Drug Design, Development and Therapy (Oct 2023)
Effect of Food on the Pharmacokinetics of Tenofovir Amibufenamide: A Phase I, Randomized, Open-Label, Two-Period Crossover Trial in Healthy Adult Subjects
Abstract
Jian Liu,1,2 Minglan Wu,1,2 Jiejing Kai,1,2 Meihua Lin,1,2 Yunliang Zheng,1,2 Yiya Jiang,1,2 Qian Huang,1,2 You Zhai,1,2 Yunqing Qiu2,3 1Department of Clinical Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People’s Republic of China; 2Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, Hangzhou, Zhejiang Province, People’s Republic of China; 3State Key Laboratory for Diagnosis and Treatment of Infectious Disease, the First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang Province, People’s Republic of ChinaCorrespondence: Yunqing Qiu, Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, Hangzhou, Zhejiang Province, 310003, People’s Republic of China, Tel/Fax +86 571 87236606, Email [email protected]: Tenofovir amibufenamide (TMF) is a novel nucleotide reverse transcriptase inhibitor. The aim of this study was to investigate the effect of food on the single-dose pharmacokinetic properties of TMF.Patients and Methods: In this open-label, randomized, crossover study, after an overnight fast, eligible subjects received a single 25 mg dose of TMF tablet, either under fasted conditions or following consumption of a high-fat, high-calorie meal, followed by a two-week washout period. Blood samples were collected until 144 h after administration. TMF and its metabolite, tenofovir (TFV), were analyzed using validated liquid chromatography-tandem mass spectrometry methods. The geometric mean ratio (GMR) and the corresponding 90% confidence interval (CI) values of AUC0–t, AUC0–∞, and Cmax were acquired for analysis. The absence of an effect of food was indicated if the 90% CI values were within the predefined equivalence limits of 80%– 125%. Safety and tolerability were also assessed.Results: For TMF, adjusted GMR (90% CI) values for the fed versus fasted states were 150.28% (125.36%– 180.16%), 158.24% (130.42%– 192.00%), and 57.65% (45.68%– 72.76%) for AUC0–t, AUC0–∞, and Cmax, respectively. For TFV, the GMR (90% CI) of Cmax was 82.00% (74.30%– 90.49%) after administration under fed conditions, slightly outside the bioequivalence boundary of 80%– 125%, while the corresponding values for AUC0–t and AUC0–∞ were within range. The absorption of TMF was delayed by food, with median Tmax values of 0.33 and 1.00 h in fasted and fed conditions, respectively. The adverse events observed in subjects were all mild.Conclusion: Our results demonstrated that TMF tablets were well-tolerated in healthy volunteers. When TMF tablets were taken with food, Tmax was delayed and exposures of TMF and TFV were higher than under fasted conditions. The modest changes observed are not considered clinically relevant, so TMF can be taken with or without food.Plain Language Summary: Tenofovir amibufenamide (TMF) is the first innovative, oral anti-hepatitis B drug to be developed in China. To better understand the effect of food on TMF bioavailability, 25 mg of TMF was given with or without food randomly to twenty healthy volunteers. Plasma samples were collected up to 144 h after dosing to measure the concentrations of TMF and its metabolite, tenofovir (TFV).The rate of drug absorption was measured by determining the maximum plasma concentration of drug (Cmax) and the time to Cmax (Tmax). The amount of drug absorbed was measured using the area under the plasma concentration-time curve (AUC). When subjects were fed, the AUC values for TMF and TFV were higher than when they fasted. The Cmax values for TMF and TFV under fed conditions were lower compared with fasted conditions. The Tmax of TMF was delayed when subjects were fed compared with fasted. The modest changes observed are not considered clinically relevant. The adverse events (AEs) occurring in volunteers were all mild. Our findings suggested that TMF can be taken with or without food.Graphical Abstract: Keywords: tenofovir amibufenamide, food, pharmacokinetics, safety
