period crossover study. Eighteen healthy male and female subjects were treated with 10 mg/day lenalidomide or placebo for 9 days. A single oral 25 mg dose of warfarin was administered on Day 4 of each treatment period. Blood was sampled to determine international normalized ratio (INR), prothrombin time (PT), and area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C max) warfarin and lenalidomide. The 90 % confidence intervals (CI) for the ratio of AUC or Cmax geometric means between co-administration with lenalidomide and placebo were within the 80-125 % bioequivalence bounds for R-warfarin and S-warfarin. The 90 % CI for the ratio of area under the INR curve from time zero until 144 hours after dosing (AUCINR, 0-144) or the peak INR geometric means between co-administration with lenalidomide versus placebo was also within the 85-125 % bounds. Additionally, the AUC and C max values of lenalidomide were not altered by co-administration with warfarin. Co-administration of lenalidomide with warfarin did not alter the plasma exposure or anticoagulant effect to warfarin or the plasma exposure to lenalidomide, indicating that no dose adjustment of either drug is needed when these two drugs are co-administered.
    Clinical Drug Investigation 05/2015; DOI:10.1007/s40261-015-0299-1
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    ABSTRACT: Empirical antifungal therapy prevents invasive fungal infections in patients with cancer. This study assessed the empirical efficacy of intravenous itraconazole in pediatric patients undergoing hematopoietic stem cell transplantation, and investigated the pharmacokinetics and clinical implications. Oral itraconazole syrup was started (2.5 mg/kg twice daily) for prophylaxis, and patients with persistent neutropenic fever for more than 2 days were switched to intravenous itraconazole (5 mg/kg twice daily for 2 days for induction and 5 mg/kg daily for maintenance) as empirical treatment. Empirical antifungal efficacy was assessed retrospectively in 159 transplantations, and a full pharmacokinetic study was prospectively conducted in six of these patients. Successful antifungal efficacy was defined as the fulfillment of all components of a five-part composite end point. The overall empirical antifungal success rate fulfilling all criteria was 42.1 %. No death or drug-related serious adverse events occurred during the study. Mean trough plasma concentration of itraconazole after oral prophylaxis and intravenous induction were 577.2 and 1659.7 μg/L, respectively. Mean area under the concentration-time curve of itraconazole and its metabolite at steady state were 42,837 ± 24,746 μg·h/L and 63,094 ± 19,255 μg·h/L. Intravenous itraconazole was effective and safe as an empirical antifungal agent in pediatric patients; this was due to the fast and satisfactory increase in drug concentration by switching from oral to intravenous therapy.
    Clinical Drug Investigation 05/2015; DOI:10.1007/s40261-015-0297-3
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    ABSTRACT: Combining two standard-of-care medications for Alzheimer's disease (AD) into a single once-daily dosage unit may improve treatment adherence, facilitate drug administration, and reduce caregiver burden. A new fixed-dose combination (FDC) capsule containing 28 mg memantine extended release (ER) and 10 mg donepezil was evaluated for bioequivalence with co-administered commercially available memantine ER and donepezil, and for bioavailability with regard to food intake. Two phase I, single-dose, randomized, open-label, crossover studies were conducted in 18- to 45-year-old healthy individuals. In MDX-PK-104 study, fasting participants (N = 38) received co-administered memantine ER and donepezil or the FDC. In MDX-PK-105 study, participants (N = 36) received three treatments: intact FDC taken while fasting or after a high-fat meal, or FDC contents sprinkled on applesauce while fasting. Standard pharmacokinetic parameters for memantine and donepezil were calculated from the plasma concentration time-curve using non-compartmental analyses. Linear mixed-effects models were used to compare: (a) FDC versus co-administered individual drugs; (b) FDC fasted versus with food; and (c) FDC sprinkled on applesauce versus FDC intact, both fasted. Safety parameters were also evaluated. The FDC capsule was bioequivalent to co-administered memantine ER and donepezil. There was no significant food effect on the bioavailability of the FDC components. There were no clinically relevant differences in time to maximum plasma concentration or safety profiles across treatments. An FDC capsule containing 28 mg memantine ER and 10 mg donepezil is bioequivalent to commercially available memantine ER and donepezil, and bioavailability is not affected by food intake or sprinkling of capsule contents on applesauce.
    Clinical Drug Investigation 05/2015; DOI:10.1007/s40261-015-0296-4
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    ABSTRACT: A novel formulation of diclofenac sodium suitable for subcutaneous or intramuscular injection (Akis(®), Dicloin(®)) has been developed using the complexing agent hydroxypropyl-β-cyclodextrin (HPβCD) as a solubility enhancer. Diclofenac HPβCD is available in several European countries, where it is indicated for use in adults with acute forms of pain, including postoperative pain. Clinical trials have demonstrated the analgesic efficacy of diclofenac HPβCD in terms of relieving moderate to severe postoperative pain in patients undergoing dental surgery or minor orthopaedic surgery. Subcutaneous diclofenac HPβCD also effectively relieved moderate to severe neuropathic pain, related to cancer or not. Diclofenac HPβCD was generally well tolerated in clinical trials, with injection-site reactions among the most commonly reported adverse events. The local tolerability of diclofenac HPβCD was consistently rated as 'good' or 'excellent' across all studies. Subcutaneous administration of diclofenac is a valid alternative to intramuscular delivery, with the advantages of easier administration, the availability of additional body sites suitable for injection and the potential for self-administration. Thus, diclofenac HPβCD 25, 50 or 75 mg/mL solution for subcutaneous or intramuscular injection extends the treatment options available for use in the management of pain in adults.
    Clinical Drug Investigation 05/2015; 35(6). DOI:10.1007/s40261-015-0294-6
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    ABSTRACT: Background and Objectives This study aimed to determine the efficacy and safety of fluocinolone acetonide, hydroquinone, and tretinoin (FAHT) cream for the treatment of moderate and severe facial melasma. The primary objective was assessment of clinical efficacy, instrumental measured efficacy, and integral therapeutic efficacy at the end of weeks 4 and 8. Methods A total of 233 subjects were randomly allocated (1:1 ratio) to receive topically administered FAHT cream (n = 117) or placebo (n = 116) once nightly for 8 weeks. Observed side effects were documented throughout. Results In the per protocol set (PPS; those subjects who met all requirements of the protocol), the integral therapeutic efficacy rate of FAHT cream on moderate and severe melasma was 68.57 % (vs. placebo, 0.94 %), the clinical effective rate of FAHT cream was 74.29 % (vs. placebo, 0.94 %), and the instrumental measure efficacy of FAHT cream was 71.43 % (vs. placebo, 6.60 %). The difference in efficacy between the two groups was statistically significant (p p Conclusion FAHT cream is efficacious, well tolerated, and has a high margin of safety for the treatment of moderate and severe melasma in the Chinese population.
    Clinical Drug Investigation 05/2015; 35(6). DOI:10.1007/s40261-015-0292-8
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    ABSTRACT: Controversy has surrounded the treatment of gestational diabetes mellitus (GDM) for a long time. Although the use of both glyburide and metformin are recommended as an alternate to insulin if dietary therapy fails in GDM patients, it remains unclear whether both drugs are equally safe and efficacious. Therefore, in this review we compared the efficacy and safety of glyburide with metformin in treating GDM. A systematic review and meta-analysis of randomized controlled trials was conducted that compared the efficacy and safety of glyburide with metformin in GDM patients. Electronic databases were used to conduct the literature search for study identification along with a hand search of pertinent journals and conference proceedings. The effect measure used to present the results was risk ratio (RR) with 95 % confidence interval (CI). A fixed-effects model was used to pool the data if no significant heterogeneity was reported and a random-effects model was used in the case of significant heterogeneity being reported for an outcome. Three studies involving 508 patients met the inclusion criteria of this review. A significant increase in the risk of the composite outcome, i.e., macrosomia and large for gestational age (LGA) births (RR 1.94; 95 % CI 1.03-3.66, p = 0.04), was observed in the glyburide group, whereas a non-significant increase in the risk of neonatal hypoglycemia (RR 1.92; 95 % CI 0.31-12.02) was also noticed. Results remained statistically non-significant for preterm births (RR 0.65; 95 % CI 0.24-1.77), neonatal birth weight (mean difference (MD) 120.63 g; 95 % CI -62.08 to 303.33), and cesarean section (RR 0.86; 95 % CI 0.55-1.34). A significant decrease in fasting glucose levels (MD -2.40 mg/dL; 95 % CI -4.60 to -0.21; p = 0.03) was noticed in glyburide group while the difference was non-significant for postprandial glucose levels (MD -0.84 mg/dL; 95 % CI -4.03 to 2.35). Metformin seems to be a superior choice to glyburide if oral antidiabetic drug therapy is to be initiated in GDM patients.
    Clinical Drug Investigation 05/2015; 35(6). DOI:10.1007/s40261-015-0289-3
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    ABSTRACT: Clopidogrel or aspirin are indicated for patients with recent ischemic stroke (IS) or established peripheral artery disease (PAD). We compared the cost effectiveness of clopidogrel with that of aspirin in Chinese patients with recent IS or established PAD. A discrete-event simulation was developed to evaluate the economic implications of secondary prevention with clopidogrel versus aspirin. All available evidence was derived from clinical studies. Costs from a Chinese healthcare perspective in 2013 US dollars and quality-adjusted life-years (QALYs) were projected over patients' lifetimes. Uncertainties were addressed using sensitivity analyses. Compared with aspirin, clopidogrel yielded a marginally increased life expectancy by 0.46 and 0.21 QALYs at an incremental cost-effectiveness ratio of $US5246 and $US9890 per QALY in patients with recent IS and established PAD, respectively. One-way sensitivity analyses showed that the evaluation of patients with PAD and recent IS was robust except for the parameter of patient age. Given a willingness-to-pay of $US19,877 per QALY gained, clopidogrel had a probability of 90 and 68 % of being cost effective in the recent IS or established PAD subgroups compared with aspirin, respectively. The analysis suggests that clopidogrel for secondary prevention is cost effective for patients with either PAD or recent IS in a Chinese setting in comparison with aspirin.
    Clinical Drug Investigation 05/2015; 35(6). DOI:10.1007/s40261-015-0290-x
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    ABSTRACT: A meta-analysis by Wang et al. [1] assessing hypertension risk with ramucirumab use in patients with cancer was recently published in Clinical Drug Investigation. The authors concluded that ramucirumab treatment was associated with a significant increase in hypertension risk in cancer patients, and warned that treatment efficacy may be reduced due to the need to manage hypertension.We acknowledge hypertension as an adverse reaction for ramucirumab. This is highlighted in the compound’s package insert. However, the presentation by Wang et al. of the clinical severity of these events is misleading.An analysis of pooled data was performed across six Phase III trials (ramucirumab N = 2748, placebo N = 2248). In this analysis, 21.3 % (n = 585) of patients taking ramucirumab experienced hypertension of any grade during treatment, versus 7.4 % (n = 167) for patients taking placebo. This translates to an increase of 13.9 % in the number of patients developing any grade hypertension, or about 1 ...
    Clinical Drug Investigation 04/2015; 35(6). DOI:10.1007/s40261-015-0288-4
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    ABSTRACT: Chronic hepatitis C virus (HCV) infection is a major cause of liver transplantation. Drug-drug interactions (DDIs) with cyclosporine and tacrolimus hindered the use of first-generation protease inhibitors in transplant recipients. The current study investigated DDIs between daclatasvir-a pan-genotypic HCV NS5A inhibitor with clinical efficacy in multiple regimens (including all-oral)-and cyclosporine or tacrolimus in healthy subjects. Healthy fasted subjects (aged 18-49 years; body mass index 18-32 kg/m(2)) received single oral doses of cyclosporine 400 mg on days 1 and 9, and daclatasvir 60 mg once daily on days 4-11 (group 1, n = 14), or a single oral dose of tacrolimus 5 mg on days 1 and 13, and daclatasvir 60 mg once daily on days 8-19 (group 2, n = 14). Blood samples for pharmacokinetic analysis [by liquid chromatography with tandem mass spectrometry (LC-MS/MS)] were collected on days 1 and 9 for cyclosporine (72 h), on days 1 and 13 for tacrolimus (168 h) and on days 8 and 9 (group 1) or on days 12 and 13 (group 2) for daclatasvir (24 h). Plasma concentrations were determined by validated LC-MS/MS methods. Daclatasvir did not affect the pharmacokinetic parameters of cyclosporine or tacrolimus, and tacrolimus did not affect the pharmacokinetic parameters of daclatasvir. Co-administration of cyclosporine resulted in a 40 % increase in the area under the concentration-time curve of daclatasvir but did not affect its maximum observed concentration. On the basis of these observations in healthy subjects, no clinically relevant DDIs between daclatasvir and cyclosporine or tacrolimus are anticipated in liver transplant recipients infected with HCV; dose adjustments during co-administration are unlikely to be required.
    Clinical Drug Investigation 04/2015; 35(5). DOI:10.1007/s40261-015-0279-5
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    ABSTRACT: Background and Objective Nociceptive and neuropathic pain, one of common reasons of disability and loss of quality life, are often undertreated due to safety concerns with current therapies. This study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of JNJ-38893777, a potent and selective transient receptor potential vanilloid 1 (TRPV1) channel antagonist in healthy men. Methods In a single-center, double-blind, placebo-controlled, sequential group, single-ascending-dose phase 1 study, 80 healthy men (18-45 years old; body mass index 18.5 to 2), randomized to two groups, received either JNJ-38893777 (n = 6) or placebo (n = 2) in a dose-escalation manner. The study was designed in two parts: Part 1, an early tablet formulation was administered under fasting conditions at 5, 15, 45, 125, 250, or 500 mg; Part 2, a new tablet formulation was administered in a fasting state (250 mg) and a high-fat fed state (250 mg, 375 mg, or 500 mg). Serial plasma and urine samples (collected over 120 h post-dose) were analyzed using LC-MS/MS for pharmacokinetic evaluations. Results JNJ-38893777 concentrations peaked from 3.0 to 5.5 h (median) post-administration, and then declined multi-exponentially with a prolonged terminal phase. Renal clearance was negligible. Maximum concentration (C max) and area under the concentration-time curve from time zero to infinity (AUC∞) of the early formulation increased with increasing doses but less than dose-proportionally over 5-500 mg (fasted) doses. The new tablet formulation showed no improvements in the fasting state but showed an 11- to 22-fold increase in JNJ-38893777 exposure; interindividual variability reduced from 73-85 % to 23-24 %, and a significant increase (P Conclusion JNJ-38893777 was tolerated at single doses up to 500 mg (fed) and is suitable for further clinical development.
    Clinical Drug Investigation 04/2015; 35(6). DOI:10.1007/s40261-015-0285-7
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    ABSTRACT: In 2012, tenofovir disoproxil fumarate (TDF) was approved for use in children over 2 years of age at a dose of 8 mg/kg/day, and is the WHO recommended first-line therapy for children over 10 years of age or 35 kg in weight, at 300 mg daily. Whilst postmarketing experience of paediatric TDF is limited, prior off-licence use has occurred at our centre due to its tolerability, efficacy and resistance profiles. In this article we describe a single-centre experience of TDF nephrotoxicity in children aged <16 years. We conducted a retrospective case-note audit of children with perinatally-acquired HIV who ever received TDF-based antiretroviral therapy. From 2001 to December 2013, 70 children [39 (56 %) females] ever received TDF. Median age at the start of TDF treatment was 12 years (interquartile range 10-14). Seven (10 %) children developed asymptomatic renal tubular leak with associated hypophosphataemia (3) and hypokalaemia (1), all resulting in TDF withdrawal and biochemical resolution. Comparison of the nephrotoxic group versus the rest of the cohort showed no significant differences for age, sex, antiretroviral regimen or CD4 count. Lower weight (p = 0.05) and initial dose of TDF received (p = 0.0048) were significantly associated with TDF-induced nephrotoxicity: median dose of TDF (7.8 mg/kg/day) compared with the remainder of the cohort (6.5 mg/kg/day). Concurrent use of protease inhibitors (PIs) with TDF may be a contributing factor to the development of nephrotoxicity (odds ratio 6; 95 % CI 0.7-54; p = 0.111). Although all children with TDF-associated nephrotoxicity had biochemical resolution on drug withdrawal, renal monitoring of children receiving TDF is important, especially with the co-administration of PIs. Postmarketing surveillance is essential in the paediatric setting.
    Clinical Drug Investigation 04/2015; 35(5). DOI:10.1007/s40261-015-0287-5
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    ABSTRACT: Teduglutide (Gattex(®)) is a recombinant analogue of human glucagon-like peptide-2 and is indicated for the treatment of adults with short bowel syndrome (SBS) dependent on parenteral support (PS). In a pivotal, 24-week clinical trial in SBS patients, subcutaneous teduglutide 0.05 mg/kg once daily increased absorption from the remnant intestine as evidenced by significant reductions in PS volume requirements versus placebo. Improvements attained in absorption in the first 6 months of therapy were maintained during the extension trial (total teduglutide treatment periods of up to 30 months), with evidence indicating that benefits accrue over time. Among patients who received teduglutide treatment for up to 30 months, 11 of 30 were able to achieve at least one additional day off PS and another ten achieved complete independence from PS. Subcutaneous teduglutide was generally well tolerated in clinical trials, including over the long term, with most adverse events that led to study discontinuation being gastrointestinal in origin.
    Clinical Drug Investigation 04/2015; 35(5). DOI:10.1007/s40261-015-0286-6
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    ABSTRACT: This open-label, crossover study evaluated the dose proportionality of a hydrocodone extended-release (ER) tablet employing the CIMA(®) Abuse-Deterrence Technology platform. Healthy volunteers were randomized to receive single doses of hydrocodone ER 15, 30, 45, 60, and 90 mg separated by a minimum 14-day washout. Subjects received naltrexone to minimize opioid-related adverse events (AEs). Blood samples were collected for 72 h after each hydrocodone administration. Pharmacokinetic measures included maximum observed plasma hydrocodone concentration (C max) and area under the plasma concentration-time curve from time zero to infinity (AUC∞). Dose proportionality was concluded if the confidence interval (CI) of the slope of the regression line for C max and AUC∞ versus dose fell within 0.875-1.125. In total, 60 subjects were evaluable for pharmacokinetics. The mean C max was 12.6, 20.7, 30.3, 41.2, and 62.5 ng/mL and the mean AUC∞ was 199, 382, 592, 766, and 1189 ng·h/mL for hydrocodone ER 15, 30, 45, 60, and 90 mg, respectively. C max and AUC∞ increased linearly with increasing dose. The 90 % CIs of the slope of the regression line for C max (0.880-0.922) and AUC∞ (0.984-1.026) indicated systemic exposure to hydrocodone increased in a dose-proportional manner. In these naltrexone-blocked subjects, no increased incidence of AEs was apparent with increasing dose. Hydrocodone exposure increased in a dose-proportional manner after administration of hydrocodone ER 15-90 mg tablets in healthy, naltrexone-blocked subjects.
    Clinical Drug Investigation 03/2015; 35(5). DOI:10.1007/s40261-015-0280-z
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    ABSTRACT: Avibactam is a novel non-β-lactam β-lactamase inhibitor effective against Ambler class A, C and some class D β-lactamases that is currently in clinical development in combination with ceftazidime for the treatment of serious Gram-negative infections. It restores the in vitro activity of a range of β-lactams, including ceftazidime, against extended-spectrum β-lactamase-producing pathogens. Two phase I studies assessed the safety and pharmacokinetics of avibactam in healthy subjects when administered alone or with ceftazidime. The first study (NXL104-1001) was a placebo-controlled, single-ascending dose study assessing avibactam 50, 100, 250, 500, 1000, 1500 or 2000 mg given as a 30-min intravenous infusion. After a 7-day washout, subjects in the 250 and 500 mg dosing groups received a second avibactam dose with concomitant ceftazidime 1000 or 2000 mg, respectively. The second study (NXL104-1002) was performed in two parts. Part 1 assessed multiple-ascending doses of avibactam. Subjects were randomized to receive avibactam 500, 750 or 1000 mg every 8 h (q8 h) over 5 days, or ceftazidime-avibactam 2000-500 mg q8 h over 10 days. Part 2 assessed bioavailability of avibactam after a single oral dose (500 mg) relative to a single 30-min intravenous infusion (500 mg). No serious or severe adverse events were reported in either study. Avibactam exposure generally increased proportionally to dose and there was no trend for accumulation after multiple doses. Almost all avibactam was excreted largely unchanged in the urine within the first 6 h. Concomitant ceftazidime did not affect avibactam's safety and pharmacokinetic profile. Avibactam exposure after oral dosing was very low at 6.2 % of that observed after intravenous infusion. Avibactam was generally well tolerated across all dosing regimens, when given alone or with ceftazidime. Avibactam exposure was dose related in both studies, and avibactam pharmacokinetics were linear and not affected by ceftazidime.
    Clinical Drug Investigation 03/2015; 35(5). DOI:10.1007/s40261-015-0283-9
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    ABSTRACT: The controlled-release (CR) formulation of pregabalin is designed to remain in the stomach for a prolonged period while slowly releasing pregabalin for absorption in the small intestine. This study evaluated the effect of the gastrointestinal prokinetic agent, erythromycin, on the pharmacokinetics of a single dose of pregabalin CR 330 mg administered following an evening meal and the safety and tolerability of a single dose of pregabalin CR 330 mg when administered with and without multiple doses of erythromycin 500 mg. This was a phase I, open-label, randomized, two-period, two-treatment crossover study. Participants received (in a randomized sequence) a single oral dose of pregabalin CR 330 mg alone and pregabalin CR 330 mg co-administered with multiple doses of erythromycin 500 mg. The CR formulation was administered immediately following a standardized 600-750 calorie 30 % fat evening meal. Erythromycin 500 mg was administered orally approximately 1 h prior to pregabalin CR, as well as 6 and 12 h following the first erythromycin dose. Blood samples were collected up to 48 h post-pregabalin CR dose. Pharmacokinetic parameters were estimated from concentration-time data using standard noncompartmental methods. Adverse events were monitored throughout. Eighteen healthy participants (aged 19-52 years) received pregabalin CR. Co-administration of pregabalin CR with erythromycin resulted in a 17 % decrease in total exposure [area under the plasma concentration-time curve from zero to infinity (AUC∞)] and a 13 % decrease in peak plasma concentrations (C max) relative to pregabalin CR administered alone. The 90 % CI for the ratio of the adjusted geometric mean AUC∞ was 76.5-89.2 % (outside the 80-125 % range prespecified for bioequivalence). Adverse events were of mild to moderate severity and the adverse event profile was similar for pregabalin CR administered with and without erythromycin. Co-administration of multiple high doses of erythromycin resulted in 17 % lower pregabalin exposure for a single dose of pregabalin CR 330 mg than for pregabalin CR 330 mg administered alone. Although the two treatments did not achieve formal bioequivalence, the impact of co-administered erythromycin treatment was small and not considered clinically relevant.
    Clinical Drug Investigation 03/2015; 35(5). DOI:10.1007/s40261-015-0281-y