Ying Chen1,2, Yang Deng3, Miao Yan1,2,4, Zhenyan Hou1,4, Yao Li1,4, Bikui Zhang5,6,7, Hualin Cai8,9. 1. Department of Pharmacy, The Second Xiangya Hospital, Institute of Clinical Pharmacy, Central South University, Changsha, 410011, People's Republic of China. 2. Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, People's Republic of China. 3. Department of Pharmacy, The Third Hospital of Changsha, and The Clinical Application Research Institute of Antibiotics in Changsha, Changsha, 410015, Hunan, People's Republic of China. 4. Institute of Clinical Pharmacy, Central South University, Changsha, 410011, People's Republic of China. 5. Department of Pharmacy, The Second Xiangya Hospital, Institute of Clinical Pharmacy, Central South University, Changsha, 410011, People's Republic of China. 505995@csu.edu.cn. 6. Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, People's Republic of China. 505995@csu.edu.cn. 7. Institute of Clinical Pharmacy, Central South University, Changsha, 410011, People's Republic of China. 505995@csu.edu.cn. 8. Department of Pharmacy, The Second Xiangya Hospital, Institute of Clinical Pharmacy, Central South University, Changsha, 410011, People's Republic of China. hualincai@csu.edu.cn. 9. Institute of Clinical Pharmacy, Central South University, Changsha, 410011, People's Republic of China. hualincai@csu.edu.cn.
Abstract
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. METHODS: 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. RESULTS: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. CONCLUSIONS: 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.
RCT Entities:
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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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