Received for publication September 6, 2005.
Revised November 28, 2005.
Accepted for publication November 29, 2005.

Evaluation of Microdosing to Assess Pharmacokinetic Linearity in Rats using LC/MS/MS

Abstract

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 LC/MS/MS technology for oral microdosing assessment in rats, a commonly used preclinical species. The non-labeled drugs fluconazole and tolbutamide were studied due to their similar pharmacokinetics characteristics in rats and humans. We demonstrate that pharmacokinetics can be readily characterized by LC/MS/MS at microdose of 1 µg/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 1000-fold higher doses in rats for these drugs, which are known to show 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 on 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 where 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 employing traditional LC/MS/MS for microdose pharmacokinetic assessment in humans.

Key words: mass spectrometry, pharmacokinetics

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