PEDIATRICS Vol. 101 No. 3 March 1998, pp. 335-343

A Phase I/II Study of the Protease Inhibitor Ritonavir in Children With Human Immunodeficiency Virus Infection

Received Jul 21, 1997; accepted Oct 30, 1997.

Brigitta U. Mueller^*, Robert P. Nelson Jr, John Sleasman^§, Judy Zuckerman^*, Margo Heath-Chiozzi, Seth M. Steinberg^¶, Frank M. Balis^#, Pim Brouwers^*, Ann Hsu, Rima Saulis, Shizuko Sei^*, Lauren V. Wood^*, Steve Zeichner^*, T. Teresa K. Katz, Colleen Higham^*, Diane Aker^*, Maureen Edgerly^*, Paul Jarosinski^**, Leslie Serchuck^*, Scott M. Whitcup, David Pizzuti, and Philip A. Pizzo^*

From the ^* HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland; the  University of South Florida, All Children's Hospital, St Petersburg, Florida; the ^§ University of Florida, Gainesville, Florida;  Abbott Laboratories, Abbott Park, Illinois; ^¶ Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland; ^# Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland; ^** Pharmacy Department, National Institutes of Health, Bethesda, Maryland; and the  National Eye Institute, Bethesda, Maryland.

Background.  Ritonavir, a potent antiretroviral protease inhibitor, has been approved for the treatment of adults and children with human immunodeficiency virus (HIV) infection. In a phase I/II study, we assessed the safety, tolerability, and pharmacokinetic profile of the oral solution of ritonavir in HIV-infected children and studied the preliminary antiviral and clinical effects.

Methods.  HIV-infected children between 6 months and 18 years of age were eligible. Four dose levels of ritonavir oral solution (250, 300, 350, and 400 mg/m² given every 12 hours) were evaluated in two age groups (2 years, >2 years). Ritonavir was administered alone for the first 12 weeks and then in combination with zidovudine and/or didanosine. Clinical and laboratory parameters were monitored every 2 to 4 weeks.

Results.  A total of 48 children (median age, 7.7 years; range, 0.5 to 14.4 years) were included in this analysis. Dose-related nausea, diarrhea, and abdominal pain were the most common toxicities and resulted in discontinuation of ritonavir in 7 children. Ritonavir was well absorbed at all dose levels, and plasma concentrations reached a peak 2 to 4 hours after a dose. CD4 cells counts increased by a median of 79 cells/mm³ after 4 weeks of monotherapy and were maintained throughout the study. Plasma HIV RNA decreased by 1 to 2 log₁₀ copies/mL within 4 to 8 weeks of ritonavir monotherapy, and this level was sustained in patients enrolled at the highest dose level of 400 mg/m² for the 24-week period.

Conclusions.  The oral solution of ritonavir has potent antiretroviral activity as a single agent and is relatively well tolerated by children when administered alone or in combination with zidovudine or didanosine.

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