Therapeutic Drug Monitoring for Precision Dosing of Janus Kinase Inhibitors: Protocol for a Prospective Observational Study.

Background: Janus kinase inhibitors (JAKIs) are small molecules used orally to treat inflammatory and hematological disorders. They have demonstrated impressive efficacy across multiple indications. However, concerns have emerged regarding their safety profile. Despite their growing clinical use, therapeutic drug monitoring is not yet established for JAKIs, but it could help address exposure-dependent efficacy and tolerability issues through individualized treatment approaches.

Objective: This protocol aims to characterize the pharmacokinetics of the 6 most prescribed JAKIs in Switzerland (abrocitinib, baricitinib, fedratinib, ruxolitinib, tofacitinib, and upadacitinib) and identify factors influencing drug exposure. It seeks to explore exposure-response relationships to assess the impact of drug exposure markers on efficacy and safety. Ultimately, these findings will contribute to establishing therapeutic intervals.

Methods: This prospective observational study, conducted throughout Switzerland, was approved by the Cantonal Ethics Committee in August 2023. Consenting adults (aged ≥18 years) who are capable of judgment and who are prescribed JAKIs are enrolled in the study, either for sparse sampling during routine medical visits to collect trough or random plasma concentrations or for a detailed pharmacokinetic substudy involving serial blood sampling over an 8-hour period. The characterization of JAKI pharmacokinetics, including associated variability and the effect of specific covariates, such as age, body weight, BMI, sex, disease type, drug-drug interactions, or concomitant pathophysiological conditions, will be performed using nonlinear mixed effect modeling techniques. Relationships between JAKI exposure and efficacy and safety will be assessed.

Results: By August 2024, a total of 276 blood samples were collected from 107 patients, the majority being female individuals (n=62, 57.9%). The patients had a median age of 51 (range 17-87) years and a median body weight of 69 (range 39-132) kg. Most patients recruited were taking ruxolitinib (n=44, 41.1%), upadacitinib (n=39, 36.4%), or baricitinib (n=11, 10.3%).

Conclusions: The framework of the study will allow the characterization of the pharmacokinetic profiles of JAKIs and their variability in real-world conditions. On the basis of novel therapeutic drug monitoring approaches, we expect to explore the relationship between drug exposure, treatment response, and tolerability, providing essential information for precise dose optimization.

International Registered Report Identifier (irrid): RR1-10.2196/70312.