A therapeutic drug monitoring algorithm for refining the imatinib trough level obtained at different sampling times.
BACKGROUND
Correlation analyses have demonstrated that maintaining an adequate imatinib (IM) trough concentration would be important for clinical response in patients with chronic myeloid leukemia (CML) and Kit-positive gastrointestinal stromal tumors. The objectives of the current work were to use a pharmacokinetic model to refine the trough levels obtained at different sampling times and to propose a therapeutic drug monitoring algorithm and an acceptable sampling time window for imatinib trough sampling.


METHODS
The pharmacokinetics of IM in patients (pts) with CML were characterized based on historical data from a Phase III study. In the elimination phase the concentration of IM (C(t)) follows a mono-exponential decline, and the standardized trough concentration (C(min,std) = C(tau)) can be described by a simple algorithm C(min,std) = C(t)* exp(k(e) x Delta t), where Delta t = t - tau, and tau is 24 hours for qd or 12 hours for bid dosing and k(e) is the elimination rate constant. The percent deviation of C(t) from C(min,std) was simulated for different Delta t and k(e) values to define a sampling time window Delta t, within which the percent deviation is <20%.


RESULTS
Simulation analysis shows that C(t) is largely dependent on Delta t and k(e). The percent deviation of C(t) at 3 hours before or after tau from C(min,std) will be 7.1%, 13.1%, and 23.4% for pts with low, typical, and high k(e) values, 0.023/hour, 0.041/hour, and 0.070/hour, respectively. However, if a correction is made for C(t) by the algorithm using the typical k(e) value of 0.041 per hour, the percent deviation at 3 hours will be reduced to 5.3%, 0%, and 9.1% for pts with low, typical, and high k(e) values, respectively. Even if the sampling window is extended to +/-6 hours, the corresponding percent deviation will still be reasonable: 10.2%, 0%, and 19.0%, respectively.


CONCLUSIONS
By using the algorithm, the pharmacokinetic sampling window can be extended to a wider window to make the trough sampling easy to implement in the clinical setting, provided that the sampling time and dosing time are accurately recorded.
Wang
Yanfeng
Y
Clinical Pharmacology Oncology, , Novartis Pharmaceuticals Corporation, Florham Park, New Jersey 07932, USA. yanfeng.wang@novartis.com
Chia
Yen Lin
YL
Nedelman
Jerry
J
Schran
Horst
H
Mahon
Francois-Xavier
FX
Molimard
Mathieu
M
D000465:Algorithms; D001549:Benzamides; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D017277:Drug Approval; D016903:Drug Monitoring; D006801:Humans; D000068877:Imatinib Mesylate; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016030:Kidney Transplantation; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology*
D001549:Benzamides; D007166:Immunosuppressive Agents; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D051544:Cytochrome P-450 CYP3A; D011505:Protein-Tyrosine Kinases