Your browser doesn't support javascript.
Elevated acute phase proteins affect pharmacokinetics in COVID-19 trials: Lessons from the CounterCOVID - imatinib study.
Bartelink, Imke H; Bet, Pierre M; Widmer, Nicolas; Guidi, Monia; Duijvelaar, Erik; Grob, Bram; Honeywell, Richard; Evelo, Amanda; Tielbeek, Ivo P E; Snape, Sue D; Hamer, Henrike; Decosterd, Laurent A; Jan Bogaard, Harm; Aman, Jurjan; Swart, Eleonora L.
  • Bartelink IH; Department of Clinical Pharmacology and Pharmacy, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands.
  • Bet PM; Department of Clinical Pharmacology and Pharmacy, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands.
  • Widmer N; Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
  • Guidi M; Specialised Centre for Emergency and Disaster Pharmacy, Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland.
  • Duijvelaar E; Pharmacy of the Eastern Vaud Hospitals, Rennaz, Switzerland.
  • Grob B; Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
  • Honeywell R; Center for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
  • Evelo A; Department of Pulmonary Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands.
  • Tielbeek IPE; Department of Clinical Pharmacology and Pharmacy, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands.
  • Snape SD; Department of Clinical Pharmacology and Pharmacy, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands.
  • Hamer H; Department of Clinical Pharmacology and Pharmacy, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands.
  • Decosterd LA; Department of Clinical Pharmacology and Pharmacy, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands.
  • Jan Bogaard H; Exvastat Ltd., Cambridge, UK.
  • Aman J; Department of Clinical Chemistry, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands.
  • Swart EL; Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
CPT Pharmacometrics Syst Pharmacol ; 10(12): 1497-1511, 2021 12.
Article in English | MEDLINE | ID: covidwho-1449945
ABSTRACT
This study aimed to determine whether published pharmacokinetic (PK) models can adequately predict the PK profile of imatinib in a new indication, such as coronavirus disease 2019 (COVID-19). Total (bound + unbound) and unbound imatinib plasma concentrations obtained from 134 patients with COVID-19 participating in the CounterCovid study and from an historical dataset of 20 patients with gastrointestinal stromal tumor (GIST) and 85 patients with chronic myeloid leukemia (CML) were compared. Total imatinib area under the concentration time curve (AUC), maximum concentration (Cmax ) and trough concentration (Ctrough ) were 2.32-fold (95% confidence interval [CI] 1.34-3.29), 2.31-fold (95% CI 1.33-3.29), and 2.32-fold (95% CI 1.11-3.53) lower, respectively, for patients with CML/GIST compared with patients with COVID-19, whereas unbound concentrations were comparable among groups. Inclusion of alpha1-acid glycoprotein (AAG) concentrations measured in patients with COVID-19 into a previously published model developed to predict free imatinib concentrations in patients with GIST using total imatinib and plasma AAG concentration measurements (AAG-PK-Model) gave an estimated mean (SD) prediction error (PE) of -20% (31%) for total and -7.0% (56%) for unbound concentrations. Further covariate modeling with this combined dataset showed that in addition to AAG; age, bodyweight, albumin, CRP, and intensive care unit admission were predictive of total imatinib oral clearance. In conclusion, high total and unaltered unbound concentrations of imatinib in COVID-19 compared to CML/GIST were a result of variability in acute phase proteins. This is a textbook example of how failure to take into account differences in plasma protein binding and the unbound fraction when interpreting PK of highly protein bound drugs, such as imatinib, could lead to selection of a dose with suboptimal efficacy in patients with COVID-19.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Acute-Phase Proteins / Protein Kinase Inhibitors / Imatinib Mesylate / COVID-19 Type of study: Controlled clinical trial / Prognostic study / Randomized controlled trials Limits: Aged / Female / Humans / Male / Middle aged Language: English Journal: CPT Pharmacometrics Syst Pharmacol Year: 2021 Document Type: Article Affiliation country: Psp4.12718

Similar

MEDLINE

...
LILACS

LIS


Full text: Available Collection: International databases Database: MEDLINE Main subject: Acute-Phase Proteins / Protein Kinase Inhibitors / Imatinib Mesylate / COVID-19 Type of study: Controlled clinical trial / Prognostic study / Randomized controlled trials Limits: Aged / Female / Humans / Male / Middle aged Language: English Journal: CPT Pharmacometrics Syst Pharmacol Year: 2021 Document Type: Article Affiliation country: Psp4.12718