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Pediatric Infectious Disease Journal:
doi: 10.1097/INF.0b013e31818cc053
Original Studies

Early Initiation of Lopinavir/Ritonavir in Infants Less Than 6 Weeks of Age: Pharmacokinetics and 24-Week Safety and Efficacy

Chadwick, Ellen Gould MD*; Pinto, Jorge MD, DSc†; Yogev, Ram MD*; Alvero, Carmelita G. MS‡; Hughes, Michael D. PhD‡; Palumbo, Paul MD§; Robbins, Brian PhD¶; Hazra, Rohan MD∥; Serchuck, Leslie MD∥; Heckman, Barbara E. BS**; Purdue, Lynette PharmD††; Browning, Renee RN, MSN††; Luzuriaga, Katherine MD‡‡; Rodman, John PharmD¶#; Capparelli, Edmund PharmD§§; the International Maternal Pediatric Adolescent Clinical Trials Group (IMPAACT) P1030 Team

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Abstract

Background: With increasing recognition of the benefits of early antiretroviral therapy initiation in perinatally HIV-infected infants, data are needed regarding the pharmacokinetics (PK), safety, and efficacy of recommended first-line protease inhibitors such as lopinavir/ritonavir (LPV/r).

Methods: A prospective, phase I/II, open-label, dose-finding trial evaluated LPV/r at a dose of 300/75 mg/m2 twice daily plus 2 nucleoside analogs in HIV-1-infected infants ≥14 days to <6 weeks of age. Intensive 12-hour PK evaluations were performed after 2 weeks of LPV/r therapy, and doses were modified to maintain LPV predose concentrations >1 μg/mL and area under the curve (AUC) <170 μg hr/mL.

Results: Ten infants enrolled [median age 5.7 (range, 3.6–5.9) weeks] with median HIV-1 RNA of 6.0 (range, 4.7–7.2) log10 copies/mL; all completed 24 weeks of follow-up. Nine completed the intensive PK evaluation at a median LPV dose of 267 (range, 246–305) mg/m2 q12 hours; median measures were AUC = 36.6 (range, 27.9–62.6) μg hr/mL; predose concentration = 2.2 (range, 0.99–4.9) μg/mL; maximum concentration = 4.76 (range, 2.84–7.28) μg/mL and apparent clearance (L/h/m2) = 6.75 (range, 2.79–12.83). Adverse events were limited to transient grade 3 neutropenia in 3 subjects. By week 24, 2 of 10 subjects had experienced a protocol-defined virologic failure.

Conclusions: Although the LPV AUC in this population was significantly lower than that observed in infants ages 6 weeks to 6 months, LPV/r-based antiretroviral therapy in doses of 300/75 mg/m2 BID was well tolerated and resulted in virologic control in 8 of 10 infants by 24 weeks. Additional investigation is needed to understand the long-term implications of the lower LPV exposure in this age group.

© 2009 Lippincott Williams & Wilkins, Inc.

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