Prediction of the pharmacokinetics of pemetrexed with a low test dose: A proof‐of‐concept study. Issue 2 (21st September 2022)

• Record Type: Journal Article
• Authors: Boosman, René J.; de Rouw, Nikki; Huitema, Alwin D. R.; Burgers, Jacobus A.; ter Heine, Rob
• Other Names: Rieder Michael guestEditor.; Likic Robert guestEditor.
• Is Part Of: British journal of clinical pharmacology. Volume 89:Issue 2(2023)
• Page Start: 699
• Page End: 704
• Publication Date: 2022-09-21
• Subjects: low test dose -- microdose -- NONMEM -- pemetrexed -- pharmacokinetics; Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.15520
• Languages: English
• ISSNs: 0306-5251

Abstract

Abstract : Purpose: Pemetrexed is a cytotoxic drug used for the treatment of lung cancer and mesothelioma. The use of a low test dosing of cytotoxic drugs may aid in dose individualization without causing harm. The aim of this proof‐of‐concept study was to assess if the pharmacokinetics (PKs) of a test dose could predict the PKs of a therapeutic pemetrexed dose. Methods: Ten patients received both a low test dose (100 μg) and a therapeutic dose of pemetrexed after which plasma concentrations pemetrexed were measured. PK analysis was performed by means of nonlinear mixed‐effects modelling. The predictive performances of test dose clearance and renal function towards a therapeutic dose were assessed. Results: The PKs of a pemetrexed test dose were best described by a one‐compartment model with linear elimination. A high variability in the administered dose was observed for the test dose, but not for the therapeutic dose. A statistically significant correlation between test dose clearance and therapeutic dose clearance was observed (Spearman's rho: 0.758, P = 0.02). The predictive performance of test dose clearance was worse than renal function: mean predictive error (+95% confidence interval [CI]) 53.9% (50.1‐57.6%) vs 19.4% (12.4‐26.4%) and normalized root‐mean square error (+95% CI) 57.8% (30.5‐85.1%) vs 25.7% (20.3‐31.0%). Conclusion: We show that test dosing of pemetrexed is feasible, but there seems no added value for a low test dosing in the dose individualization of pemetrexed.