Drug interaction profile for GSK2248761, a next generation non-nucleoside reverse transcriptase inhibitor
| Autor: | Piscitelli, Steve, Kim, Joseph, Gould, Elizabeth, Lou, Yu, White, Scott, de Serres, Mark, Johnson, Mark, Zhou, Xiao-Jian, Pietropaolo, Keith, Mayers, Douglas |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
Simvastatin Indoles Anti-HIV Agents Pyridines Atazanavir Sulfate Organophosphonates Ethinyl Estradiol Deoxycytidine Risk Assessment Lopinavir Double-Blind Method Cytochrome P-450 CYP2D6 Inhibitors Raltegravir Potassium Atorvastatin Cytochrome P-450 CYP3A Emtricitabine Humans Drug Interactions Pyrroles Least-Squares Analysis Rosuvastatin Calcium Tenofovir Darunavir Sulfonamides Cross-Over Studies Ritonavir Adenine Phosphinic Acids Pyrrolidinones Fluorobenzenes Drug Combinations Pyrimidines Cytochrome P-450 CYP2D6 Heptanoic Acids Linear Models Cytochrome P-450 CYP3A Inhibitors Reverse Transcriptase Inhibitors Androstenes Female Patient Safety Hydroxymethylglutaryl-CoA Reductase Inhibitors Oligopeptides Contraceptives Oral |
| Popis: | To evaluate potential drug interactions with antiretroviral therapies or supportive therapies for use in conjunction with the once daily, next generation non-nucleoside reverse transcriptase inhibitor GSK2248761 in patients with HIV-1 infection.A series of phase I drug interaction studies was conducted.GSK2248761 was shown to be a weak CYP3A4 and CYP2D6 inhibitor in a clinical study with a probe cocktail. Mean plasma concentration-time profiles for atazanavir, tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), darunavir (DRV, administered with ritonavir [RTV]), and drospirenone/ethinylestradiol were similar following co-administration of GSK2248761. Plasma raltegravir AUC(0,τ) and C(max) increased by 18% with no change in Cτ when raltegravir was co-administered with GSK2248761. Lopinavir (LPV) plasma AUC(0,τ), C(max) and Cτ decreased by 23%, 14% and 40%, respectively, following administration of lopinavir/ritonavir with GSK2248761. Atorvastatin, rosuvastatin and simvastatin AUC(0,∞) and C(max) increased following co-administration with GSK2248761, with the largest changes observed for simvastatin (3.7-fold and 4.3-fold). Changes in maximum and extent of GSK2248761 exposure were marginal after co-administration with atazanavir, TDF/FTC and raltegravir compared with GSK2248761 administered alone. Co-administration of GSK2248761 with DRV/RTV and LPV/RTV increased plasma GSK2248761 exposures by 1.25- to ≤2-fold compared with GSK2248761 administered alone, and increases in GSK2248761 exposure were higher following single dose co-administration of DRV/RTV or LPV/RTV compared with multiple doses. There were few drug-related AEs, and no treatment-related trends in blood chemistry, haematology, urinalysis, vital signs or ECG findings.These studies indicate that GSK2248761 was safe and well tolerated in healthy adults treated in these studies at the doses and duration of therapy evaluated. |
| Databáze: | OpenAIRE |
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