s-1743 and HIV-Infections

Dose selection is one of the key decisions made during drug development in pediatrics. There are regulatory initiatives that promote the use of model-based drug development in pediatrics. Pharmacometrics or quantitative clinical pharmacology enables development of models that can describe factors affecting pharmacokinetics and/or pharmacodynamics in pediatric patients. This manuscript describes some examples in which pharmacometric analysis was used to support approval and labeling in pediatrics. In particular, the role of pharmacokinetic (PK) comparison of pediatric PK to adults and utilization of dose/exposure-response analysis for dose selection are highlighted. Dose selection for esomeprazole in pediatrics was based on PK matching to adults, whereas for adalimumab, exposure-response, PK, efficacy, and safety data together were useful to recommend doses for pediatric Crohn's disease. For vigabatrin, demonstration of similar dose-response between pediatrics and adults allowed for selection of a pediatric dose. Based on model-based pharmacokinetic simulations and safety data from darunavir pediatric clinical studies with a twice-daily regimen, different once-daily dosing regimens for treatment-naïve human immunodeficiency virus 1-infected pediatric subjects 3 to <12 years of age were evaluated. The role of physiologically based pharmacokinetic modeling (PBPK) in predicting pediatric PK is rapidly evolving. However, regulatory review experiences and an understanding of the state of science indicate that there is a lack of established predictive performance of PBPK in pediatric PK prediction. Moving forward, pharmacometrics will continue to play a key role in pediatric drug development contributing toward decisions pertaining to dose selection, trial designs, and assessing disease similarity to adults to support extrapolation of efficacy.

Topics: Adalimumab; Adolescent; Adolescent Development; Adult; Age Factors; Anti-HIV Agents; Anti-Inflammatory Agents; Anticonvulsants; Child; Child Development; Child, Preschool; Crohn Disease; Dose-Response Relationship, Drug; Drug Approval; Drug Dosage Calculations; Drug Labeling; Esomeprazole; Gastroesophageal Reflux; HIV Infections; Humans; Infant; Infant, Newborn; Models, Biological; Pharmaceutical Preparations; Pharmacokinetics; Proton Pump Inhibitors; Seizures; Vigabatrin

The effects of proton pump inhibitors on the pharmacokinetics of atazanavir and amprenavir (administered as fosamprenavir) were rigorously evaluated in healthy volunteers in two studies, but formal studies in persons infected with human immunodeficiency virus (HIV) are lacking. We describe a 65-year-old man with HIV who underwent a 12-hour intensive pharmacokinetic study while receiving esomeprazole with atazanavir-ritonavir and subsequently, an 8-hour study while receiving esomeprazole with fosamprenavir-ritonavir. Consistent with the data in healthy volunteers, a major interaction between esomeprazole and atazanavir-ritonavir was observed in this patient-marked reductions in atazanavir trough plasma concentration and in the area under the concentration-time curve from 0-24 hours-whereas an interaction between esomeprazole and fosamprenavir-ritonavir was not apparent in this patient.

Topics: Aged; Anti-HIV Agents; Anti-Ulcer Agents; Atazanavir Sulfate; Carbamates; Drug Interactions; Esomeprazole; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Male; Oligopeptides; Organophosphates; Prospective Studies; Proton Pump Inhibitors; Pyridines; Sulfonamides

A study suggested that the two drugs might be used together, without lowering the blood level of Lexiva. But the timing of the doses may be critical.

Topics: Anti-HIV Agents; Carbamates; Drug Administration Schedule; Drug Interactions; Esomeprazole; Furans; HIV Infections; Humans; Organophosphates; Sulfonamides