Decreased Disposition of Anticancer Drugs Predominantly Eliminated via the Liver in Patients with Renal Failure

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Author(s): Ken-ichi Fujita *, Natsumi Matsumoto, Hiroo Ishida, Yutaro Kubota, Shinichi Iwai, Motoko Shibanuma, Yukio Kato .

Journal Name: Current Drug Metabolism

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Abstract:

Background: Evidence has revealed that renal impairment can affect the systemic exposure of drugs which are predominantly eliminated via the liver. The modulation of drug-metabolizing enzymes and transporters expressed in the liver and/or small intestine by diverse entities, including uremic toxins, in systemic circulation of patients with severe renal failure is considered as the cause of atypical pharmacokinetics, which sometimes induce undesirable adverse events that are especially critical for drugs with narrow therapeutic window such as anticancer drugs. A dosing strategy for anticancer drugs in these patients need to be established.

Methods: The effect of renal impairment on the systemic exposure and safety of anticancer drugs was summarized. The proposed mechanisms for the alterations in pharmacokinetics of these anticancer drugs were also discussed.

Results: Changes in pharmacokinetics and clinical response were reported in 9 out of 10 cytotoxic anticancer drugs investigated, although available information was limited and sometimes controversial. Systemic exposure of 3 out of 16 tyrosine kinase inhibitors was higher in patients with severe renal failure than that in patients with normal kidney function. An increase in systemic exposure of anticancer drugs in patients with renal impairment is likely to be observed for substrates of OATP1B1, despite the limited evidence.

Conclusion: The molecular basis for the effect of uremia on non-renal drug elimination still needed to be clarified with further studies to generate generalizable concepts, which may provide insights into establishing better clinical usage of anticancer drugs, i.e. identifying patients at risk and dose adjustment.

Keywords: Renal failure, cytotoxic anticancer drug, tyrosine kinase inhibitor, non-renal clearance, systemic exposure, drug-metabolizing enzyme, transporter, organic-anion transporting polypeptide 1B1.

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(E-pub Ahead of Print)
DOI: 10.2174/1389200220666190402143125
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