|
|
Preliminary Analysis of Abacavir Succinate (ABC) Pharmacokinetics in Neonates Differs from Adults and Young Children G. M. JOHNSON*1, J. H. RODMAN2, J. MCDOWELL3, A. WIZNIA4, and S. V. HETHERINGTON3 for the PACTG 321 Team. 1 Med. Univ. of South Carolina, Charleston; 2 St. Jude Children’s Res. Hosp., Memphis, TN; 3Glaxo Wellcome Inc., Res. Triangle Park, NC; and 4 Jacobi Med. Ctr., Bronx, NY ABC (1592U89), a nucleoside analog with excellent activity against HIV-1 and favorable safety and bioavailability profiles, is increasingly used in older children and adults. Primary routes of metabolism include glucuronyl transferase and dehydrogenases that are known to be immature at birth. PACTG 321 is an ongoing phase I multicenter dose escalation study of the pharmacokinetics (PK), safety and tolerance of ABC combined with standard postnatal zidovudine in full term infants born to HIV-infected women. Evaluation of single dose oral ABC administration (2mg/kg) has been completed in 9 of the enrolled neonates less than 30 days of age. Serial blood samples were collected for up 24 hours. The mean (range) values for Cmax were 1.31 (.90 – 1.63) mcg/ml and Tmax 3.1 (1.1 –6.1) hrs. Mean (range) oral clearances (CL/F) and elimination half-lives (T1/2) were 2.52 (1.74 – 3.0) ml/min/kg and 5.3 (4.0 – 7.3) hours. Cl/F correlated with weight but was not discernibly different by postnatal age in the small number of subjects studied. ABC disposition in neonates appeared to be substantially different than previously found in children or adults. CL/F is approximately 15% of that found in children receiving 8 mg/kg (19 ml/min/kg; Antimicrob Agents Chemo 43:609, 1999). Either decreased absorption, delayed prolonged absorption or lower systemic clearance may contribute to these PK differences in the neonate. The modestly lower average Cmax (approximating levels in 3-6 month olds receiving 4 mg/kg) and prolonged Tmax relative to data in older children suggest that while absorption may be slower it is not appreciably decreased while the longer T1/2 and low CL/F are consistent with lower systemic clearance in neonates. The dose of 2 mg/kg in neonates yields AUC values similar or greater than current recommended doses in older children receiving 8 mg/kg and has been well tolerated thus far, supporting further studies of this novel nucleoside analog in neonates. Beyond establishing appropriate dosing, ABC PK studies will provide useful insights into neonatal drug metabolism. Key Words: Abacavir, Neonate, Pharmacokinetics |
|
© 7th
Conference on Retroviruses and Opportunistic Infections, |