A model informed pre-clinical approach for identification of exposure-response and pharmacodynamic interactions in early tuberculosis drug development
(English)Manuscript (preprint) (Other academic)
Tuberculosis treatment involves the use of multiple drugs and therefore there is a risk of not only pharmacokinetic interactions but also pharmacodynamic interactions. From many perspectives identification of pharmacodynamic interactions is not reasonable to carry out in a clinical setting. Thus, the aim of this work was to develop a model-informed pre-clinical approach for identification of exposure-response and pharmacodynamic interactions of drug combinations in order to inform early anti-tuberculosis drug development. In vitro time-kill experiments were performed with Mycobacterium tuberculosis using rifampicin, isoniazid or ethambutol alone as well as in different combinations at clinically relevant concentrations. The Multistate Tuberculosis Pharmacometric model was used to characterize the natural growth and exposure-response relationships of each drug after mono-exposure. Pharmacodynamic interactions during combination exposure were characterized using the General Pharmacodynamic Interaction model with successful separation of each drug’s effect on the potency (EC50) of the other drugs. The approach outlined in this work constitutes groundwork for model informed input to the development of new and enhancement of existing anti-tuberculosis combination regimens.
tuberculosis, pharmacodynamic interactions, multistate tuberculosis pharmacometric model, general pharmacodynamic interaction model, isoniazid, rifampicin, ethambutol
IdentifiersURN: urn:nbn:se:uu:diva-303870OAI: oai:DiVA.org:uu-303870DiVA: diva2:1010194