Evaluation of microdosing to assess pharmacokinetic linearity in rats using liquid chromatography-tandem mass spectrometry.
The microdosing strategy allows for early assessment of human pharmacokinetics of new chemical entities using more limited safety assessment requirements than those requisite for a conventional phase I program. The current choice for evaluating microdosing is accelerator mass spectrometry (AMS) due to its ultrasensitivity for detecting radiotracers. However, the AMS technique is still expensive to be used routinely and requires the preparation of radiolabeled compounds. This report describes a feasibility study with conventional liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology for oral microdosing assessment in rats, a commonly used preclinical species. The nonlabeled drugs fluconazole and tolbutamide were studied because of their similar pharmacokinetics characteristics in rats and humans. We demonstrate that pharmacokinetics can be readily characterized by LC-MS/MS at a microdose of 1 microg/kg for these molecules in rats, and, hence, LC-MS/MS should be adequate in human microdosing studies. The studies also exhibit linearity in exposure between the microdose and >or=1000-fold higher doses in rats for these drugs, which are known to show a linear dose-exposure relationship in the clinic, further substantiating the potential utility of LC-MS/MS in defining pharmacokinetics from the microdose of drugs. These data should increase confidence in the use of LC-MS/MS in microdose pharmacokinetics studies of new chemical entities in humans. Application of this approach is also described for an investigational compound, MLNX, in which the pharmacokinetics in rats were determined to be nonlinear, suggesting that MLNX pharmacokinetics at microdoses in humans also might not reflect those at the therapeutic doses. These preclinical studies demonstrate the potential applicability of using traditional LC-MS/MS for microdose pharmacokinetic assessment in humans.
Balani
Suresh K
SK
DMPK, Drug Safety & Disposition, Millennium Pharmaceuticals, Inc., 45 Sidney Street, Cambridge, MA 02139, USA. suresh.balani@mpi.com
Nagaraja
Nelamangala V
NV
Qian
Mark G
MG
Costa
Arnaldo O
AO
Daniels
J Scott
JS
Yang
Hua
H
Shimoga
Prakash R
PR
Wu
Jing-Tao
JT
Gan
Liang-Shang
LS
Lee
Frank W
FW
Miwa
Gerald T
GT
D000818:Animals; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D016014:Linear Models; D008297:Male; D013058:Mass Spectrometry; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000097:blood*; D010599:Pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D004364:Pharmaceutical Preparations