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PEDIATRICS Vol. 102 No. 1 July 1998, pp. 101-109

A Phase I/II Study of the Protease Inhibitor Indinavir in Children With HIV Infection

Received Oct 29, 1997; accepted Jan 28, 1998.

Brigitta U. Mueller*, John SleasmanDagger , Robert P. Nelson Jr§, Sharon Smith*, Paul J. Deutschparallel , William Juparallel , Seth M. Steinberg, Frank M. Balis#, Paul F. Jarosinski**, Pim Brouwers*, Goutam Mistryparallel , Gregory Winchellparallel , Sheryl Zwerski*, Shizuko Sei*, Lauren V. Wood*, Steve Zeichner*, and Philip A. Pizzo*

From the * HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland; the Dagger  University of Florida, Gainesville, Florida; the § University of South Florida, All Children's Hospital, St. Petersburg, Florida; parallel  Merck Research Laboratories, Rahway, New Jersey; the  Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland; the # Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland; and the ** Pharmacy Department, National Institutes of Health, Bethesda, Maryland.

Background.  Indinavir, an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, is approved for the treatment of HIV infection in adults when antiretroviral therapy is indicated. We evaluated the safety and pharmacokinetic profile of the indinavir free-base liquid suspension and the sulfate salt dry-filled capsules in HIV-infected children, and studied its preliminary antiviral and clinical activity in this patient population. In addition, we evaluated the pharmacokinetic profile of a jet-milled suspension after a single dose.

Methods.  Previously untreated children or patients with progressive HIV disease despite antiretroviral therapy or with treatment-associated toxicity were eligible for this phase I/II study. Three dose levels (250 mg/m2, 350 mg/m2, and 500 mg/m2 per dose given orally every 8 h) were evaluated in 2 age groups (<12 years and >= 12 years). Indinavir was initially administered as monotherapy and then in combination with zidovudine and lamivudine after 16 weeks.

Results.  Fifty-four HIV-infected children (ages 3.1 to 18.9 years) were enrolled. The indinavir free-base suspension was less bioavailable than the dry-filled capsule formulation, and therapy was changed to capsules in all children. Hematuria was the most common side effect, occurring in 7 (13%) children, and associated with nephrolithiasis in 1 patient. The combination of indinavir, lamivudine, and zidovudine was well tolerated. The median CD4 cell count increased after 2 weeks of indinavir monotherapy by 64 cells/mm3, and this was sustained at all dose levels. Plasma ribonucleic acid levels decreased rapidly in a dose-dependent way, but increased toward baseline after a few weeks of indinavir monotherapy.

Conclusions.  Indinavir dry-filled capsules are relatively well tolerated by children with HIV infection, although hematuria occurs at higher doses. Future studies need to evaluate the efficacy of indinavir when combined de novo with zidovudine and lamivudine.

Key words: protease inhibitor, child, HIV-1, CD4 cells, HIV RNA, pharmacokinetics.


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