Nelfinavir Pharmacokinetics in Stable Human Immunodeficiency Virus-Positive Children: Pediatric AIDS Clinical Trials Group Protocol 377

Abstract

ABSTRACT. Objective. Pharmacokinetic data obtained from children who have human immunodeficiency virus (HIV) infection are essential for the safe and effective use of antiretroviral agents in pediatric populations. The objective of this study was to assess the impact of body weight on the pharmacokinetic disposition of nelfinavir (NFV) in the absence and presence of nevirapine (NVP) and compare the pharmacokinetic profiles of twice-daily (BID) and three-times-daily (TID) NFV regimens.Methods. This was an intensive pharmacokinetic substudy nested in a phase II, multicenter, randomized, open-label trial. Forty-five HIV-infected children receiving NFV 30 mg/kg TID and 6 HIV-infected children receiving NFV 55 mg/kg BID were enrolled in this study and assigned to 1 of 4 stavudine-containing regimens, 3 containing NFV and 2 containing NVP. Area under the plasma concentration-time curves from 0 to 8 hours (AUC 0 -8 hours ) and from 0 to 12 hours (AUC 0 -12 hours ) for the TID and BID regimens, respectively, were determined. For comparative purposes, the AUC 0 -24 hours was also calculated for each regimen.Results. NFV exposure in the absence of NVP was decreased in children who were <25 kg compared with those who were >25 kg (a 2.6-fold difference in median AUC 0 -8 hours ). NFV pharmacokinetics in the presence of NVP did not differ between the <25 kg and >25 kg groups. The AUC 0 -24 hours for children who were <30 kg and on NFV BID was comparable to the AUC 0 -24 hours for children who were >25 kg and on NFV TID but was 2.7-fold greater than AUC 0 -24 hours for children who were <25 kg and on NFV TID.Conclusions. NFV in the absence of NVP resulted in less than half the drug exposure in children who were <25 kg compared with children who were >25 kg. NFV dosed at 55 mg/kg BID in children who are <30 kg provides comparable exposure to that measured in children who are >25 kg and receiving NFV 30 mg/kg TID. Pediatrics 2003;112:e220 -e227. URL: http://www. pediatrics.org/cgi/content/full/112/3/e220; pharmacokinetics, nelfinavir, children, HIV, protease inhibitor, nevirapine.

Nevirapine Exposure with WHO Pediatric Weight Band Dosing: Enhanced Therapeutic Concentrations Predicted Based on Extensive International Pharmacokinetic Experience

“…Children received combination therapy with NVP, PIs (NFV and RTV), and NRTIs. NVP measurements included intensive PK studies, with up to seven plasma samples collected over the dosing interval, and population pharmacokinetics, with up to two samples collected from the dosing interval (12).…”

“…While many studies have looked at NVP in HIV-infected infants, children, and adolescents (12,15,17,23,26), no comprehensive population analyses have been performed to assess NVP across the pediatric age continuum. The current evaluation combines PK data from eight studies of NVP in infants, children, and adolescents, generating a robust NVP PK data set of pediatric patients from three continents.…”

Effect of Host Genetic Variation on the Pharmacokinetics and Clinical Response of Nnrtis

“…This is also supported by studies showing that the clearance of CYP substrates including warfarin [61], antipyrine [62], and nelfinavir [63,64] are increased in young children. Therefore, we examined if the CYP2B6-G516T genotype in young children would have a greater impact on EFV oral clearance than older children [21,23].…”

Bayesian Parameter Estimates of Nelfinavir and Its Active Metabolite, Hydroxy-tert-Butylamide, in Infants Perinatally Infected with Human Immunodeficiency Virus Type 1

“…The powder formulation can feasibly be given to newborn infants. However, little is known about the safety and pharmacokinetics of NFV in this population (3,4,7,9,13,16,21,22,26,27 , abstr. 661, 2000).…”

“…Like other such agents, it prevents cleavage of the HIV-1 Gag and Gap-Pol precursor polyproteins by the protease, resulting in the production of immature, noninfectious virus particles. NFV is available in both tablet and powder formulations; after oral administration, the plasma NFV concentrations have been found to be similar for these two formulations (7). The powder formulation can feasibly be given to newborn infants.…”