Population pharmacokinetics and pharmacodynamics of nelfinavir and its active metabolite M8 in HIV-1-infected children.
BACKGROUND
The objectives of this study are to develop and validate a population pharmacokinetic model that adequately describes the pharmacokinetics of nelfinavir and its active metabolite M8 in HIV-1-infected children; to define factors involved in the pharmacokinetic variability, which could aid in defining dosing strategies; and to correlate the pharmacokinetics to the treatment response.


METHODS
Protease inhibitor-naive, HIV-1-infected children were included. A population pharmacokinetic model of nelfinavir and M8 was developed using NONMEM. Bayesian analysis was used to estimate pharmacokinetic values. A pharmacokinetic-pharmacodynamic analysis was performed to study relationships between these values and the virologic response to therapy.


RESULTS
From 38 children, 724 nelfinavir and 636 M8 plasma concentrations were available. The pharmacokinetics of both compounds were described simultaneously with a one-compartment model with first-order elimination. Clearance (CL/F) and volume of distribution (V/F) were 32.6 L/h (interindividual variability [IIV]: 31.6%) and 281 L/h (IIV: 29.7%) for nelfinavir and 86.2 L/h (IIV: 43.1%) and 42.3 L/h for M8. No factors could be defined that affected the pharmacokinetics of nelfinavir or M8. The overall virologic response was 78% (HIV-1 RNA <500 copies/mL, on-treatment analysis). No differences in exposure to nelfinavir and M8 were observed between responders and nonresponders. The only factor distinguishing the two groups was a higher baseline HIV-1 RNA concentration in nonresponders.


CONCLUSIONS
A model was developed and validated that adequately described the population pharmacokinetics of nelfinavir and M8 in a childhood population. No factors affecting dosing strategies were identified, and no correlation could be demonstrated between the exposure to nelfinavir and M8 and the virologic treatment response.
Crommentuyn
Kristel M L
KM
Department of Pharmacy & Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands. Apkcr@slz.nl
Scherpbier
Henriëtte J
HJ
Kuijpers
Taco W
TW
Mathôt
Ron A A
RA
Huitema
Alwin D R
AD
Beijnen
Jos H
JH
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections / Q000175:diagnosis* / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007223:Infant; D008297:Male; D019888:Nelfinavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009426:Netherlands; D018570:Risk Assessment; D012720:Severity of Illness Index; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D019562:Viral Load
D017320:HIV Protease Inhibitors; D013764:Tetrahydronaphthalenes; C017233:5,6-dihydroxy-2-methylaminotetralin; D019888:Nelfinavir