ABCB1 C3435T Genetic Polymorphism on Population Pharmacokinetics of Methotrexate After Hematopoietic Stem Cell Transplantation in Korean Patients: A Prospective Analysis

• Published in: Clinical therapeutics Vol. 34; no. 8; pp. 1816 - 1826
• Main Authors: Kim, In-Wha, PhD, Yun, Hwi-yeol, PhD, Choi, Boyoon, MS, Han, Nayoung, MS, Park, Seon-Yang, MD, PhD, Lee, Eun Sook, PharmD, Oh, Jung Mi, PharmD
• Format: Journal Article
• Language: English
• Published: Bridgewater, NJ EM Inc USA 01.08.2012; Elsevier; Elsevier Limited
• Subjects: Adolescent; Adult; Anti-Bacterial Agents - therapeutic use; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Blood diseases; Bone marrow; Chi-Square Distribution; Drug Interactions; Female; Genotype; Glomerular Filtration Rate; Graft vs Host Disease - etiology; Graft vs Host Disease - prevention & control; hematopoietic stem cell transplantation; Hematopoietic Stem Cell Transplantation - adverse effects; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - blood; Immunosuppressive Agents - pharmacokinetics; Internal Medicine; Leukemia; Male; Medical Education; Medical sciences; Metabolic Clearance Rate; methotrexate; Methotrexate - administration & dosage; Methotrexate - blood; Methotrexate - pharmacokinetics; Middle Aged; Models, Biological; nonlinear mixed-effect modeling (NONMEM); Penicillins - therapeutic use; pharmacogenetics; Pharmacology. Drug treatments; Phenotype; Polymorphism, Genetic; population pharmacokinetics; Prospective Studies; Republic of Korea; Stem cells; Studies; Transplants & implants; Treatment Outcome; Young Adult; Asia; Korea; hematopoietic stem cell transplantation; methotrexate; nonlinear mixed-effect modeling (NONMEM); pharmacogenetics; population pharmacokinetics; Antineoplastic agent; Human; Population pharmacokinetics; Pharmacogenetics; Genetic variability; Stem cell; Hematopoietic cell; Genotype; Modeling; Antifolate; Prospective; Antimetabolic; Mixed; Genetics; Methotrexate; Hematopoietic stem cell transplantation; Polymorphism
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2012.06.022

Abstract Background Methotrexate (MTX) is often used to prevent graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). However, MTX has great pharmacokinetic variability and its use can result in fatal complications and/or infections after HSCT. Objectives The purposes of this study were to build a population pharmacokinetic model of MTX treatment in Korean patients who have undergone HSCT and to identify covariates, including genetic polymorphisms, that affect the pharmacokinetic properties of MTX. Methods Clinical characteristics and MTX concentration data for 20 post-HSCT patients were collected. For each patient, ABCB1 , ABCC2 , ATIC , GGH , MTHFR , and TYMS genotyping was performed. Population pharmacokinetic analysis was performed using the NONMEM program. Analysis of MTX pharmacokinetic properties was accomplished using a 2-compartment pharmacokinetic model that incorporated first-order conditional estimation methods with interaction. The effects of a variety of demographic and genetic factors on MTX disposition were investigated. Results The study population consisted of 12 men (60%) and 8 women (40%). Median age and body weight were 28 years (range, 18–49 years) and 55.6 kg (range, 44.8–80.8 kg), respectively. Within the study population, the estimated mean MTX clearance (CL) was 7.08 L/h, whereas the mean central compartment volume (V1 ) of MTX distribution was 19.4 L. MTX CL was significantly affected by glomerular filtration rate (GFR), penicillin use, and the ABCB1 3435 genotype. Interindividual variabilities for CL and V1 were 21.6% and 73.3%. A 10-mL/min GFR increase was associated with a 32% increase in mean MTX CL, whereas penicillin use was associated with a decrease in MTX CL of 61%. MTX CL was significantly greater (by ∼21%) in patients with the ABCB1 3435 CC and CT genotype than in those with the ABCB1 3435 TT genotype ( P < 0.001). Conclusions There was great interindividual variation in MTX pharmacokinetic properties in patients who had undergone HSCT. GFR, concurrent penicillin use, and the presence of the ABCB1 3435 C<T genotypes significantly affected MTX CL. The MTX population pharmacokinetic model developed here may provide useful information for individualizing MTX therapy after HSCT.