Genotyping as a Key Element of Sample Size Optimization in Bioequivalence of Risperidone Tablets

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 AUC_last, AUC_∞ and C_max 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 CV_w of risperidone in natural logarithm-transformed C_max 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 CV_w, which may be a feasible method to decrease the sample size for the bioequivalence study of highly variable drugs.