Critical evaluation of methods for estimation of increase in systemic drug exposure for renally impaired patients
Abstract: Introduction: The effect of renal impairment (RI) on systemic exposure is assessed in phase I with RI studies and/or in phase III with population pharmacokinetic analysis. Regulatory review has indicated that the estimated effect of RI from the two methods may differ. Aim: To map the estimated effect of RI on systemic exposure based on phase I and III data, to investigate if the estimated effect based on the two data sources differ and to investigate causes to this potential discrepancy. Methods: Marketing authorisation applications (MAA) were scrutinised with focus on impact of RI on systemic exposure estimated based on phase I and III data. In addition, a simulation-estimation study was performed to explore causes to discrepancies. Phase I and III data were simulated and analysed with non-compartmental analysis (NCA) and population analysis. The phase III data were simulated under several alternative conditions thought to be potential sources for discrepancies, such as uncertainty in creatinine clearance (CLCR) measurements and varying number of subjects. Results: Six examples were found in MAAs in which a discrepancy was observed, where phase III tended to estimate a lower effect of RI compared with phase I. In the simulation-estimation study, the NCA of phase I data over-predicted the effect of RI on systemic exposure, while the population analysis of phase III data estimated the effect of RI without bias. Uncertainty in CLCR measurement in the phase III data resulted in under-prediction of the effect of RI on systemic exposure. Conclusions: A discrepancy in the estimated effect of RI on systemic exposure between phase I and III was observed in existing MAAs. The NCA of phase I RI study and uncertain CLCR measurements were identified as possible reasons to the discrepancy.
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