2014 - Alicante - Spain

PAGE 2014: Drug/Disease modeling - Oncology
Stefaan Rossenu

Population Pharmacokinetics of MK-3475, a human Anti-PD-1 Monoclonal Antibody in patients with progressive locally advanced or metastatic carcinoma, melanoma, and non-small cell lung carcinoma

Malidi Ahamadi (1), Marita Prohn (2), Stefaan Rossenu (2), Jung Hoon Lee (1), Rik de Greef (2), Dinesh de Alwis (1), and Jeroen Elassaiss-Schaap (2)

(1) Quantitative Pharmacology and Pharmacometrics, Merck Research Laboratory, Merck and Co., USA, (2) Netherlands

Objectives: MK-3475 is a potent antibody against the cellular immune 'switch' programmed death -1 (PD-1) with high activity in the treatment of metastatic melanoma [1]. We characterized the pharmacokinetic (PK) profile of patients receiving MK-3475 and quantified the effect of intrinsic factors on MK-3475 exposure to evaluate the need for dose modifications.

Methods: A total of 7034 serum concentrations from 337 patients were used to describe the PK of MK-3475. The relationships between all PK parameters and various baseline covariates were examined, including: age, sex, eGFR, bilirubin, AST, albumin and IgG, using stepwise covariate modeling. The posterior power of the analysis to detect clinically relevant effects was assessed using simulations in order to aid interpretation of the robustness of negative covariate findings.

Results: A two-compartmental population PK model with a linear clearance from the central compartment described well MK-3475 pharmacokinetics [2]. Clearances and volumes were allometrically scaled by bodyweight consistent with literature findings [2]. Covariate analysis identified statistically significant effects on clearance of baseline albumin (negative slope) and IgG levels (positive slope) as well as an effect of gender on clearance and central volume of distribution. Furthermore results from power simulation indicated that the power of the population PK model to detect the effect of a continuous/categorical covariate was generally 90% or higher if an effect of 20% on clearance would be present in 10% (20% for categorical covariate) of the population. The observed effects on clearance were well below effect sizes that would result in clinically relevant changes in exposure.

Conclusion: Results from this analysis indicated that PK parameters of MK-3475 have a low clearance, limited volume of distribution and low variability in the central volume of distribution (CV of 13.5%) consistent with other monoclonal antibodies [2] (CV of 26% (12-84%)). The posterior power was high allowing robust inference on the absence of impact of covariates.



References:
[1] Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC,`McDermott DF, et al. Safety, activity, and immune correlates of Anti-PD-1 antibody in cancer. N Engl J Med 2012;366(26):2517-9.
[2] Nathanael L. Dirks and Bernd Meibohm, Clin Pharmacokinet 2010; 49 (10): 633-659.


Reference: PAGE 23 (2014) Abstr 3229 [www.page-meeting.org/?abstract=3229]
Poster: Drug/Disease modeling - Oncology
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