Pharmacokinetic-target engagement modelling of an anti-CCL17 monoclonal antibody in healthy volunteers and osteoarthritis patients
Eirini Panoilia1, Marylore Chenel2, Sarah Siederer1
1Clinical Pharmacology Modelling and Simulation, GSK, UK , 2Pharmetheus AB, Sweden
Introduction/Objectives: GSK3858279 is a human monoclonal antibody that binds to chemokine (C-C motif) ligand 17 (CCL17) with high affinity, thereby preventing downstream consequences of the G-protein coupled CC-chemokine receptor CCR4 signalling pathway. A population pharmacokinetic/target engagement (PK/TE) modelling analysis was performed with the objective of characterising the time course of GSK3858279 PK as well as its binding to its soluble target, CCL17, to evaluate the PK/TE relationship in healthy volunteers and osteoarthritis (OA) patients to support design and dose predictions in late phase studies. Methods: The current analysis was based on a dataset containing serum concentrations of total GSK3858279 (877 samples) and total CCL17 (1712 samples). Data were collected from 118 healthy volunteers and OA patients (77% male; median weight (WT) 81.9 kg; median age 53 years) over a wide range of single intravenous (IV) doses (0.1-10mg/kg IV), a single subcutaneous (SC) dose (3 mg/kg up to 240 mg maximum) and 240 mg weekly SC dosing [1,2]. A PK/TE model was developed using non-linear mixed effects modelling implemented in NONMEM (version 7.4) and facilitated by Perl-speaks-NONMEM (version 5.2.6). WT on clearance (CL) and volume of distribution terms as well as on distribution rate constant of GSK3858279 from peripheral to central compartment (Krd) was incorporated into the model as a mechanistic covariate. Any other potential covariate effects (e.g., study on total CCL17 baseline (BASE)) were tested by adding them into the model and were subject to the model discrimination criteria. Overall model goodness of fit was assessed graphically and by statistical tests. Results: 2 Phase 1 studies (118 healthy volunteers and OA patients) were included in the analysis. A 2-compartment model with first order absorption and first order elimination from the central compartment, with saturable free GSK3858279 distribution to the peripheral compartment and drug-target binding in the central compartment best described the total GSK3858279 and total CCL17 concentration changes over time. A target-mediated drug disposition approach, with a quasi-steady state approximation was adopted to describe GSK3858279 binding to CCL17 in the central compartment. The estimated CL was 2.47 L/day, the central volume of distribution (Vc) was 4.61 L, the Krd was 0.110 1/day, the BASE was 0.0737 nM, the internalisation rate constant (Kint) was 0.0531 1/day, and the maximum velocity of enzymatic reaction (Vmax) was 55.3 nmol/day. The following covariate-parameter relationships were included in the model: baseline WT on CL, Vc and Krd terms (which were allometrically scaled to 0.75, 1 and -0.25, respectively) and study on BASE. An exponential distribution characterised the inter-individual variability on CL (9.91%), Vc (7.97%), Krd (28.1%), BASE (7.96%), Kint (64.5%), and Vmax (18.7%). Residual variability was explained by a proportional error model and was estimated for each route of administration. Of note, there was high shrinkage (59.8%) on the Kint parameter. Diagnostic plots showed good agreement between the observed and model-predicted total GSK3858279 and total CCL17 concentration-time profiles. Conclusions: The developed PK/TE model described adequately the PK profile of total GSK3858279 and disposition of total CCL17 in healthy adults and OA patients. WT was included as a mechanistic covariate on CL, Vc, and Krd, with fixed allometric exponents. A study-specific BASE was estimated which significantly improved model performance and was supported by the observed data. The proposed model could be used as prior to support design characteristics and dose predictions in late phase studies.
[1] Nijjar JS, Abbott-Banner K, Alvarez Y, Aston N, Bass D, Bentley JH et al. Efficacy, safety and tolerability of GSK3858279, an anti-CCL17 monoclonal antibody and analgesic, in healthy volunteers and patients with knee osteoarthritis pain: a phase I, randomised, double-blind, placebo-controlled, proof-of-mechanism and proof-of-concept study. Ann Rheum Dis 2024; ard-2023-225434. doi: 10.1136/ard-2023-225434. [2] Boyle Y, Hijma HJ, Rees J, Nijjar J, Panoilia E, Alvarez Y et al. Randomized, placebo-controlled study on the effects of intravenous GSK3858279 (anti-CCL17) on a battery of evoked pain tests in healthy participants. Clin Transl Sci 2024; 17(9):e13873. doi: 10.1111/cts.13873.