141: A Comparative Analysis of Pharmacokinetics of Oncology Drugs Between Healthy Volunteers & Patients With Cancer

Statement of Purpose, Innovation or Hypothesis: There has been an increasing use of healthy volunteers (HVs) in early oncology drug development. The results of dedicated pharmacokinetic (PK) studies in HVs provide insight into drug characteristics and facilitate optimized clinical studies in cancer patients (CPs). Here, we investigate the PK differences of orally dosed small molecule oncology drugs between HVs and CPs, as well as the underlying causes.

Description of Methods & Materials: Small molecule oral oncology drugs were compiled based on new drug applications approved from 1999 to 2022. PK data were primarily obtained from the FDA new drug application review. Whenever information on clinical studies or drug characteristics was not available, other health authority documents such as the EMA assessment report, and published literature, were considered. The exposure metrics of drugs in HVs and CPs were collected, taking multiple factors into account such as food effects, dose linearity, and formulation effect, to ensure comparisons are valid. A meaningful numerical difference was determined when the dose-normalized AUC of the HV to CP ratio exhibited a greater than 25% difference (i.e., the ratio was outside the range of 0.8-1.25).Drug characteristics (i.e., fu,p) were also obtained to understand the mechanisms of drug PK difference between HV and CP.

Data & Results: In total, we have examined 73 drugs in our study, and identified 33 drugs that have extractable  PK data in both HVs and CPs. Among these, 9, 9, and 15 drugs show higher, comparable, and lower AUC ratios between HVs and CPs, respectively. For the drugs that show a meaningful numerical difference in dose-normalized AUC between HVs and CPs, the median (min-max) of AUC ratio is 1.414 (1.257-1.918) and 0.548 (0.260-0.794) in the higher and lower HV/CP ratio group, respectively. Our analyses in drug properties suggest that the unbound fraction in plasma (fu,p) tends to be higher, and the fraction eliminated unchanged in urine (fe) tends to be higher, when the HV/CP ratio of AUC is lower. Other factors such as drug solubility, major metabolizing enzyme, and major transporter were investigated but did not appear to explain the drug PK difference between HVs and CPs.

Interpretation, Conclusion or Significance: A comprehensive literature search was conducted to quantify and understand the drug PK difference between HVs and CPs. For a total of 24 drugs, we have identified fu,p and fe as two important covariates. One plausible explanation is that the cancer patients have relatively poorer kidney function and hence less renal drug clearance capacity, as a result, for drugs with higher fe, the HV/CP AUC ratio is lower.

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