Abstracts

Rationale: Carisbamate (CRS) is a novel neurotherapeutic agent currently under investigation for epilepsy and neuropathic pain. This open-label, sequential, drug-drug interaction study was designed to evaluate potential pharmacokinetic (PK) interactions between CRS and the oral contraceptive Ortho Tri-Cyclen Lo (OT-CL). Methods: Healthy adult women (n=40) with a history of regular menstrual cycles each received CRS monotherapy 200mg q12h for 14 days; OT-CL monotherapy daily (qd; 2 treatment cycles); and CRS 200mg q12h for 14 days coadministered with OT-CL qd (1 treatment cycle) in sequential order. Serial and trough PK blood samples were collected for the determination of plasma ethinyl estradiol (EE), norelgestromin (NGMN), norgestrel (NG), and CRS concentrations prior to and at steady-state. Serum samples for the determination of sex hormone binding-globulin (SHBG) concentrations were also taken at screening (baseline) and during both OC monotherapy and when concomitantly administered with CRS. The primary statistical analyses for the evaluation of a potential drug-drug interaction used estimated least square means and intrasubject variances from mixed-effects models to construct 90% confidence intervals (CIs) for the difference in treatment means for the PK parameters: area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C_max). These statistical analyses were then conducted for 2 populations based on pre-determined criteria: (1) all subjects (n=33), and (2) the first group excluding those whose PK profiles did not meet criteria for achieving steady state levels (n=25). Results: The results of the analysis of variance (ANOVA) and 90% CIs for CRS, EE, and NGMN systemic exposures as measured by AUC and C_max were found to be within the bioequivalence (BE) criteria limits (80-125%) for both analysis scenarios. The results of the ANOVA and 90% CIs for NG systemic exposures fell below the BE criteria (90% CIs for AUC = 70.88-93.71%; and for C_max = 76.24-95.14%) for analysis group 1, but were within the criteria for analysis group 2 (90% CIs for AUC = 91.18-101.62%; and for C_max = 91.06-103.27%). A high degree of overlap was observed in the range of SHBG values in the subjects taking OT-CL with and without CRS. CRS 200mg q12h when administered alone and in combination with OT-CL was well-tolerated. Conclusions: Carisbamate 200mg q12h did not influence the steady-state PK of the estrogenic and progestational components of a frequently prescribed oral contraceptive or vise versa. Based on these results, impairment of contraceptive efficacy by CRS is unlikely and an adjustment in CRS dose in women administered OT-CL is not warranted. Carisbamate 200mg q12h given alone and in combination with OT-CL was safe and well tolerated in healthy women. Support for this work was provided by Johnson & Johnson Pharmaceutical Research & Development, L.L.C.