Calculated Log D Is Inversely Correlated With Select Camptothecin Clearance and Efficacy in Colon Cancer Xenografts

Quantitative structure-property relationships are often derived to identify molecular determinants of drug potency and facilitate drug design. However, compound activity is typically based on in vitro bioassays, and the influence of physicochemical properties on pharmacokinetic/pharmacodynamic (PK/PD) behavior is not considered. Here, we integrate PK/PD and quantitative structure-property relationship modeling to evaluate the role of lipophilicity in camptothecin antitumor responses in colon cancer xenografts. Drug exposure and tumor growth profiles for 5 camptothecins were extracted from the literature. A PK/PD model with time-dependent transduction was developed, which characterized PK and tumor growth inhibition. Correlations between drug lipophilicity (log D), in vitro potency (IC50), and in vivo efficacy and systemic clearance parameters were tested. Models were qualified using leave-one-out cross-validation. Efficacy and clearance of analogs decreased linearly with increasing log D values; efficacy exhibiting a steeper decline relative to clearance. Cross-validated R2 for predicting in vivo efficacy was 0.55 and 0.18 using log D and in vitro IC50 as the descriptors. Lipophilicity may represent a better predictor of in vivo efficacy than in vitro IC50 measurements for camptothecins. The identified relationships between efficacy, clearance, and lipohilicity may help guide development of new camptothecin analogs and delivery systems with improved pharmacologic profiles.