Experimental Validation of a Mathematical Framework to Simulate Antibiotics with Distinct Half-Lives Concurrently in an In Vitro Model

Abstract

Antimicrobial resistance has been steadily increasing in prevalence, and combination therapy is commonly used to treat infections due to multidrug resistant bacteria. Under certain circumstances, combination therapy of three or more drugs may be necessary, which makes it necessary to simulate the pharmacokinetic profiles of more than two drugs concurrently in vitro. Recently, a general theoretical framework was developed to simulate three drugs with distinctly different half-lives. The objective of the study was to experimentally validate the theoretical model. Clinically relevant exposures of meropenem, ceftazidime, and ceftriaxone were simulated concurrently in a hollow-fiber infection model, with the corresponding half-lives of 1, 2.5, and 8 h, respectively. Serial samples were obtained over 24 h and drug concentrations were assayed using validated LC-MS/MS methods. A one-compartment model with zero-order input was used to characterize the observed concentration-time profiles. The experimentally observed half-lives corresponding to exponential decline of all three drugs were in good agreement with the respective values anticipated at the experiment design stage. These results were reproducible when the experiment was repeated on a different day. The validated benchtop setup can be used as a more flexible preclinical tool to explore the effectiveness of various drug combinations against multidrug resistant bacteria.

Keywords

• pharmacokinetics
• pharmacodynamics
• experimental therapeutics
• antimicrobial agents