Medhat M. Said1,2, J Delgado San Martin3, AMK Rothman4, S Villar5,6, J Aman7,8, EL Swart1,2,9, RAA Mathot1, MR Wilkins3, IH Bartelink1,2
1Department of Pharmacy and Clinical Pharmacology, Amsterdam UMC, location VUmc, 2Cancer Center Amsterdam, 3Imperial College London, Hammersmith Hospital , 4Department of Infection, Immunity and Cardiovascular Disease, The Medical School Sheffield, 5MRC Biostatistics Unit, University of Cambridge, 6Papworth Trials Unit Collaboration, Royal Papworth Hospital NHS Foundation Trust, 7Department of Pulmonary Medicine, Amsterdam UMC, location VUmc, 8Amsterdam Cardiovascular Sciences, 9Amsterdam Institute for Infection and Immunity
Introduction: Pulmonary arterial hypertension (PAH) is a rare and progressive disease marked by increased mean pulmonary artery pressure, often leading to right heart failure. Repurposing imatinib for PAH has been of interest due to its role in modulating pathways involved in this condition, such as platelet-derived growth factor receptor (PDGFR) inhibition and c-kit [1]. Despite imatinib treatment showing clinical benefits (IMPRES trial [2]), regulatory approval of imatinib for PAH patients has been hampered by its safety profile, notably frequent adverse events (AE) and high rates of drug discontinuation (57%). A dry powder inhaled formulation of imatinib was developed to reduce AEs while reaching therapeutically relevant imatinib concentrations in the lungs (IMPAHCT trial [3]). Nevertheless, no meaningful clinical improvements were found and further development has been halted. However, the optimal dose for efficacy and toxicity in PAH has not been well explored, and previous attempts with local delivery have proven ineffective. Therefore, an adaptive dose-finding study (PIPAH trial [1]) was carried out to explore tolerability and safety of oral imatinib doses between 100-400 mg QD. The dosing protocol in this study was designed according to a continuous reassessment method, aimed at achieving the maximum tolerated dose for each patient. Oral imatinib has shown promising efficacy, but we need to better understand the safety risks. In this study, we applied repeated time-to-event (RTTE) modelling to characterize the occurrence of adverse events in the PIPAH trial, providing a framework for refining dosing strategies for imatinib in PAH patients. Objectives: •Characterize the relationship between imatinib exposure and adverse events in PIPAH patients •Evaluate the impact of dose modifications and risk of different dosing regimens Methods: In the open-label, multicentre, adaptive phase I/II PIPAH study, patients with symptomatic PAH were given 100, 200, 300, or 400 mg imatinib QD according to a single-dose escalation protocol for a maximum of 24 weeks [1]. Clinicians were allowed to modify and/or interrupt the dose according to clinical need. At steady-state, plasma samples were taken 2, 4, 6, and 8 hours after administration of the daily dose of imatinib to measure total and unbound imatinib concentrations. For exposure, daily area-under-the-curve at steady-state (AUCss) were computed for total imatinib and unbound imatinib. AUCss was derived based on the maximum a posteriori estimates of the individual pharmacokinetic model parameters and daily dosing history using a previously developed PK model [4]. All adverse events were reported and graded based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). A longitudinal parametric survival analysis was performed using interval-censored RTTE models to describe the time to an adverse event. Model parameters were estimated in NONMEM 7.4 with Pirana, PsN and and ggplot2 libraries for R 4.2.3. Exponential, Gompertz, Weibull, and log-logistic distributions were investigated as hazard models. Linear, exponential, and Emax models were tested for the dose/exposure-response relationship using daily dose or daily AUCss. Visual Predictive Check of Kaplan Meier survival curves as well as objective function value were used to evaluate the model fit. Results: Fifteen patients out of seventeen patients from the PIPAH study, for whom PK samples were measured, were included in the modeling. One patient received a starting dose of 100 mg, four received 200 mg, seven received 300 mg, and three received 400 mg. The average AAG concentration was 0.79 g/L. Dose interruptions occurred in 4 patients, two at week 4 follow up. Two patients, one on 400 mg and one on 300 mg, restarted after a break on a lower dose. Longitudinal AE data were well-modeled by a log-logistic RTTE model. Inclusion of AUCss improved the model fit significantly compared to daily dose (?OFV -13.1 vs -2.6). Total imatinib AUCss using an Emax model was the best predictor of AEs, with an EC50 of 4350 µg*h/L CV (260.4 %). Visual inspection indicated that AEs were more likely to occur at 400 mg daily dose in the first 4 weeks. Conclusions: Our proposed PK-RTTE model accurately predicted the observed AEs in patients included in the PIPAH trial, evaluating the toxicity risk of multiple dosing regimen of oral imatinib, including dose modifications.
(1) Wilkins, M. R., Mckie, M. A., Law, M., Roussakis, A. A., Harbaum, L., Church, C., Coghlan, J. G., Condliffe, R., Howard, L. S., Kiely, D. G., Lordan, J., Rothman, A., Suntharalingam, J., Toshner, M., Wort, S. J., & Villar, S. S. (2021). Positioning imatinib for pulmonary arterial hypertension: A phase I/II design comprising dose finding and single-arm efficacy. Pulmonary circulation, 11(4), 20458940211052823. https://doi.org/10.1177/20458940211052823 (2) Hoeper, M. M., Barst, R. J., Bourge, R. C., Feldman, J., Frost, A. E., Galié, N., Gómez-Sánchez, M. A., Grimminger, F., Grünig, E., Hassoun, P. M., Morrell, N. W., Peacock, A. J., Satoh, T., Simonneau, G., Tapson, V. F., Torres, F., Lawrence, D., Quinn, D. A., & Ghofrani, H. A. (2013). Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation, 127(10), 1128–1138. https://doi.org/10.1161/CIRCULATIONAHA.112.000765 (3) Gillies, H., Chakinala, M. M., Dake, B. T., Feldman, J. P., Hoeper, M. M., Humbert, M., Jing, Z. C., Langley, J., McLaughlin, V. V., Niven, R. W., Rosenkranz, S., Zhang, X., & Hill, N. S. (2024). IMPAHCT: A randomized phase 2b/3 study of inhaled imatinib for pulmonary arterial hypertension. Pulmonary circulation, 14(1), e12352. https://doi.org/10.1002/pul2.12352 (4) Said, M. M., Schippers, J. R., Atmowihardjo, L., Li, Y., van der Plas, M. S., Bogaard, H. J., Bos, L. D. J., Mathôt, R. A. A., Aman, J., Swart, E. L., & Bartelink, I. H. (2025). Disease-Drug-Drug Interaction of Imatinib in COVID-19 ARDS: A Pooled Population Pharmacokinetic Analysis. CPT: pharmacometrics & systems pharmacology. https://doi.org/10.1002/psp4.13299
Reference: PAGE 33 (2025) Abstr 11655 [www.page-meeting.org/?abstract=11655]
Poster: Drug/Disease Modelling - Safety