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Pharmacogenetic and safety analysis of cinacalcet hydrochloride in healthy Chinese subjects
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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
AME Publishing Company
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723585/ https://www.ncbi.nlm.nih.gov/pubmed/33313130 http://dx.doi.org/10.21037/atm-20-1329 |
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author | Liu, Yang-Jie Sun, Lu-Ning Cheng, Zi-Ping Qian, Yi Ma, Zeng-Qing Zhang, Xue-Hui Zhang, Hong-Wen Xie, Li-Jun Yu, Lei Yuan, Zi-Qing-Yun Liu, Yun Wang, Yong-Qing |
author_facet | Liu, Yang-Jie Sun, Lu-Ning Cheng, Zi-Ping Qian, Yi Ma, Zeng-Qing Zhang, Xue-Hui Zhang, Hong-Wen Xie, Li-Jun Yu, Lei Yuan, Zi-Qing-Yun Liu, Yun Wang, Yong-Qing |
author_sort | Liu, Yang-Jie |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7723585 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | AME Publishing Company |
record_format | MEDLINE/PubMed |
spelling | pubmed-77235852020-12-10 Pharmacogenetic and safety analysis of cinacalcet hydrochloride in healthy Chinese subjects Liu, Yang-Jie Sun, Lu-Ning Cheng, Zi-Ping Qian, Yi Ma, Zeng-Qing Zhang, Xue-Hui Zhang, Hong-Wen Xie, Li-Jun Yu, Lei Yuan, Zi-Qing-Yun Liu, Yun Wang, Yong-Qing Ann Transl Med Original Article 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. AME Publishing Company 2020-11 /pmc/articles/PMC7723585/ /pubmed/33313130 http://dx.doi.org/10.21037/atm-20-1329 Text en 2020 Annals of Translational Medicine. All rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Original Article Liu, Yang-Jie Sun, Lu-Ning Cheng, Zi-Ping Qian, Yi Ma, Zeng-Qing Zhang, Xue-Hui Zhang, Hong-Wen Xie, Li-Jun Yu, Lei Yuan, Zi-Qing-Yun Liu, Yun Wang, Yong-Qing Pharmacogenetic and safety analysis of cinacalcet hydrochloride in healthy Chinese subjects |
title | Pharmacogenetic and safety analysis of cinacalcet hydrochloride in healthy Chinese subjects |
title_full | Pharmacogenetic and safety analysis of cinacalcet hydrochloride in healthy Chinese subjects |
title_fullStr | Pharmacogenetic and safety analysis of cinacalcet hydrochloride in healthy Chinese subjects |
title_full_unstemmed | Pharmacogenetic and safety analysis of cinacalcet hydrochloride in healthy Chinese subjects |
title_short | Pharmacogenetic and safety analysis of cinacalcet hydrochloride in healthy Chinese subjects |
title_sort | pharmacogenetic and safety analysis of cinacalcet hydrochloride in healthy chinese subjects |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723585/ https://www.ncbi.nlm.nih.gov/pubmed/33313130 http://dx.doi.org/10.21037/atm-20-1329 |
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