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

ABSTRACT

Guidance from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency recommends using Child-Pugh classification for pharmacokinetic evaluation in noncancer subjects with hepatic impairment (HI). Therefore, dosing recommendations for oncology compounds for patients with HI are commonly based on Child-Pugh classification. In oncology clinical practice, National Cancer Institute classification (NCIc), is commonly used for evaluating hepatic function and dosing decisions for oncology patients. This work evaluated the discordance between the 2 systems and the impact on dosing recommendations. The classification system in HI studies was reviewed for FDA-approved oncology compounds. Discordance between Child-Pugh and NCIc was evaluated for sunitinib, dacomitinib, palbociclib, bosutinib, and axitinib. Pharmacokinetic (PK) analyses were conducted based on Child-Pugh classification and NCIc. Review of 117 approved oncology compounds showed prevalent use of Child-Pugh classification for dedicated HI studies in noncancer subjects. NCIc is commonly used in cancer patient studies. NCIc tended to classify subjects as less impaired versus Child-Pugh (64.9%, 73.7%, and 61.5% of subjects with mild, moderate, and severe HI, respectively, via Child-Pugh were classified as at least 1 category less impaired via NCIc). PK analyses by NCIc were consistent with Child-Pugh for sunitinib, dacomitinib, and palbociclib. For bosutinib, NCIc showed less impact of HI than Child-Pugh; an opposite trend was observed for axitinib. The impact of this considerable discordance between the 2 systems on dosing decisions 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.