TY - JOUR
T1 - Explaining Interpatient Variability in Adalimumab Pharmacokinetics in Patients with Crohn's Disease
AU - Berends, Sophie E.
AU - Strik, Anne S.
AU - van Selm, Juliet C.
AU - Löwenberg, Mark
AU - Ponsioen, Cyriel Y.
AU - D'Haens, Geert R.
AU - Mathôt, Ron A.
PY - 2018
Y1 - 2018
N2 - Background: A significant proportion of patients with Crohn's disease (CD) require dose escalation or fail adalimumab (ADL) therapy over time. ADL, a monoclonal antibody directed against tumor necrosis factor, is approved for treatment of CD. Understanding pharmacokinetics (PK) of ADL is essential to optimize individual dosing in daily practice. The aim of this study was to evaluate PK of ADL in patients with CD and to identify factors that influence PK of ADL. Methods: In a retrospective cohort study, the authors reviewed the charts of 96 patients with CD receiving ADL induction and maintenance treatment. This patient cohort was used for external validation of population pharmacokinetic models of ADL available from literature. In addition, a novel population PK model was developed using nonlinear mixed-effects modeling. Results: None of the literature models properly described the PK of ADL in our cohort. Therefore, a novel population pharmacokinetic model was developed. Clearance of ADL increased 4-fold in the presence of anti-ADL antibodies. Patients who received ADL every week had a 40% higher clearance compared with patients receiving ADL every other week. Conclusions: Clearance of ADL increased in the presence of anti-ADL antibodies and was associated with weekly ADL administrations. In clinical practice, the decision to intensify ADL treatment to weekly administrations is primarily based on disease activity. Increased disease activity may be the result of lower drug concentrations due to higher clearance. However, increased disease activity may also increase clearance due to increased target engagement. The causal relationship between these factors remains to be elucidated.
AB - Background: A significant proportion of patients with Crohn's disease (CD) require dose escalation or fail adalimumab (ADL) therapy over time. ADL, a monoclonal antibody directed against tumor necrosis factor, is approved for treatment of CD. Understanding pharmacokinetics (PK) of ADL is essential to optimize individual dosing in daily practice. The aim of this study was to evaluate PK of ADL in patients with CD and to identify factors that influence PK of ADL. Methods: In a retrospective cohort study, the authors reviewed the charts of 96 patients with CD receiving ADL induction and maintenance treatment. This patient cohort was used for external validation of population pharmacokinetic models of ADL available from literature. In addition, a novel population PK model was developed using nonlinear mixed-effects modeling. Results: None of the literature models properly described the PK of ADL in our cohort. Therefore, a novel population pharmacokinetic model was developed. Clearance of ADL increased 4-fold in the presence of anti-ADL antibodies. Patients who received ADL every week had a 40% higher clearance compared with patients receiving ADL every other week. Conclusions: Clearance of ADL increased in the presence of anti-ADL antibodies and was associated with weekly ADL administrations. In clinical practice, the decision to intensify ADL treatment to weekly administrations is primarily based on disease activity. Increased disease activity may be the result of lower drug concentrations due to higher clearance. However, increased disease activity may also increase clearance due to increased target engagement. The causal relationship between these factors remains to be elucidated.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85053896132&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29529008
U2 - https://doi.org/10.1097/FTD.0000000000000494
DO - https://doi.org/10.1097/FTD.0000000000000494
M3 - Article
C2 - 29529008
SN - 0163-4356
VL - 40
SP - 202
EP - 211
JO - Therapeutic drug monitoring
JF - Therapeutic drug monitoring
IS - 2
ER -