Accounting for Pharmacokinetic Variability of Certolizumab Pegol in Patients with Crohn’s Disease
| Autor: | Brian G. Feagan, Ann Gils, Jason Coarse, Diane R. Mould, Niels Vande Casteele, Iram Hasan, William J. Sandborn |
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| Rok vydání: | 2017 |
| Předmět: |
Adult
Male medicine.medical_specialty Time Factors Adolescent Population Serum Albumin Human Models Biological Gastroenterology Antibodies Continuous variable Young Adult 03 medical and health sciences 0302 clinical medicine Crohn Disease Pharmacokinetics Internal medicine medicine Humans Tissue Distribution Pharmacology (medical) In patient Certolizumab pegol education Aged Aged 80 and over Pharmacology Volume of distribution Clinical Trials as Topic Crohn's disease education.field_of_study business.industry Middle Aged medicine.disease NONMEM C-Reactive Protein Nonlinear Dynamics 030220 oncology & carcinogenesis Certolizumab Pegol Linear Models Female 030211 gastroenterology & hepatology business Immunosuppressive Agents medicine.drug |
| Zdroj: | Clinical Pharmacokinetics. 56:1513-1523 |
| ISSN: | 1179-1926 0312-5963 |
| DOI: | 10.1007/s40262-017-0535-3 |
| Popis: | Certolizumab pegol is an effective biologic for patients with Crohn’s disease (CD). Individual differences in certolizumab pegol apparent clearance (CL/F) affect exposure and possibly efficacy. A previously developed population pharmacokinetic (PK) model did not account for dynamic changes in clinical parameters during therapy. The aim of this study was to refine the existing PK model to capture the time-varying influence of covariates. Data collected from 2157 Crohn’s disease patients in nine studies were analyzed using nonlinear mixed-effects modeling software (NONMEM). Certolizumab pegol concentration–time data were described by a one-compartment PK model with first-order absorption, and one-compartment disposition with linear, time-dependent elimination using antidrug antibody (ADAb) concentration as a continuous variable. The final dataset consisted of 12,926 analyzable records. Parameter estimates were absorption rate constant 1.83/day, CL/F 0.527 L/day, and apparent volume of distribution (V/F) 8.33 L. ADAb concentration (2.5–214 units/mL) increased the median CL/F by 142–174%. For a typical patient, body weight (46.8–100.5 kg) increased the median CL/F and V/F from 82 to 120%. Albumin (32–48 g/L) decreased and C-reactive protein (0.5–54.0 mg/L) increased the median CL/F from 123 to 85% and from 83 to 113%, respectively. Between-patient variability of CL/F was 19.6%. By incorporating time-varying covariates, this population PK model reduces between-patient variability on CL/F estimates, and the relative influence of ADAb can now be assessed. As Crohn’s disease patient covariates are often time-dependent, this model is more reflective of patient drug exposure with sustained treatment. |
| Databáze: | OpenAIRE |
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