FDA hepatic dysfunction child-pugh national cancer institute dosing oncology compounds

Discordance Between Child-Pugh and National Cancer Institute Classifications for Hepatic Dysfunction: Implications on Dosing Recommendations for Oncology Compounds

by Mohamed Elmeliegy PhD, Derek Z. Yang BS, Engie Salama PharmD, Kourosh Parivar MPharm, Diane D. Wang PhD

Jul 20^th 2020
18 mins
Clinical Pharmacology: Volume 61, Issue 1, January 2021, Pages 105-115

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Summary

The FDA and European Medicines Agency recommend using Child-Pugh classification for pharmacokinetic evaluation in noncancer subjects with hepatic impairment (HI).
Dosing recommendations for oncology compounds for patients with HI are commonly based on Child-Pugh classification.
In oncology clinical practice, the National Cancer Institute classification (NCIc) is commonly used for evaluating hepatic function and dosing decisions for oncology patients.
This study evaluated the discordance between Child-Pugh and NCIc systems and their impact on dosing recommendations.
The classification system in HI studies was reviewed for FDA-approved oncology compounds.
Significant discordance was found between Child-Pugh and NCIc classifications for drugs like sunitinib, dacomitinib, palbociclib, bosutinib, and axitinib.
NCIc tended to classify subjects as less impaired compared to Child-Pugh.
Pharmacokinetic analyses by NCIc were consistent with Child-Pugh for sunitinib, dacomitinib, and palbociclib.
For bosutinib, NCIc showed less impact of HI than Child-Pugh, while the opposite trend was observed for axitinib.
The considerable discordance between the two systems impacts dosing decisions and bears consideration.
When Child-Pugh is used for HI study enrollment, exploratory PK analyses based on NCIc should be conducted.
Prescribers should attempt to use the same classification system in the product label for dosing decisions.

Efficacy and safety of new anticancer agents are often established in clinical studies that exclude patients with advanced degrees of organ impairment. Therefore, dedicated hepatic impairment (HI) studies are conducted to compare drug exposure in subjects with varying degrees of liver dysfunction with a control group with normal hepatic function. The results from these studies are interpreted in the context of the exposure-safety and exposure-efficacy relationships to guide dosing recommendation for oncology compounds in these sub-populations. Regulatory guidance recommends conducting HI studies when drug pharmacokinetics (especially metabolism and biliary excretion) are expected to be significantly altered in patients with liver dysfunction or for drugs with a relatively narrow therapeutic index...

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