The pharmacokinetics of letrozole: association with key body mass metrics.
OBJECTIVE
To characterize the pharmacokinetics (PK) of letrozole by noncompartmental and mixed effect modeling analysis with the exploration of effect of body compositions on the PK.


METHODS
The PK data of 52 normal healthy male subjects with intensive PK sampling from two separate studies were included in this analysis. Subjects were given a single oral administration of 2.5 mg letrozole (Femara®), an antiestrogenic aromatase inhibitor used to treat breast cancer. Letrozole concentrations were measured using validated high-performance liquid chromatography with tandem mass spectrometry. PK analysis was performed using NONMEM® 7.2 with first-order conditional estimation with interaction method. The association of body composition (body mass index, soft lean mass, fat free mass, body fat mass), CYP2A6 genotype (*1/*1, *1/*4), and CYP3A5 genotype (*1/*1, *1/*3, *3/*3) with the PK of letrozole were tested.


RESULTS
A two-compartment model with mixed first and zero order absorption and first order elimination best described the letrozole concentration-time profile. Body weight and body fat mass were significant covariates for central volume of distribution and peripheral volume of distribution (Vp), respectively. In another model built using more readily available body composition measures, body mass index was also a significant covariate of Vp. However, no significant association was shown between CYP2A6 and CYP3A5 genetic polymorphism and the PK of letrozole in this study.


CONCLUSIONS
Our results indicate that body weight, body fat mass, body mass index are associated with the volume of distribution of letrozole. This study provides an initial step toward the development of individualized letrozole therapy based on body composition.
Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Pungnap-2-dong, Seoul, Repubic of South Korea.
Seok-Joon
SJ
Jin
Jin Ah
JA
Jung
Sang-Heon
SH
Cho
Un-Jib
UJ
Kim
Sangmin
S
Choe
Jong-Lyul
JL
Ghim
Yook-Hwan
YH
Noh
Hyun-Jung
HJ
Park
Jung-Chul
JC
Kim
Jin-A
JA
Jung
Hyeong-Seok
HS
Lim
Kyun-Seop
KS
Bae
D000328:Adult; D047072:Aromatase Inhibitors / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001823:Body Composition; D065637:Cytochrome P-450 CYP2A6; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005838:Genotype; D006801:Humans; D000077289:Letrozole; D008297:Male; D008954:Models, Biological; D009570:Nitriles / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic; D014230:Triazoles / Q000493:pharmacokinetics*
D047072:Aromatase Inhibitors; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C510164:CYP3A5 protein, human; D065637:Cytochrome P-450 CYP2A6; D051544:Cytochrome P-450 CYP3A