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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

Pediatric Infectious Disease Journal: March 2009 - Volume 28 - Issue 3 - pp 215-219
doi: 10.1097/INF.0b013e31818cc053
Original Studies

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.

From the *Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Chicago, IL; †School of Medicine, Federal University of Minas Gerais, Minas Gerais, Brazil; ‡Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, MA; §Division of Infectious Diseases and International Health, Dartmouth Medical School, Lebanon, NH; ¶St. Jude Children's Research Hospital, Memphis, TN; ∥Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD; **Pediatric Division, Frontier Science and Technology Research Foundation, Amherst, NY; ††Henry M. Jackson Foundation-Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; ‡‡University of Massachusetts Medical School, Worcester, MA; and §§Department of Pediatrics and Skagg's School of Pharmacy and Pharmaceutical Sciences, University of California San Diego School of Medicine, San Diego, CA.

Accepted for publication September 4, 2008.

Brian Robbins is currently at University of Nebraska Medical Center, Omaha, NE.

#John Rodman died April 29, 2006.

Supported by Grants U01AI068632 and 1 U01 AI068616 from the National Institute of Allergy and Infectious Diseases. This project has been funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and Department of Health and Human Services, under contract no. HHSN272200800014C. This study was also supported by Abbott Laboratories.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.

Address for correspondence: Ellen Gould Chadwick, MD, Department of Pediatrics, Division of Infectious Diseases, 2300 Children's Plaza, Box 20, Chicago, IL 60614. E-mail: egchadwick@childrensmemorial.org.

© 2009 Lippincott Williams & Wilkins, Inc.