Safety and pharmacokinetics of nelfinavir coadministered with zidovudine and lamivudine in infants during the first 6 weeks of life.
The safety and pharmacokinetics of nelfinavir coadministered with zidovudine and lamivudine were studied in 26 infants during the first 6 weeks of life. Cohort 1 infants (n = 7) received 10 mg/kg 3 times a day, and cohort 2 infants (n = 19) received 40 mg/kg twice a day. Two cohort 1 infants at week 1 and none at week 6 exceeded the target 24-hour area under the curve (AUC) of 30 mug.h/mL, equal to the 10th percentile of the AUC for adults receiving standard nelfinavir dosing. In cohort 2, the median 24-hour AUC was 38 mug.h/mL at both time points, with considerable variability among the infants. Three of 11 cohort 2 infants at week 1 and 4 of 11 at week 6 did not meet the AUC target. Median nelfinavir oral clearance was 2.1 L/h/kg at weeks 1 and 6. The median ratio of the plasma concentrations of the nelfinavir metabolite M8 to unchanged nelfinavir increased from 0.16 (range: 0-0.38) during week 1 to 0.56 (range: 0.4-1.47) during week 6 (P < 0.01). There were no significant differences in any of the other pharmacokinetic parameters when week 1 and week 6 results were compared. Few adverse events were attributed to nelfinavir. These data suggest that nelfinavir is well tolerated in infants at these doses, but exposure was frequently less than that seen in adults taking standard nelfinavir dosing. Further investigations of larger doses, such as 75 mg/kg twice a day, should be undertaken.
Mirochnick
Mark
M
Department of Pediatrics, Boston University School of Medicine, Boston, MA, USA. mark.m@bu.edu
Stek
Alice
A
Acevedo
Midnela
M
Keller
Margaret
M
Holland
Diane
D
Capparelli
Edmund
E
Connor
James
J
Huang
Sharon
S
Hughes
Michael
M
Watts
Heather
H
Mofenson
Lynne
L
Bryson
Yvonne
Y
D015331:Cohort Studies; D005260:Female; D005865:Gestational Age; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D006801:Humans; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control*; D019888:Nelfinavir / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000821:virology*
D017320:HIV Protease Inhibitors; D019888:Nelfinavir