Pharmacokinetics of nelfinavir and its active metabolite, hydroxy-tert-butylamide, in infants perinatally infected with human immunodeficiency virus type 1.
BACKGROUND
In children younger than 2 years of age vertically infected with HIV-1, the recommended pediatric dosing regimen for nelfinavir (20 to 30 mg/kg three times a day) provides insufficient drug exposure. This study was conducted to determine the steady state pharmacokinetics of nelfinavir and its active metabolite, M8, in this population.


METHODS
Fourteen infants (2.3 to 8.5 months) underwent 18 intensive pharmacokinetic studies of nelfinavir and M8 at steady state. Nelfinavir and M8 concentrations were measured by high performance liquid chromatography coupled with mass spectrometry, and individual pharmacokinetic values were determined.


RESULTS
A mean nelfinavir daily dose of 135.7 +/- 18.8 mg/kg (twice or three times a day) resulted in median C(min), C(max), area under the plasma concentration-time curve (AUC(0-24 h)) and CL/ for nelfinavir of 0.627 mg/l, 2.39 mg/l, 30.6 mg*h/l and 4.2 liters/h/kg, respectively. When normalized for a daily dose of nelfinavir of 150 mg/kg/day, 16.7% of C(max) and 27.8% of AUC(0-24 h) values were below the tenth percentile for adult values.


CONCLUSIONS
During the first year of life, nelfinavir requirement is much higher than in older children and adults to obtain similar drug exposure. The mechanisms underlying such differences may involve higher first past metabolism and/or drug interactions or might be related to feeding conditions.
Litalien
Catherine
C
Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, Paris, France.
Faye
Albert
A
Compagnucci
Alexandra
A
Giaquinto
Carlo
C
Harper
Lynda
L
Gibb
Diana M
DM
Jacqz-Aigrain
Evelyne
E
D016049:Didanosine / Q000378:metabolism / Q000494:pharmacology; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D007223:Infant; D018445:Infectious Disease Transmission, Vertical; D008297:Male; D019888:Nelfinavir / Q000378:metabolism / Q000493:pharmacokinetics*; D012367:RNA, Viral / Q000097:blood; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D018119:Stavudine / Q000378:metabolism / Q000494:pharmacology
D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D018119:Stavudine; D019888:Nelfinavir; D016049:Didanosine