Abstract 729 - Pharmacokinetics (PK) of Nelfinavir and Its Metabolite (M8) in HIV-Infected Infants Following BID or TID Administration.

729 Pharmacokinetics (PK) of Nelfinavir and Its Metabolite (M8) in HIV-Infected Infants Following BID or TID Administration.

E. Capparelli*¹, J. Sullivan², L. Mofenson³, B. Smith⁴, B. Graham⁵, P. Britto⁶, M. Becker⁷, and K. Luzuriaga⁸.
¹Univ. of California, San Diego, La Jolla;³Univ. of Massachusetts, Worcester;⁴NICHD/NIH, Bethesda, MD;⁵NIAID/NIH, Bethesda, MD;⁶FSTRF, Amherst, NY;⁷Harvard Univ., Boston, MA; and⁸Agouron, La Jolla, CA.

Background:Nelfinavir (NFV) dosed at 25 mg/kg TID or 55 mg/kg BID in older children achieves NFV exposure similar to 750 mg TID in adults. However, the PK of NFV in infants <2 years of age are not well described following BID or TID administration. The objective of this study was to examine the PK of NFV in infants <2 years of age.

Methods:24 HIV-infected infants (INF) between 15 days and 2 years of age, naïve to antiretroviral therapy (<6 weeks of ZDV), were enrolled into NFV-containing cohorts of Pediatric ACTG Study 356. NFV therapy was initiated at ~25 mg/kg TID (n = 18) or ~60 mg/kg BID (n = 6) and given in combination with nevirapine, d4T and 3TC. Plasma NFV concentrations (n = 177) were obtained pre-dose (C0) and at 1.5 (C1.5) and 4 (C4) hours post- dose after 4, 32, 56 and 80 weeks of therapy. Eight subjects (<3 months of age) also had intensive PK samples collected at week 1. NFV doses were adjusted based on week 1 levels. NFV TID levels were compared to NFV levels in older children (CHD). Subjects were maintained on NFV therapy as long as their HIV RNA remained <1000 copies.

Results:The median age at enrollment was 3.1 months (range 0.8—10.5). The median Cl/F in subjects with intensive PK was 2.75 l/hr/kg (range 1.8 to >10) and similar between BID and TID dosing. Median (Q1—Q3) dose-adjusted (25 mg/kg TID/55 mg/kg BID) NFV concentrations (mg/ml) were:

NFV metabolite (M8) concentrations were low and frequently BQL (<0.1 mg/ml). The median M8 ratio was 10.2% for NFV levels of >1.0 mg/ml. 16/18 of subjects enrolled at least 1 year ago (all TID) have maintained HIV RNA copies <1,000 copies >1 year (median 80 weeks).

Conclusions:NFV concentrations in infants are highly variable and overall lower than those seen in adult and older pediatric populations. Further evaluation of the NFV safety, effectiveness, pharmacokinetics, and dose requirements in infants is necessary and ongoing.