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Population pharmacokinetic model for nelfinavir and its active metabolite hydroxy‐tert‐butylamide, in infants perinatally infected with human immunodeficiency virus type 1
Author(s) -
JacqzAigrain E.,
Payen S.,
Faye A.,
Compagnucci A.,
Giaquinto C.,
Bressolle F.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.057
Subject(s) - nelfinavir , active metabolite , pharmacokinetics , metabolite , population , medicine , virology , human immunodeficiency virus (hiv) , pharmacology , antiretroviral therapy , viral load , environmental health
Nelfinavir mesylate (NFV) is a nonpeptidic inhibitor of the human immunodeficiency virus type 1 protease (HIV‐1). This drug is metabolized through CYP2C19 (a cytochrome P450 isoenzyme) to form the hydroxy‐ tert ‐butylamide (M8), the most abundant metabolite of NFV. This metabolite appears to have in vitro antiviral activity comparable with that of the parent drug. Few studies have been performed to evaluate the pharmacokinetics of NFV and its active metabolite in a pediatric population. The objective of this study was to develop a population pharmacokinetic model for NFV and M8 in a population of children younger than 2 years of age vertically infected with HIV‐1. Plasma concentrations were obtained during repeated NFV administrations (two to three‐time a day) in 22 infants (1.5–16.3 months). The initial administered dose ranged from 81 to 200 mg/kg/day. Pharmacokinetic parameter estimates were obtained by compartmental methods to describe the disposition of metabolite that is dependent on the disposition of the parent compound. M8 was shown to be formation rate‐limited and was characterized by first‐order rate constants of formation and elimination. Because the fraction of the NFV dose metabolized to M8 (F M ) was unknown in this patient population, the volume of distribution divided by F M was estimated for M8. Estimated NFV and M8 elimination half‐lives were 2.83 and 1.87 h, respectively. Estimated NFV clearance was 3.18 L/h/kg. In conclusion, the population pharmacokinetic model describing the disposition of NFV and M8 should facilitate the design of future studies to elucidate the relative contributions of the parent compound and M8 to the pharmacological and toxic effects of NFV therapy. Clinical Pharmacology & Therapeutics (2004) 75 , P15–P15; doi: 10.1016/j.clpt.2003.11.057