title: Model-Based Analysis of Unbound Lopinavir Pharmacokinetics in HIV-Infected Pregnant Women Supports Standard Dosing in the Third Trimester.
abstract: Physiological changes during pregnancy can affect drug pharmacokinetics. Here we present a population pharmacokinetic model to describe the longitudinal change of unbound lopinavir/ritonavir (LPV/RTV) PK parameters with gestational age, and to predict unbound LPV concentrations under different dosing regimens. The changes in apparent intrinsic clearances of LPV and RTV during pregnancy are described using an exponential function of gestational age. The unbound fractions of LPV/RTV are not significantly different between pregnancy and postpartum. Simulation reveals that despite increases in LPV intrinsic clearance, effective LPV inhibitory quotient (IQ) values are predicted with the standard dosing (400/100 mg b.i.d.) in >90% of simulations, with ≤4-fold increase in viral IC50. As viral susceptibility decreases, higher doses increase the likelihood of efficacy. With ≥40-fold increases in IC50, IQs suggest alternate regimens be considered. This approach refines previous LPV PK reports, and supports that standard dosing is effective with susceptible virus.
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill Chapel Hill North Carolina USA.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill Chapel Hill North Carolina USA.
authors.forename: S
authors.initials: S
authors.lastname: Malone
authors.affiliation: Division of Infectious Diseases, School of Medicine, University of North Carolina at Chapel Hill Chapel Hill North Carolina USA.
authors.forename: H M A
authors.initials: HM
authors.lastname: Prince
authors.affiliation: Division of Infectious Diseases, School of Medicine, University of North Carolina at Chapel Hill Chapel Hill North Carolina USA.
authors.forename: K B
authors.initials: KB
authors.lastname: Patterson
authors.affiliation: UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill Chapel Hill North Carolina USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Dumond
mesh_terms: D000293:Adolescent; D000328:Adult; D000465:Algorithms; D003198:Computer Simulation; D004338:Drug Combinations; D054796:Drug Dosage Calculations; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D061466:Lopinavir / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000188:drug therapy*; D011263:Pregnancy Trimester, Third; D019438:Ritonavir / Q000008:administration & dosage* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D061466:Lopinavir; D019438:Ritonavir