Study designs for renal drug studies

Introduction: Renal dose adjustment generally assumes a linear relationship between renal drug clearance and glomerular filtration rate (GFR). The theory underpinning this practice is the Intact Nephron Hypothesis (INH) [1], which assumes that nephrons are either completely functional (intact) or completely non-functional. There is a growing body of evidence to suggest that a non-linear relationship between renal drug clearance and GFR may exist, particularly for those drugs that undergo extensive tubular secretion. We propose that many renal drug study designs will not capture this non-linearity and therefore the INH remains unchallenged. The aim of this study was to assess potential designs to test the INH.

Methods: Three types of study designs were identified that could be used to test the INH using a generic probe substrate. These were: (1) comparison of the clearance (CL) of the probe with GFR based on plasma data (where GFR was measured using radioisotope or equivalent exogenous marker), (2) comparison of the predicted fraction of drug excreted unchanged based on plasma data with the fraction excreted unchanged based on a mass balance study, and (3) to compare the time course of the cumulative amount of probe excreted in the urine using urine data only. The probe drug was given by iv-bolus, had a half-life of 0.693 hour and was entirely renally eliminated. For the INH conditions the elimination was entirely in accordance with GFR and for the non-INH setting the elimination was based on GFR raised to the power of 0.33 [2]. These potential designs were represented using a simple deterministic simulation in MATLAB (2016b release) under INH and non-INH conditions.

Results: Each of the three study designs yielded observable differences in the profiles for a probe that follows the INH compared with the non-INH.  The regions of maximal difference for each of the methods (based on the standardised probe) were: (1) at GFR values at approximately 20% normal, (2) at GFR values that cover the range of 50% to 100% of normal, and (3) between 4-9 half-lives of the probe and only for GFR values in the range of less than 50% of normal.

Discussion: Three potential designs to test the INH were proposed in this study. Results from this initial exploration indicate that each design will require different conditions to test the INH. In the next stage of this project an optimal discriminatory design will be determined that maximises differences in the profiles for INH and non-INH scenarios while supporting parameter estimation under each design.  Finally, this will be assessed for study power using simulation-estimation methods.

References:

  1. Bricker NS, Morrin PA, Kime SW, Jr. The pathologic physiology of chronic Bright’s disease. An exposition of the “intact nephron hypothesis”. American Journal of Medicine. 1960;28:77-98.
  2. Wright DFB, Duffull SB. A general empirical model for renal drug handling in pharmacokinetic analyses. Br J Clin Pharmacol. 2017. doi:10.1111/bcp.13306.

Sudeep Pradhan

  • University of Otago