Dose-escalating study of the safety and pharmacokinetics of nelfinavir in HIV-exposed neonates.
The pharmacokinetics of nelfinavir (NFV) in neonates younger than 4 weeks of age was assessed. Three cohorts of HIV-exposed neonates were enrolled in cohorts to receive 15, 30, and 45 mg of NFV/kg twice daily in combination with stavudine and didanosine for 4 weeks after birth. Trough NFV concentrations (C(min)) were measured at 1 and 7 days of age. Intensive pharmacokinetic evaluations were performed at 14 and 28 days of age. The median NFV C(min) values in the 15 mg/kg (6 patients), 30 mg/kg (5), and 45 mg/kg (11) cohorts at 1, 7, 14, and 28 days of age were 0.19, 1.21, 0.51, and 0.33; 1.02, 3.18, 0.73, and 0.55; and 0.67, 3.21, 0.70, and 0.73 mg/L, respectively. The median area under the plasma concentration-versus-time curve values over 12 hours in the three cohorts at 14 and 28 days of age were 14.4 and 8.7, 19.4 and 15.8, and 23.4 and 18.5 (h. mg)/L, respectively. No serious adverse events were observed. In conclusion, the systemic exposure of NFV decreased after 7 days of age, possibly because of hepatic enzyme maturation, autoinduction of NFV metabolism, and/or changes in NFV absorption. The highly variable systemic exposure observed in the study indicates that therapeutic drug monitoring seems warranted to ensure adequate NFV dosing in this population.
Rongkavilit
Chokechai
C
HIV Netherlands-Australia-Thailand Research Collaboration (HIV-NAT), The Thai Red Cross AIDS Research Centre, Bangkok, Thailand. crongkav@dmc.org
van Heeswijk
Rolf P G
RP
Limpongsanurak
Sompop
S
Thaithumyanon
Pimolrat
P
Boonrod
Chantana
C
Hassink
Elly A M
EA
Srigritsanapol
Aeumporn
A
Chuenyam
Theshinee
T
Ubolyam
Sasiwimol
S
Hoetelmans
Richard M W
RM
Ruxrungtham
Kiat
K
Lange
Joep M A
JM
Cooper
David A
DA
Phanuphak
Praphan
P
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D016049:Didanosine / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D019888:Nelfinavir / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D018119:Stavudine / Q000627:therapeutic use; D016896:Treatment Outcome
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D018119:Stavudine; D019888:Nelfinavir; D016049:Didanosine