Drug interaction profile for GSK2248761, a next generation non‐nucleoside reverse transcriptase inhibitor
Authors: Piscitelli Steve , Kim Joseph , Gould Elizabeth , Lou Yu , White Scott , de Serres Mark , Johnson Mark , Zhou Xiao‐Jian , Pietropaolo Keith , Mayers Douglas 
Published: January 2012

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• In healthy subjects, GSK2248761 was shown to be safe and well tolerated with single doses up to 1200 mg once daily and with multiple doses up to 800 mg once daily for 7 days. Furthermore, a phase IIa monotherapy study demonstrated that GSK2248761 30 to 800 mg once daily for 7 days was well tolerated in HIV‐1–infected subjects and that doses ≥100 mg once daily were associated with antiviral activity (∼1.8 log10 copies ml−1). However, the potential for drug interactions with co‐administration of GSK2248761 and other antiretroviral medications or supportive medications is not known.WHAT THIS STUDY ADDS• 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. In addition, these studies indicate that few dosage modifications would be necessary if GSK2248761 were to be administered with most antiretroviral therapies or supportive medications.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 Cmax increased by 18% with no change in Cτ when raltegravir was co‐administered with GSK2248761. Lopinavir (LPV) plasma AUC(0,τ), Cmax and Cτ decreased by 23%, 14% and 40%, respectively, following administration of lopinavir/ritonavir with GSK2248761. Atorvastatin, rosuvastatin and simvastatin AUC(0,∞) and Cmax 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.