V Gotta(1,2), S Bouchet(3), N. Widmer(1), F-X Mahon(4), M Molimard(3), T Buclin(1), C Csajka(1,2)
(1) Division of Clinical Pharmacology, Department of Laboratory, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; (2) Department of Pharmaceutical Sciences, University of Lausanne and Geneva, Geneva, Switzerland; (3) Pharmacologie Clinique et Toxicologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France; (4) Hématopoïèse Leucémique et Cible Thérapeutique, Inserm U1035, Université Victor Ségalen, Bordeaux, France
Objectives: Imatinib has been increasingly proposed for therapeutic drug monitoring (TDM), as trough concentrations (Cmin) correlate with response rates in CML patients[1]. This analysis aimed to evaluate the impact of imatinib exposure on optimal molecular response[2] rates in a large European cohort of patients followed by centralized TDM[3].
Methods: Sequential PK/PD analysis was performed in NONMEM 7 on 2230 plasma (PK) samples obtained along with molecular response (PD) data from 1299 CML patients. Model-based individual Bayesian estimates of exposure, parameterized as to initial dose adjusted and log-normalized Cmin (log-Cmin) or clearance (CL), were investigated as potential predictors of optimal molecular response, while accounting for time under treatment (stratified at 3 years), gender, CML phase, age, potentially interacting comedication, and TDM frequency. PK/PD analysis used mixed-effect logistic regression (iterative two-stage method) to account for intra-patient correlation.
Results: In univariate analyses, CL, log-Cmin, time under treatment, TDM frequency, gender (all p<0.01) and CML phase (p=0.02) were significant predictors of the outcome. In multivariate analyses, all but log-Cmin remained significant (p<0.05). Our model estimates a 54.1% probability of optimal molecular response in a female patient with a median CL of 14.4 L/h, increasing by 4.7% with a 35% decrease in CL (percentile 10 of CL distribution), and decreasing by 6% with a 45% increased CL (percentile 90), respectively. Male patients were less likely than female to be in optimal response (odds ratio: 0.62, p<0.001), with an estimated probability of 42.3%.
Conclusions: Beyond CML phase and time on treatment, expectedly correlated to the outcome, an effect of initial imatinib exposure on the probability of achieving optimal molecular response was confirmed in field-conditions by this multivariate analysis. Interestingly, male patients had a higher risk of suboptimal response, which might not exclusively derive from their 18.5% higher CL, but also from reported lower adherence to the treatment[4]. A prospective longitudinal study would be desirable to confirm the clinical importance of identified covariates and to exclude biases possibly affecting this observational survey.
References:
[1] Teng JFT, Mabasa VH, Ensom MHH. The Role of Therapeutic Drug Monitoring of Imatinib in Patients with Chronic Myeloid Leukemia and Metastatic or Unresectable Gastrointestinal Stromal Tumors. Ther Drug Monit. 2012;34(1):85-97.
[2] Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27:6041-6051.
[3] European Treatment and Outcome Study for chronic myeloid leukemia (EUTOS for CML), Pharmacological monitoring project.
[4] Marin D, Bazeos A, Mahon FX, et al. Adherence Is the Critical Factor for Achieving Molecular Responses in Patients With Chronic Myeloid Leukemia Who Achieve Complete Cytogenetic Responses on Imatinib. Journal of Clinical Oncology. 2010;28:2381-2388.
Reference: PAGE 21 () Abstr 2504 [www.page-meeting.org/?abstract=2504]
Poster: Oncology