Dan Lu (1), Jin Yan Jin (1), Priya Agarwal (1), Sandhya Girish (1), Dongwei Li (1), Saileta Prabhu (1), Denise Nazzal (1), Ola Saad (1), Randy Dere (1), Neelima Koppada (1), Chee Ng (2, 3)
(1) Genentech, South San Francisco, CA, USA; (2) Children Hospital of Philadelphia, Philadelphia, PA, USA (3) School of Medicine, University of Pennsylvania, Philadelphia, PA
Objectives: Monomethyl auristatin E (MMAE) containing antibody-drug-conjugates (ADCs) are complex mixtures, therefore their pharmacokinetics are assessed by evaluating multiple analytes including total antibody (TAB), antibody-conjugated MMAE (acMMAE) and unconjugated MMAE after ADC dosing. Both TAB and acMMAE concentrations represent mixtures of various drug-to-antibody ratio (DAR) species. The objective of this analysis is to develop a semi-mechanistic multiple-analyte population model to better understand the major pathways of ADC elimination and unconjugated MMAE formation by ADC catabolism.
Methods: The pharmacokinetic (PK) data of multiple analytes for anti-CD79b ADC after a single intravenous dose (0.3, 1, 3 mg/kg) and multiple intravenous doses (1, 3, 5 mg/kg every-three-week for 4 doses), and the PK data of MMAE after a single intravenous dose administration of unconjugated MMAE (0.03 and 0.063 mg/kg) in cynomolgous monkeys were used together for modeling. Multiple semi-mechanistic models were explored to describe the PK of TAB, acMMAE and unconjugated MMAE simultaneously. Parallel hybrid ITS-MCPEM estimation algorithm was used for parameter estimation in S-ADAPT 1.57. The observed below quantification limit data were modeled using M3 method.
Results: ADC elimination clearance pathways are comprised of both deconjugation and proteolytic degradation pathways. A multiple-compartment PK model assuming a sequential deconjugation from high DAR species to low DAR species with a Weibull model for description of the deconjugation rate constant change with the DAR and michaelis-menton kinetics of proteolytic degradation adequately described the PK data of TAB and acMMAE simultaneously. The fraction of formation from the proteolytic degradation pathway to unconjugated MMAE was ~ 66%, while the fraction of formation from the deconjugation pathway was only ~ 2%.
Conclusions: The final model well described the observed TAB, acMMAE and unconjugated MMAE PK data in cynomolgous monkeys simultaneously. The model suggested ADC is eliminated via both the deconjugation pathway and the proteolytic degradation pathway, while the unconjugated MMAE is formed mainly via the proteolytic degradation pathway. This finding suggested that the unconjugated MMAE level after ADC dosing might be modulated by modifying the binding affinity of the ADC to FcRn and/or target and consequently the rate of FcRn and/or target-mediated proteolytic degradation.
Reference: PAGE 22 () Abstr 2681 [www.page-meeting.org/?abstract=2681]
Poster: Other Drug/Disease Modelling