Dose-Escalating Study of the Safety and Pharmacokinetics of Nelfinavir in HIV-Exposed Neonates.

Rongkavilit, Chokechai; van Heeswijk, Rolf P. G.; Limpongsanurak, Sompop; Thaithumyanon, Pimolrat; Boonrod, Chantana; Hassink, Elly A. M.; Srigritsanapol, Aeumporn; Chuenyam, Theshinee; Ubolyam, Sasiwimol; Hoetelmans, Richard M. W.; Ruxrungtham, Kiat; Lange, Joep M. A.; Cooper, David A.; Phanuphak, Praphan
JAIDS Journal of Acquired Immune Deficiency Syndromes:
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Summary: 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 (Cmin) were measured at 1 and 7 days of age. Intensive pharmacokinetic evaluations were performed at 14 and 28 days of age. The median NFV Cmin 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.

(C) 2002 by Lippincott Williams & Wilkins