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Evaluation of the pharmacokinetic drug-drug interaction potential of iohexol, a renal filtration marker

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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.

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Acknowledgements

This work was supported by grants UM1 CA186690, U24CA247643, and R50 CA211241. This project used the UPMC Hillman Cancer Pharmacokinetics and Pharmacodynamics Facility (CPPF) and Animal Facility (AF) and was supported in part by award P30 CA47904.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA

    Anand Joshi, Brian Kiesel, Raman Venkataramanan & Jan H. Beumer

  2. Cancer Therapeutics Program, UPMC Hillman Cancer Center, Hillman Research Pavilion, Room G27E 5117 Centre Avenue, Pittsburgh, PA, 15213-1863, USA

    Jianxia Guo, Julianne L. Holleran, Brian Kiesel, Sarah Taylor, Susan Christner, Robert A. Parise, Edward Chu & Jan H. Beumer

  3. Investigational Drug Service, UPMC Cancer Centers, Pittsburgh, PA, USA

    Brian M. Miller

  4. Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA

    S. Percy Ivy

  5. Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Edward Chu & Jan H. Beumer

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  1. Anand Joshi
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Joshi, A., Guo, J., Holleran, J.L. et al. Evaluation of the pharmacokinetic drug-drug interaction potential of iohexol, a renal filtration marker. Cancer Chemother Pharmacol 86, 535–545 (2020). https://doi.org/10.1007/s00280-020-04145-6

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