A PHASE I II STUDY OF THE PROTEASE INHIBITOR RITONAVIR IN CHILDREN WITH HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION/

Background. Ritonavir, a potent antiretroviral protease inhibitor, has been approved for the treatment of adults and children with human imm unodeficiency virus (HIV) infection. In a phase I/II study, we assesse d the safety, tolerability, and pharmacokinetic profile of the oral so lution of ritonavir in HIV-infected children and studied the prelimina ry antiviral and clinical effects. Methods. HIV-infected children betw een 6 months and 18 years of age were eligible. Four dose levels of ri tonavir oral solution (250, 300, 350, and 400 mg/m(2) given every 12 h ours) were evaluated in two age groups (less than or equal to 2 years, >2 years). Ritonavir was administered alone for the first 12 weeks an d then in combination with zidovudine and/or didanosine. Clinical and laboratory parameters were monitored every 2 to 4 weeks. Results. A to tal of 48 children (median age, 7.7 years; range, 0.5 to 14.4 years) w ere included in this analysis. Dose-related nausea, diarrhea, and abdo minal pain were the most common toxicities and resulted in discontinua tion of ritonavir in 7 children. Ritonavir was well absorbed at all do se levels, and plasma concentrations reached a peak 2 to 4 hours after a dose. CD4 cells counts increased by a median of 79 cells/mm(3) afte r 4 weeks of monotherapy and were maintained throughout the study. Pla sma HIV RNA decreased by 1 to 2 log(10) copies/ml within 4 to 8 weeks of ritonavir monotherapy, and this level was sustained in patients enr olled at the highest dose level of 400 mg/m(2) 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 childr en when administered alone or in combination with zidovudine or didano sine.