Rifampicin effect on intracellular and plasma pharmacokinetics of tenofovir alafenamide. (27th February 2019)

• Record Type: Journal Article
• Authors: Cerrone, Maddalena; Alfarisi, Omamah; Neary, Megan; Marzinke, Mark A; Parsons, Teresa L; Owen, Andrew; Maartens, Gary; Pozniak, Anton; Flexner, Charles; Boffito, Marta
• Is Part Of: Journal of antimicrobial chemotherapy. Volume 74:Number 6(2019)
• Page Start: 1670
• Page End: 1678
• Publication Date: 2019-02-27
• Subjects: Anti-infective agents -- Periodicals; Chemotherapy -- Periodicals; 615.58
• DOI: 10.1093/jac/dkz068
• Languages: English
• ISSNs: 0305-7453

Abstract

Abstract: Objectives: Tenofovir alafenamide produces lower plasma tenofovir and higher intracellular tenofovir diphosphate (DP) concentrations than tenofovir disoproxil fumarate but it is likely a victim of interactions with rifampicin. We aimed to investigate the pharmacokinetics of tenofovir alafenamide/emtricitabine with rifampicin. Patients and methods: Healthy volunteers received tenofovir alafenamide/emtricitabine at 25/200 mg once daily, followed by tenofovir alafenamide/emtricitabine + rifampicin daily followed by tenofovir disoproxil fumarate. Plasma tenofovir alafenamide, tenofovir, emtricitabine and intracellular tenofovir-DP and emtricitabine triphosphate pharmacokinetics and genetic polymorphisms were assessed. Results: Tenofovir alafenamide exposure decreased when tenofovir alafenamide/emtricitabine + rifampicin was used compared with tenofovir alafenamide/emtricitabine [geometric mean ratio (GMR) (90% CI): 0.45 (0.33–0.60)]. Plasma tenofovir and intracellular tenofovir-DP concentrations decreased with rifampicin [GMR (90% CI): 0.46 (0.40–0.52) and 0.64 (0.54–0.75), respectively]. GMR (90% CI) of intracellular tenofovir-DP AUC0–24 for tenofovir alafenamide/emtricitabine + rifampicin versus tenofovir disoproxil fumarate was 4.21 (2.98–5.95). Rifampicin did not affect emtricitabine pharmacokinetics. CYP3A4*22 rs35599367 was associated with higher plasma tenofovir alafenamide AUC0–24 at day 56. Conclusions: Following tenofovir alafenamide/emtricitabine administration with rifampicin, intracellular tenofovir-DP concentrations were still 4.21-fold higher than those achieved by tenofovir disoproxil fumarate, supporting further study during HIV/TB co-infection.