Simulation of the Impact of Atropisomer Interconversion on Plasma Exposure of Atropisomers of an Endothelin Receptor Antagonist

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Abstract

BMS-207940, a potent endothelin receptor antagonist, exists as rapidly interconverting atropisomers. The plasma interconversion t1/2 is ∼2.5 hours at 400 μg/mL under room temperature and decreases to < 0.1 hours at 20 μg/mL, making it extremely difficult to conduct pharmacokinetic studies of individual atropisomers. The pharmacokinetics of the 50/50 racemate of BMS-207940 in humans were reasonably described by a one-compartmental model with an apparent terminal elimination t1/2 of 15 hours. Given the above rates, simulations were conducted based on a one-compartmental model to explore the possible range of individual rates of atropisomer elimination and potential difference in plasma exposure to the two atropisomers. Simulations demonstrated that the elimination rates of the individual atropisomers are bounded between 0 and 0.046 h−1 and between 0.046 and 0.092 h−1, respectively. The estimation of the upper bounds for atropisomer elimination rate constants is robust and relatively insensitive to the rate of atropisomer interconversion compared to the rate of racemate elimination. Simulations of the administration of a single atropisomer or the 50/50 racemate, based on all the possible scenarios of individual atropisomer elimination, showed little difference in plasma exposure to the two atropisomers. Potential differences in plasma exposure to the two atropisomers depend, to a larger extent, on the ratio of the rate of atropisomer interconversion versus racemate elimination and, to a lesser extent, on the conformation of atropisomers administered. When atropisomer interconversion is 10-fold or more rapid than racemate elimination, the largest possible difference in plasma exposure between the two atropisomers is below 20%, regardless of the route and conformation of the atropisomer(s) administered.

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