Chenguang Zhou, Siddharth Sukumaran, Montserrat Carrasco-Triguero, Ola Saad, Saroja Ramanujan, Amrita Kamath
Genentech, Inc., California, USA
Objectives: Staphyloccocus aureus (S. aureus) is a bacterial pathogen causing life threatening diseases such as bacteremia and bone infections. We have developed a novel THIOMABTM antibiotic conjugate (TAC) to treat invasive S. aureus infections. The purpose of this study is to build a semi-mechanistic model to describe and predict the complex pharmacokinetic (PK) behavior of TAC.
Methods: The concentration-time profiles of two analytes, total antibody (Tab) and antibody-conjugated drug (acDrug), were quantified in mice (5, 25, or 50 mg/kg), rat (1, 25, or 50 mg/kg), and cynomolgus monkeys (1, 15, or 150 mg/kg) after a single intravenous (IV) dose of the anti-S. aureus TAC. A semi-mechanistic model was developed and parameter estimates were obtained by simultaneously fitting the model to all PK data at all dose levels for each species in MATLAB® SimBiology® software. The structure of the mathematical model was developed based on the known mechanisms of deconjugation and observed impact of drug-to-antibody ratios (DAR) on the PK of antibody-drug conjugates in general. Specifically, the model accounts for DAR dependent drug deconjugation and proteolytic degradation of TAC and was assessed by simultaneous fitting of different PK analytes.
Results: The same structure model described the observed Tab and acDrug concentration-time profiles in mouse, rat and monkey well. Final estimated parameters quantified the contribution of proteolytic degradation and deconjugation in clearing the conjugated drug, and suggested a similar drug deconjugation process across all three preclinical species.
Conclusions: This semi-mechanistic PK model improves our understanding of the complex PK behavior of the TAC in different species with translational application for human PK prediction.
References:
[1] Lu D, Jin JY, Girish S, Agarwal P, Li D, Prabhu S, Dere RC, Saad OM, Nazzal D, Koppada N, Ramanujan S, Ng CM. Semi-mechanistic Multiple-Analyte Pharmacokinetic Model for an Antibody-Drug-Conjugate in Cynomolgus Monkeys. Pharm Res. 2015; 32(6):1907-19.
[2] Sukumaran S, Gadkar K, Zhang C, Bhakta S, Liu L, Xu K, Raab H, Yu SF, Mai E, Fourie-O’Donohue A, Kozak KR, Ramanujan S, Junutula JR, Lin K. Mechanism-Based Pharmacokinetic/Pharmacodynamic Model for THIOMAB™ Drug Conjugates. Pharm Res. 2015; 32(6):1884-93.
Reference: PAGE 25 (2016) Abstr 5755 [www.page-meeting.org/?abstract=5755]
Poster: Drug/Disease modeling - Infection