title: Computational pharmacology of rifampin in mice: an application to dose optimization with conflicting objectives in tuberculosis treatment.
abstract: Dose selection for rifampin in the treatment of active pulmonary tuberculosis (TB) illustrates some of the challenges for dose optimization within multidrug therapies. Rifampin-based anti-TB regimens are often combined with antiretroviral therapies to treat human immunodeficiency virus (HIV) coinfection. The potent cytochrome P450 (CYP) enzyme inducing properties of rifampin give rise to significant drug-drug interactions, the minimization of which by limiting the dose, conflicts with the maximization of bacterial killing by increasing the dose. Such multiple and conflicting objectives lead to a set of trade-off optimal solutions for dose optimization rather than a single best solution. Here, we combine pharmacokinetic/pharmacodynamic (PK/PD) modeling with multiobjective optimization to quantitatively explore trade-offs between therapeutic and adverse effects of optimal dosing for the example of rifampin in TB-infected mice. The PK/PD model describes rifampin concentrations in plasma and liver following oral administration together with hepatic CYP enzyme induction and bacterial killing kinetics. We include optimization objectives descriptive of antimicrobial efficacy, CYP-mediated drug-drug interactions, and drug exposure-dependent toxicity. Results show non-conventional dosing scenarios that allow for increased efficacy relative to uniform dosing without increasing drug-drug interactions. Additionally, we find currently employed dosages for rifampin to be nearly optimal with respect to trade-offs between efficacy and toxicity. While limited by the accuracy and applicability of the PK/PD model, these results provide an avenue for experimental investigation of complex dose optimization problems. This method can be extended to include additional drugs and optimization objectives, and may provide a useful tool for individualized medicine.
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA, michael.lyons@colostate.edu.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Lyons
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012293:Rifampin / Q000494:pharmacology*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D003577:Cytochrome P-450 Enzyme System; D012293:Rifampin