The effect of efavirenz on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and norgestimate in healthy HIV-negative women.

BACKGROUND: Women of childbearing age represent a growing proportion of people living with HIV. Preventing pregnancy is important in HIV-infected women receiving efavirenz as part of their antiretroviral therapy. METHODS: The effects of coadministration of efavirenz (600 mg once daily) on the pharmacokinetics (PK) of the active components (ethinyl estradiol [EE] and 17-deacetyl norgestimate [NGMN]) of Ortho Cyclen(®) (Ortho-McNeil-Janssen Pharmaceuticals, Inc., Raritan, NJ, USA) were investigated in 28 healthy HIV-negative women. The peak plasma concentration (C(max)), area under the concentration-time curve for a dosing interval (AUC([τ])), and lowest plasma concentration (C(min)) for EE and NGMN during cycles of treatment with Ortho Cyclen with and without coadministration of efavirenz were compared. Additionally, a post hoc exploratory analysis was conducted to assess the effect of efavirenz on the PK of an additional progestin, levonorgestrel (LNG). RESULTS: Exposures to EE were similar during coadministration of efavirenz and Ortho Cyclen to those during administration of Ortho Cyclen alone. Exposures to NGMN were substantially decreased following coadministration of efavirenz and Ortho Cyclen (adjusted geometric means for C(max), AUC([τ]) and C(min) decreased by 46%, 64% and 82%, respectively) compared with Ortho Cyclen alone. Consistent with NGMN, LNG exposures were decreased 80-86% by efavirenz. CONCLUSIONS: Although efavirenz had no significant effect on the PK of EE, exposures to the progestin components of Ortho Cyclen, NGMN and LNG, were substantially reduced. The results reinforce the need to use reliable methods of barrier contraception, even when taking oral contraceptives and efavirenz.

Integrated pharmacokinetic/pharmacodynamic model of XV459, a potent and specific GPIIb/IIIa inhibitor, in healthy male volunteers.

Roxifiban is an oral prodrug of XV459, a potent and specific inhibitor of the glycoprotein (GP) IIb/IIIa receptor previously under investigation for the treatment of peripheral arterial disease and acute coronary care syndrome. The objective of the present analysis was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model that would be used to guide dose selection in Phase 2. This was a randomized, sequential, rising multiple-dose study in 41 healthy male volunteers given doses of 0.5 to 1.25 mg daily for 7 to 10 days. Total XV459 was measured in plasma by a sensitive and specific LC/MS/MS method. The percent inhibition of platelet aggregation (%IPA) was evaluated in citrated plasma in response to 10 microM ADP using the initial slope of the response. The resulting PK data were fit to a two-compartment model with first-order absorption and saturable oral absorption. The pharmacodynamics was modeled using a direct sigmoidal Emax model. Modeling was performed using NONMEM V. Intersubject variability was moderate in both PK and PD (15.3%-18.5%), except for V2/F (64.8%). Residual variability was low at 11.8%. Platelet count influenced both CL/F and EC50. Age and weight did not explain any additional variability in either PK or PD. The model was shown to produce realistic data when used for simulation. Overall, the results suggest that XV459 concentrations in the range of 10 to 20 ng/ml will yield %IPA values in the range of 40% to 80% inhibition. Because of the pharmacodynamically mediated PK of XV459 (due to platelet binding), the EC50 and CL/F are negatively correlated, limiting the utility of plasma concentration monitoring.