Pharmacokinetics of Tenofovir Alafenamide Fumarate and Tenofovir in the Chinese People: Effects of Non-Genetic Factors and Genetic Variations

Xue Li,1,&ast; Xin-Yi Tan,2,&ast; Xue-Jun Cui,3 Ming Yang,1 Chao Chen,1 Xiao-Yun Chen2 1Phase I Clinical Research Laboratory of Shanghai LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Department of Rheumatology of Shanghai LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 3Institute of Spinal Disease, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiao-Yun ChenDepartment of Rheumatology of Shanghai LongHua Hospital, Shanghai University of Traditional Chinese Medicine, No. 725, South Wanping Road, Shanghai, 200032, People’s Republic of ChinaTel/Fax +86-21-64289981Email lh2396@shutcm.edu.cnChao ChenPhase I Clinical Research Laboratory of Shanghai LongHua Hospital, Shanghai University of Traditional Chinese Medicine, No. 725, South Wanping Road, Shanghai, 200032, People’s Republic of ChinaTel +86-21-64385700-9707Fax +86-21-64289981Email lhchenchao@shutcm.edu.cnBackground: Tenofovir alafenamide fumarate (TAF) was approved for HBV treatment in China in 2018. Despite higher antiviral efficacy and less impact on renal function and bone mineral density, the pharmacokinetic profiles of TAF are highly variable. The objectives of this study were to investigate the pharmacokinetics of TAF in the Chinese population and explore the associations between TAF and genetic polymorphisms and non-genetic factors.Patients and Methods: A total of 64 healthy Chinese subjects aged 18∼ 65 years old were planned to enroll. According to the dietary intake status, the subjects were divided into two groups (n = 32 per group). The concentrations of TAF and tenofovir were measured by HPLC-MS/MS, and the single-nucleotide polymorphisms were analyzed by MALDI-TOF MS.Results: All the enrolled participants (18– 35 years) completed the clinical trial study. Similar to the results reported in other ethnic populations, the pharmacokinetic profiles of TAF and tenofovir were highly variable in the Chinese people, and the HFHC diet can significantly increase the systemic exposure of TAF. We determined both HFHC diet and rs7311358 (SLCO1B3) genotypes were independently associated with TAF AUC0-t, while HFHC diet, age and rs3740066 (ABCC2) variants were predictive of t1/2 of tenofovir (P < 0.05). The subjects with the AA genotype in rs7311358 had significantly higher TAF AUC0-t values (1.15 times) than those with a G allele, and the t1/2 of tenofovir in the rs3740066 TT genotype group was 1.23 times longer than that of CC genotype group. Furthermore, there was a trend of higher TAF AUC and shorter tenofovir t1/2 for the rs2032582 (ABCB1) T allele and rs3742106 (ABCC4) CC variant, respectively, although not statistically significant in the multiple linear regression analysis.Conclusion: This study provided new evidence to suggest a critical link between both genetic and non-genetic factors and TAF pharmacokinetics in the Chinese people.Keywords: tenofovir alafenamide fumarate, pharmacokinetics, SLCO1B3, ABCB1, ABCC2, ABCC4