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Accounting for Pharmacokinetic Variability of Certolizumab Pegol in Patients with Crohn's Disease.
- Source :
-
Clinical pharmacokinetics [Clin Pharmacokinet] 2017 Dec; Vol. 56 (12), pp. 1513-1523. - Publication Year :
- 2017
-
Abstract
- Background: 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.<br />Objective: The aim of this study was to refine the existing PK model to capture the time-varying influence of covariates.<br />Methods: 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.<br />Results: 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%.<br />Conclusions: 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.
- Subjects :
- Adolescent
Adult
Aged
Aged, 80 and over
Antibodies immunology
C-Reactive Protein metabolism
Certolizumab Pegol administration & dosage
Clinical Trials as Topic
Female
Humans
Immunosuppressive Agents administration & dosage
Immunosuppressive Agents pharmacokinetics
Linear Models
Male
Middle Aged
Nonlinear Dynamics
Serum Albumin, Human metabolism
Time Factors
Tissue Distribution
Young Adult
Certolizumab Pegol pharmacokinetics
Crohn Disease drug therapy
Models, Biological
Subjects
Details
- Language :
- English
- ISSN :
- 1179-1926
- Volume :
- 56
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Clinical pharmacokinetics
- Publication Type :
- Academic Journal
- Accession number :
- 28353055
- Full Text :
- https://doi.org/10.1007/s40262-017-0535-3