PMID- 33313130 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230106 IS - 2305-5839 (Print) IS - 2305-5847 (Electronic) IS - 2305-5839 (Linking) VI - 8 IP - 21 DP - 2020 Nov TI - Pharmacogenetic and safety analysis of cinacalcet hydrochloride in healthy Chinese subjects. PG - 1385 LID - 10.21037/atm-20-1329 [doi] LID - 1385 AB - BACKGROUND: Our study aims to explore the effect of genetics on the pharmacodynamics (PD) and pharmacokinetics (PK) of cinacalcet in healthy Chinese subjects; to investigate the effect of dietary factors on cinacalcet, and to evaluate the safety of cinacalcet under fasting and non-fasting conditions using a bioequivalence trial. METHODS: We investigated the relationship of cinacalcet PK with single nucleotide polymorphisms (SNPs) of CYP3A4, CYP1A2 and CYP2D6, and of cinacalcet PD with SNPs of calcium-sensitive receptors (CASR) and vitamin D receptors (VDR) in 65 healthy Chinese subjects recruited to participate in this study. Our study was a phase I, open-label, randomized, two-period, two-sequence crossover, a single-center clinical study designed under both fasting and non-fasting conditions to investigate the effect of dietary factors on cinacalcet. Plasma cinacalcet concentrations were analyzed using a validated HPLC-MS/MS assay. Clinical laboratory tests evaluated safety. Thirteen SNPs of CASR, VDR, and CYP genes were selected for pharmacogenetic analysis. RESULTS: CYP3A4 rs4646437 was found to be associated with the PK of cinacalcet under fasting conditions (P<0.01). Subjects carrying T alleles of rs4646437 appeared to metabolize cinacalcet poorly. The C(max) and AUC of subjects in the non-fasting group were significantly higher (P<0.0001) than those in the fasting group. The T(max), CL/F, and Vd/F in the fasting group were significantly higher (P<0.0001) than those in the non-fasting group. In the fasting group, the geometric least square mean ratios (T/R) of the C(max) and AUC(0-t) were 109.89% and 105.33%, and the corresponding 90% CIs were 98.36-122.79% and 98.04-113.15%, respectively. In the non-fasting group, the T/R of the C(max) and AUC(0-t) were 100.74% and 99.09%, and the corresponding 90% CIs were 92.65-109.54% and 94.79-103.58%, respectively. All adverse events (AEs) were mild, and no serious adverse events (SAEs) occurred during the bioequivalence trial. CONCLUSIONS: Following our investigation, we reached the following conclusions: CYP3A4 rs4646437 may affect cinacalcet PK; the reference and test preparations of cinacalcet were bioequivalent under fasting and non-fasting conditions and were safe to use; and dietary factors had a significant effect on the PK of cinacalcet, in that exposure to the drug increased when cinacalcet was taken after eating. CI - 2020 Annals of Translational Medicine. All rights reserved. FAU - Liu, Yang-Jie AU - Liu YJ AD - Research Division of Clinical Pharmacology, the First Af fi liated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China. FAU - Sun, Lu-Ning AU - Sun LN AD - Research Division of Clinical Pharmacology, the First Af fi liated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China. FAU - Cheng, Zi-Ping AU - Cheng ZP AD - Research Division of Clinical Pharmacology, the First Af fi liated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China. FAU - Qian, Yi AU - Qian Y AD - Research Division of Clinical Pharmacology, the First Af fi liated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China. FAU - Ma, Zeng-Qing AU - Ma ZQ AD - Research Division of Clinical Pharmacology, the First Af fi liated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China. FAU - Zhang, Xue-Hui AU - Zhang XH AD - Department of Pharmacy, Jiangsu Shengze Hospital, Nanjing Medical University, Suzhou, China. FAU - Zhang, Hong-Wen AU - Zhang HW AD - Research Division of Clinical Pharmacology, the First Af fi liated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China. FAU - Xie, Li-Jun AU - Xie LJ AD - Research Division of Clinical Pharmacology, the First Af fi liated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China. FAU - Yu, Lei AU - Yu L AD - Research Division of Clinical Pharmacology, the First Af fi liated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China. FAU - Yuan, Zi-Qing-Yun AU - Yuan ZQ AD - Research Division of Clinical Pharmacology, the First Af fi liated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China. FAU - Liu, Yun AU - Liu Y AD - Department of Geriatric Endocrinology, the First Af fi liated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China. FAU - Wang, Yong-Qing AU - Wang YQ AD - Research Division of Clinical Pharmacology, the First Af fi liated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China. AD - Department of Pharmacy, Jiangsu Shengze Hospital, Nanjing Medical University, Suzhou, China. LA - eng PT - Journal Article PL - China TA - Ann Transl Med JT - Annals of translational medicine JID - 101617978 PMC - PMC7723585 OTO - NOTNLM OT - CYP3A4 OT - Cinacalcet OT - bioequivalence OT - calcium-sensitive receptors (CASR) OT - pharmacokinetics (PK) COIS- Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-1329). The authors have no conflicts of interest to declare. EDAT- 2020/12/15 06:00 MHDA- 2020/12/15 06:01 PMCR- 2020/11/01 CRDT- 2020/12/14 10:59 PHST- 2020/12/14 10:59 [entrez] PHST- 2020/12/15 06:00 [pubmed] PHST- 2020/12/15 06:01 [medline] PHST- 2020/11/01 00:00 [pmc-release] AID - atm-08-21-1385 [pii] AID - 10.21037/atm-20-1329 [doi] PST - ppublish SO - Ann Transl Med. 2020 Nov;8(21):1385. doi: 10.21037/atm-20-1329.