In vitro model to simulate multiple drugs with distinct elimination half-lives

Abstract

Objective: The prevalence of drug resistance in pathogens such as HIV and selected bacteria has been steadily rising, resulting in an increased need for using multiple agents concurrently. Agents used in these combination therapies may have different elimination half-lives in humans. There is an unmet need for in vitro models to evaluate the efficacy of these combinations to guide early drug development. In order to realistically reflect in vivo conditions, useful in vitro model systems must be capable of simulating multiple pharmacokinetic profiles with distinct elimination half-lives. The goal of this study was to experimentally simulate four pharmacokinetic profiles with distinct elimination half-lives in an in vitro hollow-fibre system.

Methods: For illustrative purposes, fluctuating exposures of ceftriaxone were simulated with distinct half-lives of 1, 2.5, 8, and 12 hours. A parallel experimental setup was used to independently connect four supplemental reservoirs to a central reservoir. Target maximum concentration was achieved by direct drug dosing into the central reservoir; supplemental reservoirs were also dosed to offset the rapid drug elimination rate from the central reservoir. Serial pharmacokinetic samples were obtained from the central reservoir, assayed by a spectrophotometric method, and characterized by a one-compartment model.

Results: The observed maximum concentrations and elimination half-lives were in agreement with the expected values obtained from the mathematical predictions.

Conclusions: This in vitro experimental system can be used to evaluate the efficacy of up to four-drug combinations against multidrug-resistant bacteria or HIV-infected mammalian cells. The established framework represents an adaptable tool to advance the field of combination therapy.

Keywords: Antimicrobial agents; Experimental therapeutics; Pharmacokinetics.