Large-scale imatinib dose-concentration-effect study in CML patients under routine care conditions.
This observational study analyzed imatinib pharmacokinetics and response in 2478 chronic myeloid leukemia (CML) patients. Data were obtained through centralized therapeutic drug monitoring (TDM) at median treatment duration of ≥ 2 years. First, individual initial trough concentrations under 400mg/day imatinib starting dose were estimated. Second, their correlation (Cmin(400mg)) with reported treatment response was verified. Low imatinib levels were predicted in young male patients and those receiving P-gp/CYP3A4 inducers. These patients had also lower response rates (7% lower 18-months MMR in male, 17% lower 1-year CCyR in young patients, Kaplan-Meier estimates). Time-point independent multivariate regression confirmed a correlation of individual Cmin(400mg) with response and adverse events. Possibly due to confounding factors (e.g. dose modifications, patient selection bias), the relationship seemed however flatter than previously reported from prospective controlled studies. Nonetheless, these observational results strongly suggest that a subgroup of patients could benefit from early dosage optimization assisted by TDM, because of lower imatinib concentrations and lower response rates.
Division of Clinical Pharmacology, Service of Biomedicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
Verena
V
Gotta
Department of Clinical Pharmacology and Toxicology, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.
Stephane
S
Bouchet
Division of Clinical Pharmacology, Service of Biomedicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
Nicolas
N
Widmer
Novartis Oncology Region Europe, Milan, Italy.
Peter
P
Schuld
Laboratory of Clinical Pharmacology, Innovation & Development Unit, Service of Biomedicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
Laurent A
LA
Decosterd
Division of Clinical Pharmacology, Service of Biomedicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
Thierry
T
Buclin
Laboratoire Hématopoïèse Leucémique et Cible Thérapeutique, Université Victor Ségalen Bordeaux 2, Bordeaux, France.
Francois-Xavier
FX
Mahon
Division of Clinical Pharmacology, Service of Biomedicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland. Electronic address: Chantal.Csajka@chuv.ch.
Chantal
C
Csajka
Novartis Oncology Region Europe, Milan, Italy.
Mathieu
M
Molimard
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001549:Benzamides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate
Chronic myelogenous leukemia; Dose–response relationship; Drug monitoring; Pharmacodynamics; Pharmacokinetics; Therapeutic drug monitoring; Tyrosine kinase inhibitor