Evaluation of designs for renal drug studies based on the European Medicines Agency and Food and Drug Administration guidelines for drugs that are predominantly secreted.

AIMS

Dose adjustment for drugs eliminated by the kidneys generally assume a linear relationship between renal drug clearance (CL ) and glomerular filtration rate (GFR). This assumption may not hold for drugs that undergo extensive tubular secretion where nonlinearity in drug handling is expected. The aim of this study is to determine if renal drug study designs recommended by the European Medicines Agency (EMA) and Food and Drug Administration (FDA) could distinguish linear from nonlinear renal drug handling.

METHODS

In this simulation and estimation study, the study designs based on the EMA and FDA guidelines for Phase I renal drug studies were evaluated for their ability to discriminate a linear from a nonlinear relationship between CL and GFR. The number of subjects for each simulated study ranged from 4 to 960. Power, relative standard error and bias were calculated.

RESULTS

Study designs under the EMA and FDA guidelines required ≥8 and ≥48 subjects, respectively, to achieve ≥80% power to discriminate a linear from nonlinear relationship between CL and GFR. The relative standard error of estimated parameters were 13-37 and 17-44% for the designs with 24 subjects under the EMA and FDA guidelines, respectively. The bias in parameter estimates under the EMA designs were not evident, however, they were biased (13-21%) under the FDA designs.

CONCLUSION

The EMA design was found to require fewer subjects (n = 8) compared to the FDA (n = 48) to discriminate linear from nonlinear drug renal handling at ≥80% study power while both the designs perform poorly for the parameter precision.