Mita M Thapar (1), Colm Farrell (1), Maria Pitsiu (1), Orestis Papasouliotis (2), Pascal Girard (2), Martin Ullman (3)
(1) ICON Plc, (2) Merck Institute for Pharmacometrics, Lausanne, Switzerland (an affiliate of Merck KGaA, Darmstadt, Germany) (3) Fresenius-Kabi Swiss BioSim
Objectives:
The objectives of the present analysis were to develop a population (Pop) PK model to describe the PK of MSB11022, a biosimilar of adalimumab (Humira®)), in healthy subjects (single dose study) and rheumatoid arthritis (RA) patients (48 weeks treatment period) and describe any potential differences in PK using formulation/product, health status, immunogenicity and standard demographics as covariates.
A total of 178 healthy subjects with available dosing information and sampling times that received a single dose of adalimumab (40 mg s.c.) contributed a total of 3350 post-dose concentration records (including the BLQs), an average of 19 observations per subject. A total of 285 RA patients with available dosing information and sampling times that received at least one dose of adalimumab (40 mg s.c. every other week upto week 48) contributed a total of 1819 post first-dose concentration records (including the BLQs), an average of 6 observations per subject.
Methods:
A Pop PK model in healthy subjects and RA patients was developed in two steps:
- In the first step, the model was developed to describe the MSB11022 PK in healthy subjects and the effects of formulation (citrate based vs modified buffer and stabilizer), demographics and immunogenicity as covariates were investigated;
- The predictive performance of this Pop PK model, built on healthy subject data, was evaluated by using the model and parameter estimates to predict MSB11022 concentrations and the predicted concentrations were compared to the actual observations from the RA patients;
- This Pop PK model developed in healthy subjects was updated by incorporating the data from RA patients and the influence of relevant intrinsic and extrinsic patient characteristics, including immunogenicity status and the product effect (MSB11022 vs Humira®) was evaluated. Other covariates considered to be evaluated were health status (healthy subjects versus RA patients), plasma albumin, CRCL and formulation on CL/F and Vc/F.
The final Pop PK model was evaluated by performing a confidence interval visual predictive check (CIVPC)1. NONMEM® program version VII level 3.0 was used for all analyses using PDx-Pop (Version 5.2) as an interface.
Results:
- The PK of MSB11022 following single dose administration of both MSB11022 modified buffer and stabilizer and citrate based formulations in healthy subjects were well described by a two-compartment model with first-order absorption and elimination. Neutralizing antibody (nAb) status and body weight were significant predictors of PK.
- In this model, nAb positive subjects had 1.6-fold higher estimated CL of MSB11022 compared to nAb negative subjects, reflecting the lower concentrations observed in nAb positive subjects.
- There was no difference in PK of MSB11022 between the two evaluated formulations.
- Predictive performance results showed that the Pop PK model obtained using data from healthy subjects described the observed data from RA patients fairly well.
- The PK of MSB11022 following a single and multiple dose administration of both MSB11022 formulations and Humira® in healthy subjects and in RA patients were well described by a two-compartment model with first-order absorption and elimination. Body weight, nAb status and albumin were significant predictors of PK.
- This final Pop PK model predicted 2.35-fold higher CL in nAb positive subjects compared to nAb negative subjects in the healthy subject and RA patient population in the present analysis.
- The Pop PK model did not identify any difference in PK between healthy subjects and RA patients and no difference in PK was identified between MSB11022 and Humira® products.
Conclusions:
- PK of adalimumab following single-dose administration in healthy volunteers and in RA patients were adequately described by a two-compartment model with first-order absorption and elimination.
- The presence of nAb, body weight and albumin were identified as significant covariates. The model estimated 2.35-fold higher clearance in nAb positive subjects compared to the nAb negative subjects.
- No treatment differences were identified in the main PK parameters (clearance and volume), indicating the PK similarity between the MSB11022 modified buffer and stabilizer and citrate based formulations in healthy subjects and no treatment differences were identified in the main PK parameters between MSB11022 and Humira® products in RA patients.
References:
[1] Bergstrand M, Hooker AC, Wallin JE, et al (2011), Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. The AAPS Journal; 13(2):143-51
Reference: PAGE 28 (2019) Abstr 9144 [www.page-meeting.org/?abstract=9144]
Poster: Drug/Disease Modelling - Other Topics