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Optimal kinetic exposures for classic and candidate antitrypanosomals
Kirsten J Meyer1,2, David J Meyers2, Theresa A Shapiro1,2
1Division of Clinical Pharmacology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
The Journal of Antimicrobial Chemotherapy
|May 17, 2019
Summary
The shape of drug exposure, not just the dose, is crucial for antitrypanosomal efficacy. Some drugs work best in high, short bursts, while others need constant levels for maximum effect.
Area of Science:
- Pharmacology
- Parasitology
- Drug Discovery
Background:
- Drug efficacy depends on both dose and the temporal pattern of drug concentrations (pharmacokinetic profile).
- Understanding these pharmacokinetic drivers is essential for optimizing treatment and developing new antitrypanosomal agents.
Purpose of the Study:
- To investigate the impact of different drug exposure profiles on the efficacy of antitrypanosomal agents in vitro.
- To determine whether antitrypanosomals are concentration-driven or time-driven for optimal therapeutic effect.
Main Methods:
- Utilized an in vitro hollow-fibre cartridge system to simulate various drug exposure kinetics.
- Studied four clinically used antitrypanosomal drugs and two experimental candidates against Trypanosoma brucei.
- Artificially manipulated drug profiles to favor either high peak concentrations or sustained drug duration.
Main Results:
- Drug efficacy was significantly influenced by the shape of drug exposure.
- Suramin, melarsoprol, and pentamidine were concentration-driven, benefiting from high, short peaks.
- Difluoromethylornithine (DFMO) was time-driven, most effective as a constant infusion.
- New candidates like acoziborole and fexinidazole were also concentration-driven.
Conclusions:
- Antitrypanosomal drugs possess intrinsic pharmacokinetic drivers that dictate optimal efficacy.
- These findings have significant implications for the clinical management of trypanosomiasis and the design of future drug candidates.
- Tailoring drug regimens based on pharmacokinetic profiles can enhance treatment outcomes.
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