Pharmacokinetics and Bioequivalence of Two Formulations of Valsartan 80 mg Capsules: A Randomized, Single Dose, 4-Period Crossover Study in Healthy Chinese Volunteers Under Fasting and Fed Conditions

Abstract

Purpose

To compare the bioequivalence of two formulations of valsartan (80 mg capsules) under fasting and fed conditions in healthy Chinese volunteers using a full-replicate study design.

Methods

A total of 78 Subjects were randomly assigned to fasting cohort (n = 48) or fed cohort (n = 30). Each cohort includes 4 single-dose observation periods and 3-day washout periods. Blood samples were collected at designed time point. Plasma concentration of valsartan was analyzed by a validated LC-MS/MS method. Noncompartmental analysis method was employed to determine the pharmacokinetic parameters. Based on the within-subject standard deviation (S_WR) of the reference formulation, either reference-scaled average bioequivalence (RSABE) or average bioequivalence (ABE) method was used to evaluate the bioequivalence of the two formulations.

Results

Under fasting conditions, the RSABE method was used to evaluate the bioequivalence of C_max (S_WR>0.294), while ABE method was used to evaluate the bioequivalence of AUC_0-t and AUC_0-∞. The geometric mean ratio (GMR) of the test/reference for C_max was 99.52%, and the 95% upper confidence bound was <0. For AUC_0-t and AUC_0-∞ comparisons, GMRs were 102.07% and 101.92%, and the 90% CIs of the test/reference were 96.28%–108.21%, 96.28%–107.88%, respectively. Under fed conditions, the S_WR value of C_max, AUC_0-t and AUC_0-∞ all exceeded the cutoff value of 0.294 and therefore, the RSABE method was used. The GMRs for C_max, AUC_0-t and AUC_0-∞ were 98.78%, 103.33% and 103.08%, respectively, while the 95% upper confidence bound values were all <0. These results all met the bioequivalence criteria for highly variable drugs. All adverse events were mild and transient.

Conclusion

In this study, the generic formulation of valsartan 80 mg capsule was considered to be bioequivalent to the reference product under both fasting and fed conditions, and satisfied the requirements for marketing in China.

NMPA Registration No

CTR20181422.

Keywords:

• valsartan
• bioequivalence
• replicate
• pharmacokinetics
• safety

Acknowledgments

The authors would like to thank the subjects and staffs who participated in the study. The authors acknowledge Shanghai Xihua Scientific Co., Ltd. for bioanalytical method validation and sample analysis of the study. The authors also acknowledge ViaClinical Ltd. (Shanghai, China) for statistical analysis of the study.

Data Sharing Statement

All of the individual participant data collected during the trial, after deidentification, can be shared. Study Protocol, Statistical Analysis Plan, Informed Consent Form, and Clinical Study Report can also be available. All shared and available data besides the information presented in the article can be obtained by contacting the corresponding author. To gain access, data requestors will need to sign a data access agreement. Data are available indefinitely.

Author Contributions

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

Disclosure

Xiaodong Wang is the employee from Changzhou Siyao Pharmaceutical Co., Ltd. Kanyin E Zhang reports that ViaClinical Ltd received service fees from Changzhou Siyao Pharmaceutical Co. to perform this study. The authors report no other conflicts of interest in this work.