Pharmacogenetic and safety analysis of cinacalcet hydrochloride in healthy Chinese subjects

Yang-Jie Liu; Lu-Ning Sun; Zi-Ping Cheng; Yi Qian; Zeng-Qing Ma; Xue-Hui Zhang; Hong-Wen Zhang; Li-Jun Xie; Lei Yu; Zi-Qing-Yun Yuan; Yun Liu; Yong-Qing Wang

doi:10.21037/atm-20-1329

Pharmacogenetic and safety analysis of cinacalcet hydrochloride in healthy Chinese subjects

Ann Transl Med. 2020 Nov;8(21):1385. doi: 10.21037/atm-20-1329.

Authors

Yang-Jie Liu¹, Lu-Ning Sun¹, Zi-Ping Cheng¹, Yi Qian¹, Zeng-Qing Ma¹, Xue-Hui Zhang², Hong-Wen Zhang¹, Li-Jun Xie¹, Lei Yu¹, Zi-Qing-Yun Yuan¹, Yun Liu³, Yong-Qing Wang^{1

2}

Affiliations

¹ Research Division of Clinical Pharmacology, the First Afﬁliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China.
² Department of Pharmacy, Jiangsu Shengze Hospital, Nanjing Medical University, Suzhou, China.
³ Department of Geriatric Endocrinology, the First Afﬁliated Hospital of Nanjing Medical University & Jiangsu Province Hospital, Nanjing, China.

Abstract

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.

Keywords: CYP3A4; Cinacalcet; bioequivalence; calcium-sensitive receptors (CASR); pharmacokinetics (PK).