A survey of renal impairment pharmacokinetic studies for new oncology drug approvals in the USA from 2010 to early 2015: a focus on development strategies and future directions

Abstract

The US Food and Drug Administration (FDA) issued a guidance document in 2010 on pharmacokinetic (PK) studies in renal impairment (RI) on the basis of observations that substances such as uremic toxins might result in altered drug metabolism and excretion. No specific recommendations for oncology drugs were included. We surveyed the publicly available FDA review documents of 29 small molecule oncology drugs approved between 2010 and the first quarter of 2015. The objectives were as follows: (i) summarize the impact of RI on PK at the time of the initial new drug application; (ii) identify limitations of the guidance; and (iii) outline an integrated approach to study the impact of RI on these drugs. Our survey indicates that the current FDA guidance does not appear to provide clear strategic or decision pathways for RI studies in terms of small molecule oncology drugs. The FDA review documents indicate an individualized approach to the review because of the complex pharmacologic nature of these drugs and patient populations. Overall, the strategy for carrying out a RI study during clinical development or as a postmarketing study requires integration with the totality of data, including mass balance, absolute bioavailability, drug-drug interaction, hepatic dysfunction, population PK, exposure-response analysis, the therapeutic window for best guidance, and determination of the optimal doses for special oncology populations.

Fig. 1

Decision tree for determining when a renal impairment study should be carried out according to the 2010 Food and Drug Administration Draft Guidance on RI. ¹Metabolites (active/toxic) follow the same decision tree. ²The sponsor has the option of conducting a reduced study in end-stage renal disease (ESRD) patients or a full study. ³To be conducted in ESRD patients not yet on dialysis. ⁴The results are ‘positive’ when the pharmacokinetic (PK) changes are clinically significant on the basis of exposure–response of the drug. ⁵See section IV.B of the Food and Drug Administration draft guidance for the full PK study design or additional studies can be carried out including a population PK evaluation. IV, intravenously; SC, subcutaneously. From Appendix 1 of Guidance for industry: pharmacokinetics in patients with impaired renal function – study design, data analysis and impact on dosing and labeling by US FDA .