Optimizing anticancer pharmacotherapy in kidney disease: Estimation of kidney function and evaluation of heterogeneous kinase inhibitor pharmacokinetics

Kidney disease is common in cancer patients, with almost 20% of all solid tumor patients having an estimated glomerular filtration rate (GFR; eGFR) <60 mL/min. Kidney function is an essential consideration for determining anticancer pharmacotherapy, including drug selection and dosing. The overarching goals of this dissertation were to: 1) evaluate the impact of utilizing different GFR-estimation equations on anticancer drug dosing and selection; and 2) investigate the mechanism for the altered pharmacokinetics (PK) of some, but not all, kinase inhibitors observed in patients with kidney disease. A landscape analysis of all anticancer drugs FDA-approved 2015–2019 revealed that patients with kidney disease continue to be excluded from clinical drug development, thereby limiting available data detailing potential changes to anticancer drug PK and subsequent needs for dose adjustments in patients with kidney disease (CHAPTER 2). Retrospective analyses of 4118 cancer clinical trial patients demonstrated that using GFR-estimating equations that omit race may paradoxically worsen care for Black cancer patients by deeming fewer patients eligible for full-doses of anticancer drugs as compared to their non-Black counterparts (CHAPTER 3 and CHAPTER 4). A landscape analysis of the kinase inhibitors, a highly utilized therapeutic class of anticancer drugs, demonstrated that despite common PK characteristics across the class (CYP3A4 and P-gp substrates), PK in patients with kidney disease is heterogeneous (CHAPTER 5). We hypothesized that this is due to differential hepatic uptake and utilized physiologically-based pharmacokinetic (PBPK) modeling to evaluate the mechanism using two probe kinase inhibitors, sunitinib and crizotinib (CHAPTER 8). The PBPK model was informed by in silico evaluations of clinical PK of CYP3A4 (saxagliptin) and P-gp/OATP (fexofenadine) probe drugs, which indicated that CYP3A4 activity does not appreciably change in kidney disease (CHAPTER 6), but hepatic and intestinal OATP activity is decreased by approximately 20–60% (CHAPTER 7). Collectively, this work advances our knowledge of the implications of utilizing different GFR-estimating equations on clinical oncology practice and the mechanistic rationale for heterogeneous kinase inhibitor PK in individuals with kidney disease. The findings can be used to facilitate future work to improve kidney function estimation and dosing of kinase inhibitors in this patient population.