A PHASE I II STUDY OF THE PROTEASE INHIBITOR INDINAVIR IN CHILDREN WITH HIV-INFECTION/

Background. Indinavir, an inhibitor of the human immunodeficiency viru s type 1 (HIV-1) protease, is approved for the treatment of HIV infect ion in adults when antiretroviral therapy is indicated. We evaluated t he safety and pharmacokinetic profile of the indinavir free-base liqui d 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 pharmacokine tic profile of a jet-milled suspension after a single dose. Methods. P reviously untreated children or patients with progressive HIV disease despite antiretroviral therapy or with treatment-associated toxicity w ere eligible for this phase I/II study. Three dose levels (250 mg/m(2) , 350 mg/m(2), and 500 mg/m(2) per dose given orally every 8 h) were e valuated in 2 age groups (<12 years and greater than or equal to 12 ye ars). Indinavir was initially administered as monotherapy and then in combination with zidovudine and lamivudine after 16 weeks. Results. Fi fty-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 al l 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 tolerate d. The median CD4 cell count increased after 2 weeks of indinavir mono therapy by 64 cells/mm(3), and this was sustained at all dose levels. Plasma ribonucleic acid levels decreased rapidly in a dose-dependent w ay, but increased toward baseline after a few weeks of indinavir monot herapy. Conclusions. Indinavir dry-filled capsules are relatively well tolerated by children with HIV infection, although hematuria occurs a t higher doses. Future studies need to evaluate the efficacy of indina vir when combined de novo with zidovudine and lamivudine.