1636. Population Pharmacokinetics (PK) of Lopinavir During Pregnancy and Postpartum
Session: Poster Abstract Session: PK/PD Studies
Saturday, October 20, 2012
Room: SDCC Poster Hall F-H
Background: The protease inhibitor lopinavir (LPV), boosted with ritonavir (RTV), is one of the most common antiretrovirals used during pregnancy. Several independent evaluations have indicated reduced LPV drug concentrations during the third trimester.  Three different arms of IMPAACT Study P1026s observed differences between pregnancy and postpartum LPV pharmacokinetics (PK) but the mechanisms of these changes have not been fully defined.  The objective of this study was to conduct a population pharmacokinetic analysis of LPV and RTV during pregnancy and post partum across multiple arms of P1026s to help elucidate the mechanism(s) of reduced LPV concentrations during pregnancy.

Methods: P1026s LPV PK data were combined across arms, providing182 intensive, steady-state 12-hour pharmacokinetic profiles for LPV and RTV from 92 patients enrolled in the United States.  This included profiles during the 2nd trimester (n=29), 3rd trimester (n=82), and 2-8 weeks postpartum (n=71) for both the soft gel capsules (n=94) and melt-extrusion tablet (n=88) formulations.  Third trimester LPV doses ranged from 400 to 600 mg every 12 hours.  Population PK analyses of LPV and RTV were conducted by nonlinear mixed effects modeling using NONMEM version 6.2 with first order conditional estimation with interaction (FOCE-I) method.

Results: The LPV concentration data were best described by a 1 compartment model with first-order absorption and elimination.  A formulation effect (soft gel capsules vs. tablets) was found on relative bioavailability (F), with the tablets having 1.35-fold the F of the soft gel capsules.  Stage of pregnancy was a significant covariate for LPV apparent clearance (CL/F) and volume of distribution (V/F).  RTV concentrations significantly improved the LPV PK model when included as a maximum inhibitory direct response effect (Imax) on LPV CL/F. The IC50 for RTV inhibition of LPV clearance was 0.419 mcg/mL. Using the median plasma RTV concentrations from each cohort, the population predicted LPV plasma CL/Fs were 5.84 (2nd trimester) and 6.74 (3rd trimester) and 3.24 (postpartum) L/hr.

Conclusion: Altered LPV PK during pregnancy appears to be driven directly by pregnancy stage and indirectly by the impact of pregnancy on RTV PK.

Justin Hoffman, PharmD MS, Skaggs School of Pharmacy and Pharmaceuatical Sciences, University of California, San Diego, La Jolla, CA, Brookie Best, PharmD, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, Mark Mirochnick, MD, Boston University School of Medicine, Boston, MA, Alice Stek, MD, Division of Maternal-Fetal Medicine , Los Angeles County and USC Medical Center, Los Angeles, CA, Jiajia Wang, MS, School of Public Health, Harvard School of Public Health, Boston, MA, Tim Cressey, PhD, Institut de Recherche pour le Développement (IRD), Marseille, France and Edmund Capparelli, PharmD, Pediatrics, University of California, San Diego, La Jolla, CA


J. Hoffman, None

B. Best, None

M. Mirochnick, Abbott Laboratories: Scientific Advisor, Consulting fee

A. Stek, None

J. Wang, None

T. Cressey, None

E. Capparelli, Abbott: Consultant, Consulting fee

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