Impact of the 2021 CKD-EPI equation on anticancer pharmacotherapy in black and non-black cancer patients.

Cancer and kidney disease disproportionately impact Black patients. The CKD-EPI2021 equation was developed to estimate glomerular filtration rate (eGFR) without using race. We assessed the impact of using CKD-EPI2021 instead of CKD-EPI2009 or Cockcroft-Gault (CG) on dosing and eligibility of anticancer drugs in Black and non-Black patients. Utilizing the National Cancer Institute Theradex database, deindexed eGFR (mL/min) was calculated for 3931 patients (8.6 % Black) using CKD-EPI2021, CKD-EPI2009, and CG. Dosing simulations based on each eGFR were performed for ten anticancer drugs with kidney function-based eligibility or dosing cutoffs. eGFR differences using CKD-EPI2021 versus CKD-EPI2009 varied between Black and non-Black patients (p < 0.001); on average, Black patients had 10.3 mL/min lower eGFR and non-Black patients had 4.2 mL/min higher eGFR using CKD-EPI2021. This corresponded to a difference in relative odds of cisplatin ineligibility using CKD-EPI2021 versus CKD-EPI2009; Black patients had 48 % higher odds of ineligibility and non-Black patients had 27 % lower odds of ineligibility using CKD-EPI2021 (p < 0.001). When using CKD-EPI2021 versus CG, eGFR differences were similar between Black and non-Black patients (p = 0.679) and relative difference in odds of cisplatin ineligibility did not vary. Using CKD-EPI2021 versus CKD-EPI2009 differentially impacts Black versus non-Black cancer patients; Black patients have lower calculated eGFR and are less likely to receive full doses of drug using CKD-EPI2021. From the historical default of CG, adopting CKD-EPI2021 would not disparately impact patients based on race, but would result in Black patients being less likely to receive full doses of drug than if CKD-EPI2009 were used.

Inclusion of Participants with CKD and Other Kidney-Related Considerations during Clinical Drug Development: Landscape Analysis of Anticancer Agents Approved from 2015 to 2019.

BACKGROUND: The US Food and Drug Administration has prioritized efforts to expand availability of therapies, including anticancer agents, for patients with CKD. US Food and Drug Administration Guidance recommends inclusion of study participants with CKD in clinical trials, improving pharmacokinetic characterization in people with decreased GFR, and using contemporary GFR assessment methods during drug development. We performed a landscape analysis of anticancer agents approved from 2015 to 2019 to evaluate inclusion of study participants with CKD and GFR assessment methods used during drug development and subsequent translation to kidney-related safety and dosing data in product labeling. METHODS: Oncology drugs approved from 2015 to 2019 and associated pivotal trials were identified. We evaluated inclusion of study participants with CKD in pivotal trials and pharmacokinetic analyses, investigated GFR assessment methods used for pivotal trial eligibility and renal pharmacokinetic analyses, and identified kidney-related adverse drug event and dosing information. RESULTS: A total of 55 drugs and 74 pivotal trials were included. Of the pivotal trials, 95% contained kidney-related eligibility criteria, including 68% with GFR-based eligibility. The median lower limit of GFR required for inclusion was 45 ml/min or ml/min per 1.73 m 2 . Pharmacokinetic analyses were performed in CKD stages 4-5 and hemodialysis for only 29% and 6% of drugs, respectively. Estimated creatinine clearance was used in over 60% and 80% of pivotal trials and pharmacokinetic analyses, respectively. Reporting of kidney-related adverse drug events was highly variable. Product labeling for 49% of drugs contained no kidney dosing information. CONCLUSIONS: Study participants with CKD continue to be excluded from anticancer drug development, and GFR estimation in pivotal trials and renal pharmacokinetic analyses remains imprecise and heterogeneous. Furthermore, kidney-related safety and dosing information is scarcely and inconsistently presented.

Use of Physiologically Based Pharmacokinetic Modeling to Evaluate the Impact of Chronic Kidney Disease on CYP3A4-Mediated Metabolism of Saxagliptin.

We characterized the impact of chronic kidney disease (CKD) on the cytochrome P450 (CYP) 3A4-mediated metabolism of saxagliptin to its metabolite, 5-hydroxysaxagliptin, using a physiologically based pharmacokinetic (PBPK) model. A PBPK model of saxagliptin and its CYP3A4 metabolite, 5-hydroxysaxagliptin, was constructed and validated for oral doses ranging from 5 to 100 mg. The observed ratios of area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax ) between healthy subjects and subjects with CKD were compared with those predicted using PBPK model simulations. Simulations were performed with virtual CKD populations having decreased CYP3A4 activity (ie, 64%-75% of the healthy subjects' CYP3A4 abundance) and preserved CYP3A4 activity (ie, 100% of the healthy subjects' CYP3A4 abundance). We found that simulations using decreased CYP3A4 activity generally overpredicted the ratios of saxagliptin AUC and Cmax in CKD compared with those using preserved CYP3A4 activity. Similarly, simulations using decreased CYP3A4 activity underpredicted the ratio of 5-hydroxysaxagliptin AUC in moderate and severe CKD compared with simulations using preserved CYP3A4 activity. These findings suggest that decreased CYP3A4 activity in CKD underpredicts saxagliptin clearance compared with that observed clinically. Preserving CYP3A4 activity in CKD more closely estimates saxagliptin clearance and 5-hydroxysaxagliptin exposure changes observed in vivo. Our findings suggest that there is no clinically meaningful impact of CKD on the metabolism of saxagliptin by CYP3A4. Since saxagliptin is not a highly sensitive substrate and validated probe for CYP3A4, this work represents a case study of a CYP3A4 substrate-metabolite pair and is not a generalization for all CYP3A4 substrates.