Pharmacokinetics of new 625 mg nelfinavir formulation during pregnancy and postpartum

Abstract

ObjectivesOur objective was to evaluate the pharmacokinetics of nelfinavir (NFV) (625 mg tablets) 1250 mg twice daily during pregnancy and postpartum. MethodsThe participants were HIV-1-infected pregnant women enrolled in P1026s and receiving NFV (625 mg tablets) 1250 mg twice daily as part of routine clinical care. Intensive steady-state 12-h NFV pharmacokinetic profiles were performed during pregnancy and postpartum. The target NFV area under the plasma concentration-time curve (AUC 0-12 ) was ! 10th percentile NFV AUC 0-12 in non-pregnant historical controls (18.5 mg h/mL). ResultsOf 27 patients receiving NFV, pharmacokinetic data were available for four (second trimester), 27 (third trimester) and 22 (postpartum) patients. The NFV maximum concentration (C max ), 12-h post-dose concentration (C 12 ) and AUC 0-12 were significantly lower during the third trimester compared to postpartum (P 0.03). The metabolite hydroxyl-tert-butylamide (M8) AUC 0-12 and the M8/NFV AUC ratio were lower during the third trimester compared to postpartum (Po0.01). The NFV AUC 0-12 exceeded the AUC 0-12 target for 15/27 (56%) and 21/22 (95%) of third trimester and postpartum patients, respectively. The minimum concentration (C min ) was above the suggested minimum trough concentration (0.8 mg/mL) in 15% (third trimester) and 18% (postpartum). The plasma viral load was o400 HIV-1 RNA copies/mL in 81% of patients at delivery. ConclusionsThese results suggest that higher doses of NFV should be considered during pregnancy.Keywords: HIV, nelfinavir, pharmacokinetics, pregnancy IntroductionMany HIV-infected pregnant women receive nelfinavir (NFV) as part of their antiretroviral (ARV) regimens, whether for treatment or as a component of combination ARV regimens for the prevention of mother-to-child transmission of HIV. During pregnancy, physiological changes can result in changes in the absorption, distribution, metabolism and elimination of drugs. Previous data indicated that NFV exposure was inadequate in most pregnant women receiving NFV as 250 mg tablets at a dose of 750 mg orally three times daily [1]. Subsequent studies suggested that NFV exposure remained inadequate with 1250 mg taken orally twice daily [2][3][4].More recently, a new formulation of NFV as 625 mg tablets has been approved for use. In non-pregnant adults, the bioavailability of NFV is increased following Patients and methodsP1026s is an ongoing, multi-centre, prospective study of ARV pharmacokinetics among HIV-infected pregnant women receiving ARVs for routine clinical care. The current analyses address only those women using NFV. P1026s is a sub-study of P1025, a prospective cohort study of HIV-infected pregnant women receiving care at PACTG sites. Institutional review boards approved both P1025 and P1026s at all participating sites. All participants provided written informed consent prior to participation in these studies. Participants were eligible for inclusion in the NFV arm of P1026s if they met the following criteria: they were HIVinfected pregnant women ! ...

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