Pharmacokinetic Characteristics of Ritonavir and Zidovudine
Study Objective: To evaluate and describe the parameters and characteristics of different drug regimens in children infected with human immunodeficiency virus (HIV).
Design: Randomized, open-label, multicenter study.
Setting: Pediatric HIVresearch clinics in the United States and Puerto Rico.
Patients: Twenty-one HIV-infected children, aged 3-14 years, who were clinically stable and treated with the same antiretroviral therapy for 16 weeks or longer.
Intervention: In step 1, children were randomized to receive one of three treatment regimens: zidovudine plus lamivudine, ritonavir plus zidovudine and lamivudine, or ritonavir plus stavudine. Patients originally assigned to the zidovudine plus lamivudine group in step 1 were eligible to progress to step 2 if their HIV RNA values at week 12, 24, or 36 were 10,000 copies/ml or greater but 100,000 copies/ml or less. In step 2 they received a regimen of ritonavir plus stavudine and nevirapine.
Measurements and Main Results: Seven children were randomized to each of the three treatment regimens. Concentrations of the agents were quantitated at steady state after observed doses, and the pharmacokinetic parameters were determined. Nevirapine concentrations were not determined. One child was excluded from analysis because pharmacokinetic parameters could not be estimated. Ritonavir oral clearance was slower in the pooled cohort of children who received stavudine compared with zidovudine and lamivudine. Stavudine oral clearance was marginally faster when combined with ritonavir and nevirapine compared with only ritonavir.
Conclusion: Therapy for HIV is complex, and pharmacodynamic data indicate that relationships exist between systemic concentrations of antiretroviral drugs and virologic response. Careful drug interaction studies have not been conducted for all treatment regimens, and it will not be surprising if unexpected interactions are found. Pharmacokinetic studies to address these considerations should be viewed as a fundamental component of antiretroviral drug development, as they represent a tool to improve pharmacotherapy for HIV-infected children.
Antiretroviral therapy has profoundly reduced the progression of disease and mortality in adults with human immunodeficiency virus (HIV) infection. Drug regimens of nucleoside reverse transcriptase inhibitors (NRTIs) in combination with protease inhibitors also have reduced mortality in HIV-infected children. However, administration of new antiretroviral agents and novel combination regimens in children has lagged behind that in adults. This has occurred in part because the pharmacokinetic and pharmacodynamic characteristics of many antiretroviral agents and regimens have not been adequately determined.
Pediatric Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Group study 338 (PACTG 338) was the first large clinical trial undertaken to evaluate the safety, tolerance, and virologic efficacy of a dual NRTI regimen compared with a ritonavir plus single or dual NRTI regimen in clinically and immunologically stable, protease inhibitor-naïve, HIV-infected children (step 1). The study demonstrated that ritonavir-containing regimens were virologically superior to dual NRTI therapy.
These results led to a modification of PACTG 338 to allow children who had received dual NRTI therapy to receive triple therapy -- an NRTI plus nevirapine and ritonavir (step 2). The step 1 and 2 ritonavir-containing regimens had not been evaluated in children. Therefore, pharmacokinetic evaluations were planned with the objective of confirming that the usual pediatric doses were appropriate; we present the pharmacologic data from these evaluations.
Study Objective: To evaluate and describe the parameters and characteristics of different drug regimens in children infected with human immunodeficiency virus (HIV).
Design: Randomized, open-label, multicenter study.
Setting: Pediatric HIVresearch clinics in the United States and Puerto Rico.
Patients: Twenty-one HIV-infected children, aged 3-14 years, who were clinically stable and treated with the same antiretroviral therapy for 16 weeks or longer.
Intervention: In step 1, children were randomized to receive one of three treatment regimens: zidovudine plus lamivudine, ritonavir plus zidovudine and lamivudine, or ritonavir plus stavudine. Patients originally assigned to the zidovudine plus lamivudine group in step 1 were eligible to progress to step 2 if their HIV RNA values at week 12, 24, or 36 were 10,000 copies/ml or greater but 100,000 copies/ml or less. In step 2 they received a regimen of ritonavir plus stavudine and nevirapine.
Measurements and Main Results: Seven children were randomized to each of the three treatment regimens. Concentrations of the agents were quantitated at steady state after observed doses, and the pharmacokinetic parameters were determined. Nevirapine concentrations were not determined. One child was excluded from analysis because pharmacokinetic parameters could not be estimated. Ritonavir oral clearance was slower in the pooled cohort of children who received stavudine compared with zidovudine and lamivudine. Stavudine oral clearance was marginally faster when combined with ritonavir and nevirapine compared with only ritonavir.
Conclusion: Therapy for HIV is complex, and pharmacodynamic data indicate that relationships exist between systemic concentrations of antiretroviral drugs and virologic response. Careful drug interaction studies have not been conducted for all treatment regimens, and it will not be surprising if unexpected interactions are found. Pharmacokinetic studies to address these considerations should be viewed as a fundamental component of antiretroviral drug development, as they represent a tool to improve pharmacotherapy for HIV-infected children.
Antiretroviral therapy has profoundly reduced the progression of disease and mortality in adults with human immunodeficiency virus (HIV) infection. Drug regimens of nucleoside reverse transcriptase inhibitors (NRTIs) in combination with protease inhibitors also have reduced mortality in HIV-infected children. However, administration of new antiretroviral agents and novel combination regimens in children has lagged behind that in adults. This has occurred in part because the pharmacokinetic and pharmacodynamic characteristics of many antiretroviral agents and regimens have not been adequately determined.
Pediatric Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Group study 338 (PACTG 338) was the first large clinical trial undertaken to evaluate the safety, tolerance, and virologic efficacy of a dual NRTI regimen compared with a ritonavir plus single or dual NRTI regimen in clinically and immunologically stable, protease inhibitor-naïve, HIV-infected children (step 1). The study demonstrated that ritonavir-containing regimens were virologically superior to dual NRTI therapy.
These results led to a modification of PACTG 338 to allow children who had received dual NRTI therapy to receive triple therapy -- an NRTI plus nevirapine and ritonavir (step 2). The step 1 and 2 ritonavir-containing regimens had not been evaluated in children. Therefore, pharmacokinetic evaluations were planned with the objective of confirming that the usual pediatric doses were appropriate; we present the pharmacologic data from these evaluations.
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