TY - JOUR
T1 - Women Administered Standard Dose Imatinib for Chronic Myeloid Leukemia Have Higher Dose-Adjusted Plasma Imatinib and Norimatinib Concentrations Than Men
AU - Belsey, Sarah L
AU - Ireland, Robin
AU - Lang, Kathryn
AU - Kizilors, Aytug
AU - Ho, Aloysius
AU - Mufti, Ghulam J
AU - Bisquera, Alessandra
AU - De Lavallade, Hugues
AU - Flanagan, Robert J
PY - 2017/10
Y1 - 2017/10
N2 - Background: The standard dose of imatinib for the treatment of chronic-phase chronic myeloid leukemia (CML) is 400 mg·d -1. A predose plasma imatinib concentration of >1 mg·L -1 is associated with improved clinical response. This study aimed to assess the plasma imatinib and norimatinib concentrations attained in patients with chronic myeloid leukemia administered standard doses of imatinib adjusted for dose, age, sex, body weight, and response. Methods: We evaluated data from a cohort of patients treated between 2008 and 2014 with respect to dose, age, sex, body weight, and response. Results: The study comprised 438 samples from 93 patients (54 male, 39 female). The median imatinib dose was 400 mg·d -1 in men and in women. The plasma imatinib concentration ranged 0.1-5.0 mg·L -1 and was below 1 mg·L -1 in 20% and 16% of samples from men and women, respectively. The mean dose normalized plasma imatinib and norimatinib concentrations were significantly higher in women in comparison with men. This was partially related to body weight. Mixed effects ordinal logistic regression showed no evidence of an association between sex and plasma imatinib (P = 0.13). However, there was evidence of an association between sex and plasma norimatinib, with higher norimatinib concentrations more likely in women than in men (P = 0.02). Conclusions: Imatinib therapeutic drug monitoring only provides information on dosage adequacy and on short-term adherence; longer-term adherence cannot be assessed. However, this analysis revealed that approximately 1 in 5 samples had a plasma imatinib concentration <1 mg·L -1, which was suggestive of inadequate dosage and/or poor adherence and posed a risk of treatment failure. Higher imatinib exposure in women may be a factor in the increased rate of long-term, stable, deep molecular response (undetectable breakpoint cluster-Abelson (BCR-ABL) transcript levels with a PCR sensitivity of 4.5 log, MR4.5) reported in women.
AB - Background: The standard dose of imatinib for the treatment of chronic-phase chronic myeloid leukemia (CML) is 400 mg·d -1. A predose plasma imatinib concentration of >1 mg·L -1 is associated with improved clinical response. This study aimed to assess the plasma imatinib and norimatinib concentrations attained in patients with chronic myeloid leukemia administered standard doses of imatinib adjusted for dose, age, sex, body weight, and response. Methods: We evaluated data from a cohort of patients treated between 2008 and 2014 with respect to dose, age, sex, body weight, and response. Results: The study comprised 438 samples from 93 patients (54 male, 39 female). The median imatinib dose was 400 mg·d -1 in men and in women. The plasma imatinib concentration ranged 0.1-5.0 mg·L -1 and was below 1 mg·L -1 in 20% and 16% of samples from men and women, respectively. The mean dose normalized plasma imatinib and norimatinib concentrations were significantly higher in women in comparison with men. This was partially related to body weight. Mixed effects ordinal logistic regression showed no evidence of an association between sex and plasma imatinib (P = 0.13). However, there was evidence of an association between sex and plasma norimatinib, with higher norimatinib concentrations more likely in women than in men (P = 0.02). Conclusions: Imatinib therapeutic drug monitoring only provides information on dosage adequacy and on short-term adherence; longer-term adherence cannot be assessed. However, this analysis revealed that approximately 1 in 5 samples had a plasma imatinib concentration <1 mg·L -1, which was suggestive of inadequate dosage and/or poor adherence and posed a risk of treatment failure. Higher imatinib exposure in women may be a factor in the increased rate of long-term, stable, deep molecular response (undetectable breakpoint cluster-Abelson (BCR-ABL) transcript levels with a PCR sensitivity of 4.5 log, MR4.5) reported in women.
KW - Journal Article
UR - http://www.scopus.com/inward/record.url?scp=85032273991&partnerID=8YFLogxK
U2 - 10.1097/FTD.0000000000000440
DO - 10.1097/FTD.0000000000000440
M3 - Article
C2 - 28767619
SN - 0163-4356
VL - 39
SP - 499
EP - 504
JO - Therapeutic Drug Monitoring
JF - Therapeutic Drug Monitoring
IS - 5
ER -