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

Qingqing Wu; Xiaodong Wang; Qian Chen; Yang Zou; Xiaoyan Xu; Tingting Li; Chen Yu; Fu Zhu; Kanyin E Zhang; Jingying Jia; Yanmei Liu

doi:10.2147/DDDT.S253078

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

Drug Des Devel Ther. 2020 Oct 12:14:4221-4230. doi: 10.2147/DDDT.S253078. eCollection 2020.

Authors

Qingqing Wu^{1

2}, Xiaodong Wang³, Qian Chen^{1

2}, Yang Zou^{1

2}, Xiaoyan Xu^{1

2}, Tingting Li^{1

2}, Chen Yu^{1

2}, Fu Zhu^{1

2}, Kanyin E Zhang⁴, Jingying Jia^{1

2}, Yanmei Liu^{1

2}

Affiliations

¹ Center Laboratory, Shanghai Xuhui Central Hospital, Shanghai, People's Republic of China.
² Shanghai Engineering Research Center of Phase I Clinical Research & Quality Consistency Evaluation for Drugs, Shanghai, People's Republic of China.
³ Changzhou Siyao Pharmaceuticals Co., Ltd, Jiangsu, People's Republic of China.
⁴ ViaClinical Ltd, Shanghai, People's Republic of China.

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: bioequivalence; pharmacokinetics; replicate; safety; valsartan.

Publication types

Randomized Controlled Trial

MeSH terms

Adolescent
Adult
Angiotensin II Type 1 Receptor Blockers / adverse effects
Angiotensin II Type 1 Receptor Blockers / pharmacokinetics*
Area Under Curve
Asian People
Capsules
Cohort Studies
Cross-Over Studies
Drug Compounding
Eating
Fasting
Female
Healthy Volunteers
Humans
Male
Therapeutic Equivalency
Valsartan / adverse effects
Valsartan / pharmacokinetics*
Young Adult

Substances

Angiotensin II Type 1 Receptor Blockers
Capsules
Valsartan

Grants and funding

This study was sponsored by Changzhou Siyao Pharmaceutical Co., Ltd. (Changzhou, China). And it did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The study sponsor had a role in study design, data analysis, and data interpretation.