Evaluation of the pharmacokinetic drug-drug interaction potential of iohexol, a renal filtration marker
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ORIGINAL ARTICLE
Evaluation of the pharmacokinetic drug‑drug interaction potential of iohexol, a renal filtration marker Anand Joshi1 · Jianxia Guo2 · Julianne L. Holleran2 · Brian Kiesel1,2 · Sarah Taylor2 · Susan Christner2 · Robert A. Parise2 · Brian M. Miller3 · S. Percy Ivy4 · Edward Chu2,5 · Raman Venkataramanan1 · Jan H. Beumer1,2,5 Received: 29 June 2020 / Accepted: 6 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Purpose Carboplatin dose is calculated based on kidney function, commonly estimated with imperfect creatinine-based formulae. Iohexol is used to measure glomerular filtration rate (GFR) and allows calculation of a more appropriate carboplatin dose. To address potential concerns that iohexol administered during a course of chemotherapy impacts that therapy, we performed in vitro and in vivo pharmacokinetic drug-drug interaction evaluations of iohexol. Methods Carboplatin was administered IV to female mice at 60 mg/kg with or without iohexol at 300 mg/kg. Plasma ultrafiltrate, kidney and bone marrow platinum was quantitated by atomic absorption spectrophotometry. Paclitaxel microsomal and gemcitabine cytosolic metabolism as well as metabolism of CYP and UGT probes was assessed with and without iohexol at 300 µg/mL by LC–MS/MS. Results In vivo carboplatin exposure was not significantly affected by iohexol co-administration (platinum AUC combination vs alone: plasma ultrafiltrate 1,791 vs 1920 µg/mL min; kidney 8367 vs 9757 µg/g min; bone marrow 12.7 vs 12.7 µg/ mg-protein min). Paclitaxel microsomal metabolism was not impacted (combination vs alone: 6-α-OH-paclitaxel 38.3 versus 39.4 ng/mL/60 min; 3-p-OH-paclitaxel 26.2 versus 27.7 ng/mL/60 min). Gemcitabine human cytosolic elimination was not impacted (AUC combination vs gemcitabine alone: dFdU 24.1 versus 23.7 µg/mL/30 min). Iohexol displayed no relevant inhibition of the CYP and UGT enzymes in human liver microsomes. Conclusions Iohexol is unlikely to affect the clinical pharmacokinetics of carboplatin, paclitaxel, gemcitabine, or other agents used in combination with carboplatin treatment. Measuring GFR with iohexol to better dose carboplatin is unlikely to alter the safety or efficacy of chemotherapy through pharmacokinetic drug-drug interactions. Keywords Iohexol · Drug-drug interaction · Carboplatin · Gemcitabine · Paclitaxel · Renal function · Glomerular filtration rate · Pharmacokinetics · Mouse · Optimal dosing
Introduction Carboplatin is a chemotherapeutic agent that is widely used across many disease types for both primary and recurrent disease. The current dosing approach for carboplatin targets a plasma ultrafiltrate area under the concentration time curve (AUC). Carboplatin has a clear exposure–response relationship with increasing AUC resulting in increased antitumor Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00280-020-04145-6) contains supplementary material, which is available to authorized users. * Jan H. Beumer [email protected]
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