Pharmacokinetic considerations for organ dysfunction clinical trials in early drug development

It is not infrequent that patients with different cancers are affected by bodily organ dysfunction. Factors such as comorbidities, prior anticancer therapies and tumor-related issues are frequent causes of organ impairment. Since patients with bodily organ dysfunction are not frequently enrolled in conventional clinical trials due to standard study eligibility criteria, such patients are placed at a disadvantage in receiving appropriate anticancer treatment. Renal and hepatic impairment may also have potential detrimental effects on the pharmacokinetic profile of drugs, with subsequent implications for both safety and efficacy. Renal function can be classified into 5 categories (normal, mild, moderate, severe and end-stage renal dysfunction), but the main classifications used (FDA, EMA and NCI-ODWG, KIDGO) currently have different cutoffs for each group, and also differ in their methods for calculating the eGFR. Renal impairment can be a consequence of damage through a range of mechanisms (glomerular filtration, tubular secretion, tubular absorption, and renal metabolism), likely differently affecting not only the excretion of drugs, but also other parameters such as absorption, distribution, protein binding, metabolism and excretion (ADME) of drugs even in those with low renal clearance. Conversely, hepatic impairment is frequently classified as mild, moderate and severe. In oncology, the two most commonly used classifications are the Child-Pugh and NCI-ODWG scores. Both scores use objective variables that are easily measurable laboratory parameters (e.g. total bilirubin, prothrombin time, albumin and ALT/AST). Nevertheless, the Child-Pugh score also includes clinical variables including encephalopathy and ascites, which may not always accurately represent the severity of liver function in patients with different cancers. The severity of hepatic impairment varies between highly hepatic extracted drugs (EH > 7), blood flow-limited, intermediate (EH < 7-EH > 3) and low extracted drugs (EH < 3). Furthermore, hepatic impairment is also associated with variable and non-uniform reductions in CYP450 enzymes activity and changes in unbound drug, which also affect the disposition and exposure of drugs. Understanding the degree of severity of organ dysfunction and the underlying responsible mechanisms, as well as the impact on pharmacokinetics are key challenges in patients with renal and hepatic impairment, which should be assessed in early phase clinical trials if appropriate.