Pharmacokinetics and C-reactive protein modelling of anti-interleukin-6 antibody (PF-04236921) in healthy volunteers and patients with autoimmune disease
| Autor: | Satoshi Shoji, Cheryl Li, Jean S. Beebe |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pharmacology Autoimmune disease Volume of distribution education.field_of_study biology business.industry Population C-reactive protein Renal function medicine.disease 030226 pharmacology & pharmacy 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Pharmacokinetics Rheumatoid arthritis Pharmacodynamics biology.protein Medicine Pharmacology (medical) business education |
| Zdroj: | British Journal of Clinical Pharmacology. 84:2059-2074 |
| ISSN: | 0306-5251 |
| Popis: | Aims The purpose of this study was to characterize pharmacokinetics (PK) of PF-04236921, a novel anti-interleukin-6 monoclonal antibody, and its pharmacokinetic/pharmacodynamic (PK/PD) relationship on serum C-reactive protein (CRP) in healthy volunteers and patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and Crohn's disease (CD). Methods Population modelling analyses were conducted using nonlinear mixed effects modelling. Data from two phase 1 healthy volunteer studies, a phase 1 RA study, a Phase 2 CD study and a Phase 2 SLE study were included. Results A two-compartment model with first order absorption and linear elimination and a mechanism-based indirect response model adequately described the PK and PK/PD relationships, respectively. Central compartment volume of distribution (Vc) positively correlated with body weight. Clearance (CL) negatively correlated with baseline albumin concentration and positively correlated with baseline CRP and creatinine clearance, and was slightly lower in females. After correcting for covariates, CL in CD subjects was approximately 60% higher than other populations. Maximum inhibition of PF-04236921 on CRP production (Imax ) negatively correlated with baseline albumin. Imax positively correlated with baseline CRP and the relationship was captured as a covariance structure in the PK/PD model. Conclusion Integrated population PK and PK/PD models of PF-04236921 have been developed using pooled data from healthy subjects and autoimmune patients. The current model enables simulation of PF-04236921 PK and PD profiles under various dosing regimens and patient populations and should facilitate future clinical study of PF-04236921 and other anti-interleukin-6 monoclonal antibodies. |
| Databáze: | OpenAIRE |
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