Virtual Healthy Control Matching For Renal Impairment Studies: A Case Study With Glasdegib.

Abstract Background: Clinical development of drugs often requires many pharmacokinetic (PK) studies in healthy volunteers that are conducted prior to renal or hepatic impairment studies. The present analysis evaluated the feasibility of using PK data from healthy participants in other clinical studies as ‘virtual' matched healthy controls for a study of glasdegib PK in participants with moderate to severe renal impairment. Methods: Data from 83 subjects treated with a single oral dose of 100 mg glasdegib in four healthy volunteer studies was used. Virtual healthy controls were selected by renal function (estimated glomerular filtration rate (eGFR) >90mL/min) and matched by age (± 20 yr) and body weight (± 15 kg) to the renal impairment participants from the glasdegib renal impairment study. One-way analysis of variance was used to compare log transformed PK parameters for each renal impairment group to the normal or virtual-normal renal function groups. Post-hoc pairwise comparisons between groups were performed using Tukey's method. Results: A total of 9 healthy matched control subjects were included in the ‘virtual' normal renal function group. Adjusted geometric mean ratios and 90% CI for comparisons between renal impairment groups and normal or ‘virtual' normal renal function groups produced similar results (Table 1). Conclusions: Using data from healthy volunteers in earlier clinical studies to create a ‘virtual' matched normal renal function group for a renal impairment study in glasdegib produced similar results to the prospectively enrolled normal renal function group. Use of virtually matched healthy controls may be a viable option to leverage already available data efficiently and minimize exposure of healthy participants to oncology drugs. Statistical summary of renal function group comparisons, with normal or virtual normal as referenceParameters and Comparisons (Test vs. Reference)Adjusted Geometric mean (Test)Adjusted Geometric Mean (Reference)Adjusted Geometric Mean Ratio (%) (Test/Reference)Adjusted Geometric Mean Ratio (%) 90% CIAUCinf (ng*hr/mL)Moderate Impairment vs Normal Renal Function19641.19601.9204.56(135.85, 308.00)Moderate Impairment vs Virtual Normal Renal Function19641.19410.6208.71(149.42, 291.54)Severe Impairment vs Normal Renal Function19427.09601.9202.33(131.72, 310.79)Severe impairment vs Virtual Normal Renal Function19427.09410.6206.44(144.94, 294.04)AUClast (ng*hr/mL)Moderate Impairment vs Normal Renal Function19181.59474.6202.45(129.03, 317.65)Moderate Impairment vs Virtual Normal Renal Function19181.59286.5206.55(142.82, 298.73)Severe Impairment vs Normal Renal Function16630.89474.6175.53(111.87, 275.41)Severe impairment vs Virtual Normal Renal Function16630.89286.5179.09(123.83, 259.01)Cmax (ng/mL)Moderate Impairment vs Normal Renal Function1082.0791.2136.76(84.00, 222.65)Moderate Impairment vs Virtual Normal Renal Function1082.0789.4137.07(91.39, 205.59)Severe Impairment vs Normal Renal Function950.1791.2120.09(73.76, 195.51)Severe impairment vs Virtual Normal Renal Function950.1789.4120.36(80.25, 180.53)1The Adjusted geometric mean ratios (and 90% CIs) are expressed as percentages.2CI=confidence interval. Citation Format: Brian Reilly, Naveed Shaik, Swan Lin. Virtual healthy control matching for renal impairment studies: A case study with glasdegib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1365.