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Preliminary animal pharmacokinetics of the parenteral antifungal agent MK-0991 (L-743,872)
R Hajdu1, R Thompson, J G Sundelof
1Antibiotic Discovery and Development, Merck Research Laboratories, Rahway, New Jersey 07065-0900, USA. richard_hajdu@merck.com
Abstract:
MK-0991 (L-743,872) is a potent antifungal agent featuring long half-life pharmacokinetics. The pharmacokinetics of MK-0991 administered intravenously to mice, rats, rhesus monkeys, and chimpanzees is presented. Unique to MK-0991 is its consistent cross-species performance. The range of values for the pharmacokinetic parameters were as follows: clearance, 0.26 to 0.51 ml/min/kg; half-life, 5.2 to 7.6 h; and distributive volume, 0.11 to 0.27 liters/kg. The level of protein binding of MK-0991 was determined to be 96% in mouse and human serum. The compound exhibited high affinities for human serum albumin and at least two lipid components. The rationale for the selection of MK-0991 as a drug development candidate was based on its two- to threefold superior pharmacokinetic performance in chimpanzees over the performance of an otherwise equivalent analog, L-733,560. Once-daily dosing for MK-0991 is indicated by a graphical comparison of levels in the circulations of chimpanzees and mice. In a study of the pharmacokinetics of MK-0991 in mouse tissue, the organs were assayed following intraperitoneal administration. The area under the concentration-versus-time curves (AUC) segregated the tissues into three exposure categories relative to plasma. The tissues with greater exposure than that for plasma were liver (16 times), kidney (3 times), and large intestine (2 times). The exposure for small intestine, lung, and spleen were equivalent to that for plasma. Organs with lower levels of exposure were the heart (0.3 times that for plasma), thigh (0.2 times), and brain (0.06 times). Kinetically, drug was cleared more slowly from all tissues than from plasma, indicating that terminal-phase equilibrium had not been achieved by 24 h. Thus, some measure of accumulation is predicted for all tissues. Single daily doses of MK-0991 should provide adequate systemic levels of fungicidal activity as a result of its long half-life pharmacokinetics, wide distribution, and slowly accumulating concentrations in tissue.
Insights
MK-0991, a potent antifungal, shows consistent pharmacokinetics across species. Its long half-life and tissue accumulation support once-daily dosing for effective fungicidal activity.
Area of Science:
- Pharmacology
- Pharmacokinetics
- Antifungal Agents
Background:
- MK-0991 (L-743,872) is a potent antifungal agent.
- Its pharmacokinetic profile is characterized by a long half-life.
Purpose of the Study:
- To present the pharmacokinetics of MK-0991 in mice, rats, rhesus monkeys, and chimpanzees.
- To evaluate cross-species performance and tissue distribution for drug development.
Main Methods:
- Intravenous administration of MK-0991 in various animal models.
- Analysis of pharmacokinetic parameters including clearance, half-life, and distributive volume.
- Assessment of protein binding and tissue distribution via AUC analysis.
Main Results:
- Consistent cross-species pharmacokinetic performance observed for MK-0991.
- Pharmacokinetic parameters: clearance (0.26-0.51 ml/min/kg), half-life (5.2-7.6 h), distributive volume (0.11-0.27 L/kg).
- High protein binding (96%) and varied tissue distribution, with higher concentrations in liver, kidney, and large intestine.
Conclusions:
- MK-0991 demonstrates favorable pharmacokinetic properties for drug development.
- Its long half-life, wide distribution, and predicted tissue accumulation support once-daily dosing.
- MK-0991 is a promising candidate for achieving adequate systemic fungicidal activity.