Drugs suspected to be involved in the DDI-summary
Complete list of drugs taken by the patient
Warfarin 7 mg once daily
Clinical case description
42-year-old HIV-infected man with a medical history of recurrent bilateral lower extremity deep venous thromboembolism requiring indefinite anticoagulation (target INR 2-3). Warfarin dose was stable at 7 mg once daily (50 mg per week) for approximately 2 years with concomitant antiretroviral treatment consisting of efavirenz plus emtricitabine and tenofovir-DF. Due to central nervous side effects, antiretroviral treatment was switched to elvitegravir/cobicistat plus emtricitabine and tenofovir-DF. After 20 days on elvitegravir/cobicistat, INR became subtherapeutic. Warfarin dose was gradually increased to 11 mg once daily (80 mg per week) in order to maintain a therapeutic INR. This case has been published by Good BL et al. AIDS 2015; 29:985-6.
Drug Interaction Probability Scale (DIPS)
Warfarin is a racemic mixture consisting of 2 enantiomers. The S-enantiomer (more potent) undergoes metabolism by CYP2C9. The R-enantiomer is primarily metabolized by CYP1A2, CYP3A4 and CYP2C19. The observed drug-drug interaction is explained by elvitegravir inducing effect on CYP2C9 resulting in the lower exposure of R-enantiomer (more potent). The patient required a 60% warfarin dosage increase. Of interest, INR values did change 20 days after changing antiretroviral therapy which might be possibly explained by efavirenz long half-life and consequently delayed time to reach elvitegravir induction steady-state.