Oskar Clewe (1), Sebastian G. Wicha (1), Corné de Vogel (2), Jurriaan E. M. de Steenwinkel (2), Ulrika S. H. Simonsson (1)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; (2) Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands.
Objectives: For diseases such as tuberculosis, where a combination of drugs are needed to effectively combat the bacterial infestation, the possibility of both positive and negative pharmacodynamic drug interactions exist. From many perspectives establishing an initial optimal combination of drug concentrations is not reasonable to carry out in a clinical setting. This information could rather be provided from a pre-clinical setting in which cost and ethical implications are minor. This work aimed at characterizing the susceptibility of Mycobacterium tuberculosis (M. tuberculosis) to rifampicin (RIF), isoniazid (INH) and ethambutol (ETH) and assessing the pharmacodynamic interactions of combinations of the three drugs using in vitro time kill data.
Methods: In vitro time kill experiments were performed with M. tuberculosis genotype strain Beijing 1585 using both single and combination series of RIF, INH and ETH concentrations. Viability, defined as colony forming units (cfu), was assessed at day 1, 2, 3 and 6 after drug exposure. The Multistate Tuberculosis Pharmacometric (MTP) model framework [1] and the general pharmacodynamic interaction (GPDI) model based on the Bliss Independence criterion [2] was used to characterize the natural growth and drug effect from mono and combination exposure. The pharmacodynamic interactions was evaluated on effect parameter level.
Results: In mono exposure all three drugs was found to exert kill effect on the F and S bacterial state. Rifampicin was in addition to this also found to inhibit the growth of the fast multiplying state bacteria and exert kill effect on the non-multiplying state bacteria. For the effect on fast multiplying bacteria RIF was found to act synergistic on both INH and ETH, INH was found to exert agonistic effect on RIF and showed no significant deviation from an additive effect when combined with ETH, ETH was found to act synergistic on RIF but showed no deviation from an additive effect when combined with INH. For the effect on the slow multiplying bacteria all three drugs were found to act antagonistic on one another when studied in duo combinations.
Conclusions: We have shown that the MTP model together with the newly developed GPDI model approach can be used to characterize the in vitro pharmacodynamic interactions of three first-line anti-tuberculosis drugs. As this type of interaction assessment allows for characterization of drug A´s interaction with B and drug B´s interaction with A, it is highly suitable as input to selection of phase 2b anti-tuberculosis combination regimens.
References:
[1] Clewe O, Aulin L, Hu Y, Coates AR, Simonsson USH. A multistate tuberculosis pharmacometric model: a framework for studying anti-tubercular drug effects in vitro. JAC 2015; Epub Dec 24 2015.
[2] Wicha SG, Chen C, Clewe O, Simonsson USH. A general pharmacodynamic interaction model based on the Bliss Independence criterion. Abstract. PAGE 2016. Lisbon.
Acknowledgments: The research was funded by the Swedish Research Council and the Innovative Medicines Initiative Joint Undertaking (www.imi.europa.eu) under grant agreement n°115337, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution.
Reference: PAGE 25 () Abstr 5783 [www.page-meeting.org/?abstract=5783]
Poster: Drug/Disease modeling - Infection