A review of the evidence base for utilizing Child-Pugh criteria for guiding dosing of anticancer drugs in patients with cancer and liver impairment

Abstract

As the liver is vital for the metabolism of many anticancer drugs, determining the correct starting doses in cancer patients with liver impairment is key to safe prescription and prevention of unnecessary adverse effects. Clinicians typically use liver function tests when evaluating patients; however, prescribing information and summaries of product characteristics often suggest dosing of anticancer drugs in patients with liver impairment based on the Child-Pugh criteria, even though the criteria were not developed for this purpose. In this review, we assessed all the oncological small molecule and cytotoxic drugs approved by the United States Food and Drug Administration (FDA) over a 5-year period from 2014 to 2018. The various entry criteria related to these drugs—with respect to hepatic function—in key pivotal studies were compared with their approved dosing recommendations found in prescribing information and summaries of product characteristics. We found that 46% of drugs have dosing recommendations based on Child-Pugh criteria alone, despite the fact that only 8% of these drugs were tested within studies that used the Child-Pugh criteria as entry criteria. Moreover, we note that the data used to make recommendations based on Child-Pugh criteria are typically from small studies that may lack an appropriate patient population. We propose that these findings, along with details surrounding the development of the Child-Pugh criteria, call into question the validity and appropriateness of using Child-Pugh criteria for dosing recommendations of anticancer drugs.

Effect of changes in metabolic enzymes and transporters on drug metabolism in the context of liver disease: Impact on pharmacokinetics and drug–drug interactions

“…Further investigation is needed to find appropriate methods to adjust the dose in such special cases. 143 Despite some limitations, PBPK modelling and exposure response analysis in patients with hepatic impairment are useful to assess the need for dosing adjustment.…”

“…For example, while the Child–Pugh classification is widely used and recommended by the authorities as a measure of the degree of hepatic impairment, it seems that it is insufficient for dose adjustment of some anticancer drugs. Further investigation is needed to find appropriate methods to adjust the dose in such special cases 143 . Despite some limitations, PBPK modelling and exposure response analysis in patients with hepatic impairment are useful to assess the need for dosing adjustment 167 …”

“…It has been suggested that alternatives to the Child-Pugh scoring are necessary to better understand and predict drug exposure. [141][142][143] While Child-Pugh scoring is often used in clinical practice, other instruments have been developed to assess dynamic status of the liver in cirrhosis. 144 Finally, alcohol-associated liver disease is a common chronic liver disease with a strong potential for impact on PK.…”

“…Also, as described above, there are differences in protein expression depending on cirrhosis pathophysiology. It has been suggested that alternatives to the Child–Pugh scoring are necessary to better understand and predict drug exposure 141–143 . While Child–Pugh scoring is often used in clinical practice, other instruments have been developed to assess dynamic status of the liver in cirrhosis 144 …”

Safety and efficacy of cabozantinib for patients with advanced hepatocellular carcinoma who advanced to Child–Pugh B liver function at study week 8: a retrospective analysis of the CELESTIAL randomised controlled trial

“…In the REFINE observational study of patients with HCC, median OS with regorafenib was 16.0 months in patients with Child–Pugh A status compared with 8.0 months in patients with Child–Pugh B status [ 23 ]. In addition to these agents, cytotoxic anticancer agents have been evaluated in this patient population and have shown some level of efficacy and safety [ 25 , 26 ].…”