[Show abstract][Hide abstract] ABSTRACT: Domperidone effects on QTc duration were assessed in a single-center, double-blind, 4-way crossover study of 44 healthy participants randomized to 1 of 4 treatment sequences consisting of 4 treatment periods separated by 4–9 days washout. On day 1 of each 4-day period, participants began oral domperidone 10 mg or 20 mg q.i.d., matching placebo q.i.d., or single-dose moxifloxacin 400 mg (positive control)/placebo q.i.d. In each period, triplicate 12-lead electrocardiograms were recorded at baseline (30, 20, and 10 minutes predose), 8 timepoints after dosing on days 1 and 4, and predose on day 4. In mixed effects models, the largest difference for domperidone in least squares means for change from baseline QTcP versus placebo was 3.4 msec (20 mg q.i.d., day 4), 90% CI: 1.0-5.9, and <10 msec at all timepoints for both domperidone dosages. Moxifloxacin response confirmed assay sensitivity. Participants achieved expected domperidone plasma exposures. No significant exposure-response relationship was found for QTc increase per ng/mL domperidone (90% CI of the slope estimate included zero at mean Cmax on day 1 or day 4). In summary, domperidone at doses up to 80 mg/day did not cause clinically relevant QTc interval prolongation.
Preview · Article · Jun 2015 · Clinical Pharmacology in Drug Development
[Show abstract][Hide abstract] ABSTRACT: The primary objective was to compare the pharmacokinetics (PK) of rabeprazole granules versus rabeprazole tablets, and assess the effect of food on the PK of rabeprazole granules. Data from three phase 1, open-label, single-dose, randomized, crossover studies in healthy adult participants are presented separately and as a cross-study comparison; study 1: PK of phase 1 rabeprazole granules versus rabeprazole tablets under fasting conditions; study 2: PK of phase 3 rabeprazole granules versus phase 1 rabeprazole granules; study 3: bioequivalence of to-be-marketed rabeprazole granules (sprinkle capsules) versus phase 3 rabeprazole granules; and assessment of the food effect for the to-be-marketed rabeprazole granules. Overall, 123 of 130 participants enrolled completed the studies. The overall plasma exposure as measured by area under the plasma concentration-time curve (AUC) was comparable between rabeprazole granules and tablets; mean peak plasma concentration (Cmax) was lower for the granules compared with tablets. The plasma elimination half-life was short and independent of formulation. Food intake prior to administration of the to-be-marketed granules delayed the absorption and reduced the estimated parameters for bioavailability by 55% (Cmax) and 28% (AUCinf). Rabeprazole was well-tolerated.
Full-text · Article · Sep 2014 · Clinical Pharmacology in Drug Development
[Show abstract][Hide abstract] ABSTRACT: A sprinkle capsule formulation containing enteric-coated, delayed-release rabeprazole granules is being developed for the treatment of children with gastrointestinal reflux disease. The granules are designed to be mixed with vehicles that facilitate delivery to children, who may be unable to swallow solid formulations.
The primary objective of this study-conducted on the sponsor's initiative-was to compare the bioavailability of rabeprazole granules when mixed with various dosing vehicles (small amount of soft food or infant formula) with that of a rabeprazole suspension with inactive vehicle granules (reference), to determine which dosing vehicle can be used to deliver rabeprazole in children. Tolerability was also assessed.
This single-center, single-dose, randomized, open-label, 5-period crossover study was conducted in 35 healthy adult subjects. In a randomized sequence, fasting subjects received a single dose of 10-mg rabeprazole granules per treatment period, mixed with small amounts of 1 of 5 dosing vehicles (a strawberry-flavored suspension of rabeprazole granules with inactive vehicle granules reconstituted with water, yogurt [1 tablespoon], applesauce [1 tablespoon], or infant formula [5 mL], or a suspension of rabeprazole granules with inactive vehicle tablet reconstituted with water). Full plasma pharmacokinetic (PK) profiles of rabeprazole and its thioether metabolite were collected; concentrations were estimated via LC-MS/MS. PK properties were estimated using noncompartmental methods; 90% CIs around least squares mean test-to-reference ratios were calculated for C(max) and AUC values. All treatment-emergent adverse events (TEAEs) were recorded and assessed for severity (mild, moderate, or severe) and relationship to study drug.
A total of 35 subjects were enrolled (mean age, 38 years; 54.3% female; 100% white; mean weight, 71.4 kg). Thirty-four subjects completed the study. Rabeprazole and rabeprazole thioether plasma PK properties were comparable between all of the dosing vehicles tested. Median T(max) was 2.5 to 3.0 hours, and mean elimination half-life was 1.27 to 1.43 hours. The 90%CIs for the least squares mean ratios for rabeprazole and rabeprazole thioether exposure were within the 80% to 125% bioequivalence limits for all relevant comparisons. All TEAEs were of mild or moderate intensity, with headache being the most commonly reported; 21 subjects (60%) experienced TEAEs during the study. No deaths or serious AEs were reported during the study; 1 subject experienced a TEAE (urinary tract infection) that led to the discontinuation of treatment.
In these healthy adult subjects, the bioavailability of rabeprazole granules was comparable between all of the dosing vehicles tested, and rabeprazole was well tolerated. Soft food suitable for young children or infant formula may be appropriate for use as dosing vehicles for rabeprazole granules.
No preview · Article · Jun 2012 · Clinical Therapeutics
[Show abstract][Hide abstract] ABSTRACT: The pharmacokinetics of rabeprazole after a single oral dose and once-daily administration for 5 consecutive days was characterized in children 1 to 11 years old with gastroesophageal reflux disease (GERD).
The initial 8 patients received rabeprazole sodium (hereafter referred to as rabeprazole) 0.14 mg/kg (part 1); the next 20 patients were randomized to receive 0.5 or 1 mg/kg (part 2) to target concentrations in plasma expected to be safe and effective. Pharmacokinetic parameters of rabeprazole and the thioether metabolite were calculated using noncompartmental methods. Subjective evaluations of GERD severity, rabeprazole short-term effectiveness, palatability, and safety were also characterized.
Rabeprazole concentrations increased in a dose-dependent manner. Little or no accumulation was observed after repeated administration. The results suggest that formation of the thioether is an important metabolic pathway in young patients, which is consistent with adults. Plasma area under the concentration-time curve values of rabeprazole and the metabolite were poorly correlated with individual age and body weight. Furthermore, oral rabeprazole clearance values (not adjusted for weight) were similar to historical adult data. However, weight-adjusted values were higher for the pediatric patients, and approximately 2 to 3 times the milligram per kilogram dose of rabeprazole in these children was necessary to achieve comparable concentrations in adults. Subjective evaluations demonstrated an improvement of GERD symptoms in most patients after rabeprazole treatment.
Palatability of the formulation was reported to be good or excellent. Rabeprazole was well tolerated, with no notable differences in safety among the dose groups.
No preview · Article · Jun 2011 · Journal of pediatric gastroenterology and nutrition
[Show abstract][Hide abstract] ABSTRACT: This open-label, parallel-group study was designed to characterize the pharmacokinetics (PK) of carisbamate in participants with mild or moderate hepatic impairment versus those with normal hepatic function. Healthy (n = 10) and hepatic-impaired (n = 20) participants received a single 200-mg oral dose of carisbamate. Serial PK blood samples were collected up to 120 hours postdose. A modest increase in mean area under the plasma concentration-time curve from 0 to infinity (AUC(∞)) was observed for the mild impairment group compared with the normal group (ratio of geometric means ~116%), while mean maximum plasma concentration (C(max)) values were similar (ratio of geometric means ~94%). The AUC(∞) value for the moderate hepatic-impaired group was approximately 207% that of the normal group, while there was a smaller increase in C(max) (~118%) compared with the normal group. Mean half-life (t(1/2)) values were prolonged in the moderate impairment group (21 hours) relative to the normal group (11 hours). There was a decrease in apparent clearance (CL/F) and an increase in AUC(∞u) (AUC(∞) × % drug unbound). The percentage of carisbamate unbound to proteins did not change across the groups, suggesting the increases in AUC(∞) were due to decreased intrinsic hepatic clearance. Carisbamate 200 mg was well tolerated.
No preview · Article · May 2011 · The Journal of Clinical Pharmacology
[Show abstract][Hide abstract] ABSTRACT: Purpose: To evaluate the effects of age and gender on the pharmacokinetics (PK) of the broad-spectrum carbapenem antibiotic doripenem. Safety and tolerability also were assessed.
Methods: Twenty-four healthy nonelderly (N=6 M, 6 F; aged 18-29 yrs) and elderly (N=6 M, 6 F; aged 66-84 yrs) subjects with normal renal function received a single 1-hr IV infusion of doripenem 500 mg. Nonelderly males and females were matched to mean body weight (±20%) of their respective elderly gender group; 6 elderly subjects (N=3 M, 3 F) were >75 yrs of age. Blood and urine PK samples were collected for 24 hr postdose. Plasma and urine concentrations of doripenem and doripenem-M-1 (inactive metabolite) were quantified via LC/MS/MS. ANOVA models were used to evaluate the effects of age and gender on PK parameters (Cmax, AUC).
Results: The age effect was statistically significant for doripenem Cmax (p < 0.05) and AUCs (p < 0.0001); the gender effect was not statistically significant for either parameter. DOR Cmax, AUC, and t1/2 were increased by 23%, 49%, and 53% in the elderly. Doripenem CL and CLR were ~30% lower in the elderly, similar to the observed reduction in creatinine clearance (CLCR). Nonrenal clearance of doripenem (CLNR) was 40% lower in the elderly. Small differences in doripenem Cmax and AUCs (< 15%) were seen between males and females. No serious adverse events (AEs) or discontinuations due to AEs occurred.
Conclusions: The increase in doripenem exposure in the elderly was primarily due to an age-related decline in renal function and to a lesser extent an age-related reduction in CLNR. The small difference in exposure between males and females was not clinically important. No dosage adjustment is recommended in elderly subjects with normal renal function or on the basis of gender. Doripenem 500 mg was safe and well tolerated.
[Show abstract][Hide abstract] ABSTRACT: The pharmacokinetics, safety, and tolerability of doripenem in healthy subjects were evaluated in 2 studies. Study 1 was a double-blind, randomized, placebo-controlled dose-escalation study in which doripenem was administered for 7 days by infusion over 30 minutes (500 mg) or 1 hour (1000 mg). Study 2 was an open-label, randomized, 3-way crossover study in which each subject received a single dose of each of the following doripenem treatments on separate occasions: 500 mg infused over 1 hour, 500 mg infused over 4 hours, and 1000 mg infused over 4 hours. Doripenem exhibited linear pharmacokinetics with concordance between the studies for pharmacokinetic parameters. Doripenem did not accumulate with repeated dosing over 7 days. The area under the plasma concentration-time curve (AUC) for doripenem 500 mg infused over 1 hour versus 4 hours was bioequivalent, and the AUC and Cmax increased proportionally with dose for the 500- and 1000-mg doses administered over 4 hours. These results, along with the stability profile of doripenem, support its use as a prolonged infusion. All regimens of doripenem were safe and well tolerated.
No preview · Article · Aug 2009 · The Journal of Clinical Pharmacology
[Show abstract][Hide abstract] ABSTRACT: To compare the pharmacokinetics of carisbamate (RWJ-333369) in healthy Japanese and Western adults, and to comparatively assess carisbamate safety and tolerability between the two populations.
An open-label study was conducted in 24 Japanese and 24 Caucasian healthy subjects. Subjects received a single oral dose of 250 mg carisbamate on day 1 followed by a 3-day washout period; twice-daily dosing of 250 mg carisbamate on days 5-8; subsequently, 500 mg on days 9-12 and a single dose of 500 mg on day 13. Plasma samples were collected for a pharmacokinetic analysis on days 1, 8, and 13. Plasma and urine samples were analyzed for carisbamate and its urinary metabolites by liquid-chromatography-mass-spectrometry.
Following a single dose, carisbamate Cmax and area under the curve (AUC) geometric mean ratios were 16.4% and 28.8% higher in Japanese than in Caucasians, respectively; these differences were statistically significant and their 90% confidence intervals (CIs) fell outside of the 80-125% limits, which are considered not to be of clinical significance. With dose-body weight normalization, Cmax and AUC were similar in Japanese and Caucasian subjects and the 90% CIs were within the 80-125% boundaries. Carisbamate was well tolerated, and its mean oral clearance and half-life were similar in both groups, ranging from 35.1-41.4 ml/h/kg and 11.5-12.8 h.
Carisbamate plasma exposure (AUC) and C(max) in Japanese subjects is approximately 20-25% higher than in Caucasians due to a higher mg/kg dose. After body weight normalization, carisbamate pharmacokinetics was similar between Japanese and Caucasian subjects following single and multiple dosing, and showed the same dose proportionality.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the effect of age on the disposition of two different oral formulations of carisbamate (RWJ-333369), a novel neuromodulator under investigation.
The disposition of carisbamate was studied in eight men and eight women in each of the three age groups: 18-55, 65-74, and >or= 75 years (N=48). Subjects received single (100mg immediate-release [IR] tablets or 250 mg controlled-release [CR] tablets) or repeated administration (up to 500 mg IR BID or 1250 mg CR QD) of carisbamate in a randomized, double-blind, placebo-controlled, parallel-group, single-center study.
After either single or repeated IR administration, no apparent differences were observed between the two elderly and the non-elderly groups. Following single-dose CR administration, the two elderly age groups had higher exposure compared with non-elderly subjects, but the difference decreased for all doses tested after repeated administration. There was no effect of age on plasma protein binding of carisbamate. Renal clearance decreased with age for both formulations, but this decrease had no effect on the total clearance of the drug because of its limited renal elimination.
Age had no effect on pharmacokinetics of carisbamate IR formulation. The small effect observed after single-dose CR carisbamate diminished after repeated dosing. The drug was generally safe and well tolerated.
No preview · Article · Mar 2008 · Epilepsy Research
[Show abstract][Hide abstract] ABSTRACT: To characterize possible pharmacokinetic interactions between the new antiepileptic drug carisbamate (RWJ-333369) and valproic acid (VPA) or lamotrigine (LTG) following multiple dosing in healthy subjects.
Two open-label, sequential-design studies were conducted in 24 healthy adults. In Study 1, subjects received carisbamate alone (5 days 250 mg q12h; 5 days 500 mg q12h), then VPA alone (7 days 300 mg q12h; 7 days 500 mg q12h), and then a combination of VPA (500 mg q12h) and carisbamate (5 days 250 mg q12h; 5 days 500 mg q12h). In Study 2, subjects received carisbamate alone as in Study 1, then LTG alone (14 days 25 mg q12h; 14 days 50 mg q12h), and then combination of LTG (50 mg q12h) and carisbamate (3 days 250 mg q12h; 14 days 500 mg q12h).
Coadministration of VPA or LTG had minimal effect on carisbamate mean C(max) and AUC(ss) values. Mean VPA-C(max) and AUC(ss) values were approximately 15% lower when given concomitantly with carisbamate. However, the 90% confidence intervals (CIs) for the C(max) and AUC(ss) ratio with/without carisbamate were within the 80-125% equivalence range, C(max) 82-89%; AUC(ss) 81-88%. Mean LTG C(max) and AUC(ss) values were approximately 20% lower when given concomitantly with carisbamate. The 90% CIs with and without carisbamate for LTG C(max) and AUC(ss) were 79-86% and 75-81%, respectively. This modest change is not considered clinically significant.
There were no clinically significant interactions between carisbamate and VPA or LTG. Concomitant administration of carisbamate with VPA or LTG was generally safe and well tolerated.
[Show abstract][Hide abstract] ABSTRACT: To characterize the possible pharmacokinetic interaction between the new antiepileptic and CNS drug RWJ-333369 and carbamazepine (CBZ) following multiple dosing in healthy subjects.
In an 8-week, open-label, sequential design study, 24 healthy adults received multiple-dose RWJ-333369 alone (5 days 250 mg q12h; 5 days 500 mg q12h), then after a 4-day washout, multiple-dose CBZ alone (3 days 100 mg q12h; 3 days 200 mg q12h; 22 days 300 mg q12h), and then combination of CBZ (300 mg q12h), and RWJ-333369 (5 days 250 mg q12h; 5 days 500 mg q12h).
At steady-state following multiple dosing, RWJ-333369 peak plasma concentration (C(max)) and area under the concentration-time-curve within the dosing interval (AUCss) increased in proportion to dose. The C(max) and AUCss of CBZ were similar when given alone or concomitantly with RWJ-333369. The 90% confidence intervals for the ratio of CBZ C(max) and AUCss with/without RWJ-333369 were: 94-104% and 95-104%, respectively (well within the equivalence range of 80-125%). When RWJ-333369 was administered with CBZ, its mean (SD) oral clearance increased from 3.2 L/h to 4.9 L/h and consequently its mean half-life was shortened from 10.4 (1.9) h to 7.4 (1.2) h, and mean AUCss and C(max) were reduced by 37% and 30%, respectively.
There was no effect of multiple-dose RWJ-333369 on CBZ pharmacokinetics. CBZ induced RWJ-333369 clearance, resulting in shortened half-life and decreased exposure (AUCss) and C(max). Concomitant administration of RWJ-333369 with CBZ was generally safe and tolerated.
[Show abstract][Hide abstract] ABSTRACT: A clinical trial was conducted in healthy volunteers using both periodic and continuous ECG recordings to assess the effect of increasing doses of levofloxacin on the QT and QTc interval. Periodic and continuous ECGs were recorded before and after subjects were dosed with placebo and increasing doses of levofloxacin (500 mg, 1000 mg, 1500 mg) that included doses twice the maximum recommended dose of 750 mg in a double-blind, randomized, four-period, four-sequence crossover trial. Mean heart rate (HR) and the QT and QTc interval after dosing with levofloxacin and placebo were compared, and HR-QT interval relationships defined by linear regression analysis were calculated. After single doses of 1000 and 1500 mg of levofloxacin, HR increased significantly, as measured by periodic and continuous ECG recordings. This transient increase occurred at times of peak plasma concentration and was without symptoms. Mean QT intervals after placebo and mean intervals after levofloxacin were indistinguishable. Using periodic ECG recordings, single doses of 1500 mg were associated with small increases in QTc that were statistically significant. In contrast, an effect on QTc was shown only using the Bazett formula with data obtained from continuous ECG recordings. Together with the finding that levofloxacin does not influence HR-QT relationships, these findings suggest that levofloxacin has little effect on prolonging ventricular repolarization and that small increases in HR associated with high doses of levofloxacin contribute to the drug's apparent effect on QTc. Single doses of 1000 or 1500 mg of levofloxacin transiently increase HR without affecting the uncorrected QT interval. Differences in mean QTc after levofloxacin compared to placebo vary depending on the correction formula used and whether the data analyzed are from periodic or continuous ECG recordings. This work suggests that using continuous ECG recordings in assessing QT/QTc effects of drugs may be of value, particularly with drugs that might influence HR.
No preview · Article · Jun 2004 · The Journal of Clinical Pharmacology
[Show abstract][Hide abstract] ABSTRACT: Fluoroquinolones (FQs) have varying degrees of effect on rapid potassium channels which play a central role in ventricular repolarization. Slowing repolarization can prolong the QT on ECG and may increase a patient's risk for serious dysrhythmia. Methods. To define the effect of levofloxacin (Lev) on repolarization, a double-blind, 4-treatment, crossover trial was conducted where both continuous (Co; ECGs every 10s by 12-lead Holter monitor for 1 hr before and 4 hrs after dosing) and periodic (Pe; total 17 ECGs over 24 hr period before and after dosing) ECGs were recorded in subjects dosed with placebo and 3 doses of Lev (500, 1000, 1500mg). Results: Supra-therapeutic doses (1000 and 1500mg) of Lev increased mean heart rate (HR) compared to placebo (by Co recordings 80.0 v 87.8; by Pe recordings 59.5 v 65.0;P<0.05). Using either Co or Pe methods, mean QT after placebo and Lev were indistinguishable. In contrast, Lev's effect on QTc varied with different QT-correction methods and depended on whether the data analyzed was obtained from Co or Pe recordings. Using individual-subject QT correction (ISQTc) for HR and data from Co ECGs, mean QTc after 1500mg Lev was indistinguishable from placebo (414.9 ±17.1 v 413.5 ±14.9 msec). Using data from Pe ECGs and ISQTc, QTc 1.5 hrs (Cmax) after the 1500mg dose was greater than QTc after placebo (409.5 v 402.4 msec; P<0.05). No effect of Lev on HR-QT relationship was evident as assessed by linear regression analyses of data from Co ECG recordings. Conclusions: Supra-therapeutic doses of Lev transiently increase HR without affecting QT. This observation along with those indicating that different correction formulas yield different results regarding drug effect, raise concern that trials employing standard Pe ECG measurements may be insufficient in assessing Lev's effect on ventricular repolarization. Analyses using data from Co ECG recording showed less variation with different correction formula and permitted more rigorous assessment of drug effect on HR-QT relationships. Co ECG recordings may be valuable in measuring effects of antimicrobials on QT/QTc, particularly with agents that have small effects on HR.