This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Introduction: Once-daily antiretorviral therapy is being used to treat adolescents and young adults with HIV-1 infection. When new antiretrovirals are developed, information on kinetics is collected in adults, and then in children, but often the adolescent age group (age 18-24 years) is under-represented in initial or even later pharmacokinetic (PK) studies.Methods: ATN 056 is an open-label, 24-hour PK study of subjects on stable once daily ARV regimens that include atazanavir boosted with ritonavir plus tenofovir and one other ARV drug. Samples for intracellular drug concentrations and plasma concentrations will be assayed in a central laboratory experienced in these measurements. PK parameters including maximum drug concentration, minimum drug concentration, area under the concentration-time curve [0, Tlast], and apparent oral clearance will be estimated and compared with literature-based values.Results: This study will measure the pharmacokinetics of tenofovir in combination with atazanavir/ritonavir in HIV-infected adolescents and young adults on stable combination ART containing 3 or more drugs for at least 28 days. This will allow improved understanding of the drug exposure in this age group when treatment is administered at standard adult doses. By comparison with kinetics information from adult patients, this also will allow an estimate of the adequacy of the 'standard adult dose' in adolescents and young adults.Conclusions: Implications for further study may inform drug dosing strategies in this age group and whether knowledge gained from this study may be generalized to other medications. Other implication for further research may inform metabolism of other medications and medication combinations in adolescents.Hypothesis: Atazanavir is a protease inhibitor. Tenofovir is a nucleotide analogue reverse transcriptase inhibitor. Each is used once daily as part of a combination therapy regimen for treatment of adults with HIV-1 infection. These drugs are often used together because there are a limited number of antiretroviral drugs that can be administered once daily. However, tenofovir interacts with atazanavir to decrease atazanavir maximum drug concentration, area under the curve of drug plasma concentration over time (a measure of total drug exposure), and minimum drug concentration in adults, even when used in combination with ritonavir, which increases atazanavir exposure. Since control of plasma viremia depends in part on the concentrations of the drugs in plasma, such a drug interaction could lead to treatment failure, especially in persons with partial resistance to atazanavir.
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