Genotyping as a Key Element of Sample Size Optimization in Bioequivalence of Risperidone Tablets
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Background and Objectives
Risperidone is a derivative of benzisoxazole and is widely used for schizophrenia and other psychiatric illnesses in both adults and children. Previous studies have confirmed that it is a highly variable drug (within-subject variability ≥ 30%). To reduce the large sample size required for bioequivalence researches on highly variable drugs, a role for genotyping in the design of the bioequivalence study was employed.
A randomized, open-label, two-period crossover study was adopted: 20 subjects with specific genotypes carrying cytochrome P450 (CYP) 2D6*10 were randomized to two groups to receive a single oral dose of trial formulation or reference formulation with a 2-week washout period. Blood concentrations of risperidone (parent drug) and 9-hydroxy risperidone (active metabolite) were measured by high-performance liquid chromatography–tandem mass spectrometry.
Eighteen out of the 20 subjects completed the study (two did not finish the test in the second period). The pharmacokinetic parameters of AUClast, AUC∞ and Cmax for the 18 subjects after a single oral dose of the trial or reference preparation were 216.1 ± 88.7 and 220.5 ± 96.8 ng·h/mL; 221.6 ± 93.1 and 226.4 ± 103.5 ng·h/mL; 36.7 ± 10.3 and 36.0 ± 10.2 ng/mL, respectively. The CVw of risperidone in natural logarithm-transformed Cmax was 22.4 and 25.38% for 9-hydroxy risperidone.
The test formulation met the Food and Drug Administration guidelines and regulation criteria for bioequivalence. By controlling the genotype, it could actually help reduce the CVw, which may be a feasible method to decrease the sample size for the bioequivalence study of highly variable drugs.
The authors thank all the volunteers who have participated in this study.
Compliance with Ethical Standards
This work was supported in part by the Nature Science Foundation of China (No. 81401113), the Specialized Research Fund for the Doctoral Program of Higher Education of China (No. 20130162120060), and Hunan Provincial Natural Science Foundation of China (No. 2017JJ3444).
Conflict of interest
The authors declare no conflict of interest in this study.
The study was conducted in line with GCP, the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of the School of Pharmaceutical Sciences, Central South University.
Informed consent was signed by all volunteers before the study.
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