Semi-mechanistic Multiple-Analyte Pharmacokinetic Model for an Antibody-Drug-Conjugate in Cynomolgus Monkeys.

Abstract

PurposeA semi-mechanistic multiple-analyte population pharmacokinetics (PK) model was developed to describe the complex relationship between the different analytes of monomethyl auristatin E (MMAE) containing antibody-drug conjugates (ADCs) and to provide insight regarding the major pathways of conjugate elimination and unconjugated MMAE release in vivo.MethodsFor an anti-CD79b-MMAE ADC the PK of total antibody (Tab), conjugate (evaluated as antibody conjugated MMAE or acMMAE), and unconjugated MMAE were quantified in cynomolgus monkeys for single (0.3, 1, or 3 mg/kg), and multiple doses (3 or 5 mg/kg, every-three-weeks for 4 doses). The PK data of MMAE in cynomolgus monkeys, after intravenous administration of MMAE at single doses (0.03 or 0.063 mg/kg), was included in the analysis. A semi-mechanistic model was developed and parameter estimates were obtained by simultaneously fitting the model to all PK data using a hybrid ITS-MCPEM method.ResultsThe final model well described the observed Tab, acMMAE and unconjugated MMAE concentration-time profiles. Analysis suggested that conjugate is lost via both proteolytic degradation and deconjugation, while unconjugated MMAE in systemic circulation appears to be mainly released via proteolytic degradation of the conjugate.ConclusionsOur model improves the understanding of ADC catabolism, which may provide useful insights when designing future ADCs.Electronic supplementary materialThe online version of this article (doi:10.1007/s11095-014-1585-y) contains supplementary material, which is available to authorized users.