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Efavirenz (EFV) and Nelfinavir (NFV) Pharmacokinetics (PK) in HIV-Infected Children under 2 Years of Age R. C. BRUNDAGE*1, C. V. FLETCHER1, T. FENTON2, W. D. FISKE3, M. I. BECKER4, L. PURDUE5, J. McNAMARA5, L. MOFENSON5, S. A. SPECTOR6, and S. E. STARR7 for the PACTG 382 Study Team.
1Univ. of Minnesota, Minneapolis; 2Harvard Sch. of Publ. Hlth., Boston, MA; 3DuPont Pharmaceuticals Co., Wilmington, DE; 4Agouron Pharmaceuticals, San Diego, CA; 5NIH, Bethesda, MD; 6Univ. of California, San Diego; and 7Univ. of Pennsylania, Philadelphia Rationale: PACTG 382 evaluated EFV and NFV in combination with at least one NRTI in children age 3 mos to 8 yrs. An AUC-controlled design was used to determine the pediatric doses and minimize the potential for subtherapeutic dosing of EFV and NFV. PK data from age strata 2 (S2; ages 2 to 8 yrs) were used to establish doses in strata 1 (S1; ages 3 mo to 2 yrs).
Methods: The EFV suspension starting dose was 720 mg/day allometrically scaled to body size [(wt kg/70)0.7]; NFV (tablet or powder form) was dosed at 35-45 mg/kg TID. EFV and NFV PK studies were conducted at wks 2 and 6, and doses were adjusted to achieve target plasma AUC values of 190-380 µMxh for EFV and ³10 mgxh/L for NFV. These represent the 50-95th and ³10th percentile of AUC values in adults for EFV and NFV, respectively.
Results: In 18 S2 subjects, the median week 2 EFV AUC was 158 µMxhr with 11 AUCs below target. For NFV, the median AUC was 19.3 mgxhr/L with 5 below target. In 10 children under 2 yrs accrued in S1, median AUCs were 115.4 µMxhr and 9.2 mgxhr/L for EFV and NFV, respectively. 7 EFV and 5 NFV AUCs were below target. For both drugs, the percentage of subjects with AUCs below target was considered unacceptable, and enrollment was stopped until revised starting doses could be determined. PACTG 382 will reopen using an EFV dose allometrically scaled to 1200mg QD and a NFV disintegrated tablet dose of 50mg/kg TID.
Conclusions: Adopting doses for children under 2 yrs based on doses in older children may not always be appropriate. EFV and NFV dosing strategies used for older children did not produce adequate exposures in children under 2 yrs, requiring revised doses in PACTG 382. To establish age-appropriate dosing recommendations for new antiretrovirals, PK studies should be performed in children across all age ranges.
Key Words: children, efavirenz, pharmacokinetics
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