Aim: 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.
Methods: A series of phase I drug interaction studies was conducted.
Results: 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.
Conclusions: 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.
Trial registration: ClinicalTrials.gov NCT00920088 NCT01101893 NCT01138072 NCT01195974.
© 2012 ViiV Healthcare. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.