Evidence for a pharmacokinetic interaction between eslicarbazepine and rosuvastatin: Potential effects on xenobiotic transporters.

INTRODUCTION: Patients with partial-onset seizures and comorbid cardiovascular disease may concomitantly receive eslicarbazepine acetate (ESL), an antiepileptic drug, and rosuvastatin, an HMG-CoA reductase inhibitor. This study evaluated the effect of multiple-dose ESL on the pharmacokinetic (PK) parameters of a single dose of rosuvastatin in healthy subjects. METHODS: This was a Phase I, single-center, fixed-sequence, open-label study. Healthy subjects received two treatments, in sequence. Treatment A: a single 40mg oral dose of rosuvastatin on Day 1, followed by a washout period (Days 1-4); treatment B: titration of ESL (400-800mg once daily) on Days 5-18, followed by ESL 1200mg once daily on Days 19-35, with a single dose of rosuvastatin (40mg) on Day 32. Subjects then entered a 2-week follow-up period. Plasma concentrations of rosuvastatin were quantified for PK analyses. Safety and tolerability were assessed throughout the study. RESULTS: Thirty-three healthy subjects were enrolled and 30 completed the study. Mean rosuvastatin (standard deviation) t1/2 was similar when rosuvastatin was used concomitantly with ESL and when it was used alone (26.5 [16.3]h, and 22.4 [9.5]h, respectively). The geometric least squares mean ratios (90% confidence intervals) of rosuvastatin exposure levels between rosuvastatin used concomitantly with ESL and rosuvastatin used alone were as follows: Cmax, 64.0% (55.9-73.3%); AUC(0-∞), 63.0% (57.1-69.4%); and AUC(0-last), 60.9% (55.2-67.1%). Concomitant use of ESL and rosuvastatin was generally well tolerated. CONCLUSIONS: Rosuvastatin exposure was 36-39% lower with steady-state administration of ESL, potentially due to reduced oral bioavailability of rosuvastatin. Consequently, when rosuvastatin is used with ESL, a rosuvastatin dose adjustment may be necessary if a clinically significant change in lipids is noted.

A Pharmacokinetic Study Comparing Eslicarbazepine Acetate Administered Orally as a Crushed or Intact Tablet in Healthy Volunteers.

The relative bioequivalence of crushed versus intact eslicarbazepine acetate (ESL) tablets (800 mg) administered orally in healthy adults was evaluated in an open-label, randomized, 2-period crossover study with a 5-day washout between treatments. Sample blood levels of eslicarbazepine and (R)-licarbazepine were determined; pharmacokinetic parameters were derived for eslicarbazepine. Bioequivalence was established if the 90% confidence intervals (CIs) for the geometric mean treatment ratios of eslicarbazepine AUC(0-∞) and Cmax were within the prespecified 80%-125% range. Twenty-seven subjects in the intent-to-treat population (n = 28) completed both treatment periods. Eslicarbazepine exposure measures were similar for crushed versus intact ESL tablets: average Cmax , 11 700 versus 11 500 ng/mL; AUC(0-∞) , 225 000 versus 234 000 ng·h/mL; AUC(0-last) , 222 000 versus 231 000 ng·h/mL, respectively. Geometric least squares mean ratios (90%CIs) comparing eslicarbazepine exposure measures were within the 80%-125% range (Cmax , 102.63% [97.07%-108.51%]; AUC(0-∞) , 96.72% [94.36%-99.13%]; AUC0-last , 96.69% [94.24%-99.21%]). In conclusion, ESL administered orally as a crushed tablet sprinkled on applesauce, or intact were bioequivalent in healthy subjects. Eslicarbazepine bioavailability was not significantly altered by crushing, indicating that ESL tablets can be administered intact or crushed.

First human study of a chimeric anti-methamphetamine monoclonal antibody in healthy volunteers.

This first-in-human study examined the safety and pharmacokinetics of ch-mAb7F9, an anti-methamphetamine monoclonal antibody, in healthy volunteers. Single, escalating doses of ch-mAb7F9 over the range of 0.2 to 20 mg/kg were administered to 42 subjects who were followed for 147 d. Safety was measured by physical examinations, adverse events, vital signs, electrocardiograms, and clinical laboratory testing. Serum ch-mAb7F9 concentration and immunogenicity analyses were performed. There were no serious adverse reactions or discontinuations from the study due to adverse events. No trends emerged in the frequency, relatedness, or severity of adverse events with increased dose or between active and placebo treated subjects. Ch-mAb7F9 displayed expected IgG pharmacokinetic parameters, including a half-life of 17-19 d in the 3 highest dose groups and volume of distribution of 5-6 L, suggesting the antibody is confined primarily to the vascular compartment. Four (12.5%) of the 32 subjects receiving ch-mAb7F9 were confirmed to have developed a human anti-chimeric antibody response by the end of the study; however, this response did not appear to be dose related. Overall, no apparent safety or tolerability concerns were identified; a maximum tolerated dose was not reached in this Phase 1 study. Ch-mAb7F9 therefore appears safe for human administration.

Ketoconazole and rifampin significantly affect the pharmacokinetics, but not the safety or QTc interval, of casopitant, a neurokinin-1 receptor antagonist.

Casopitant, an antiemetic, is a neurokinin-1 receptor antagonist metabolized primarily by cytochrome P450 3A4 (CYP3A4). Three phase 1 studies with 131 healthy subjects examined the impact of a strong CYP3A inhibitor (ketoconazole) and inducer (rifampin) on the pharmacokinetics and safety of casopitant. Oral casopitant was administered alone (study 1, 100-mg single dose; study 2, 150 mg on day 1, 50 mg on days 2 and 3; study 3, 150-mg single dose) with either 400 mg daily of oral ketoconazole or 600 mg daily of oral rifampin. Ketoconazole increased the maximum observed plasma concentration (C(max)) and area under the plasma concentration time curve to the last sampling time, t (AUC(0-t)) of single-dose casopitant 2.7-fold and 12-fold and increased the C(max) of 3-day casopitant 2.5-fold on day 1 and 2.9-fold on day 3, whereas AUC((0-tau)) increased 4.3-fold on day 1 and 5.8-fold on day 3. Neither safety signals nor prolongation of Fredericia-corrected QT was observed at these increased exposures in study 2. Repeat-dose rifampin reduced the C(max) and AUC((0-t)) of casopitant 96% and 90%, respectively. These clinical studies confirmed the role of CYP3A in the metabolism and disposition of casopitant. Coadministration of casopitant with strong inhibitors of CYP3A is likely to increase plasma exposure of casopitant, whereas coadministration with strong inducers of CYP3A is likely to decrease casopitant exposure and compromise efficacy.