title: Thioridazine pharmacokinetic-pharmacodynamic parameters "Wobble" during treatment of tuberculosis: a theoretical basis for shorter-duration curative monotherapy with congeners.
abstract: Phenothiazines are being repurposed for treatment of tuberculosis. We examined time-kill curves of thioridazine and first-line drugs against log-growth-phase and semidormant bacilli under acidic conditions and nonreplicating persistent Mycobacterium tuberculosis. While both the potency and the efficacy of first-line drugs declined dramatically as M. tuberculosis replication rates decreased, those of thioridazine improved. The mutation prevalence to 3 times the thioridazine MIC was <1 × 10(-11), better than for ≥2 first-line drugs combined. Hollow fiber system studies revealed that the relationship between sterilizing effect and pharmacodynamic indices (PDI) was characterized by an r(2) of 0.88 for peak/MIC, an r(2) of 0.47 for the area under the concentration-time curve (AUC) to MIC, and an r(2) of 0.14 for the cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (%TMIC) at the end of the first week. However, the PDI linked to effect "wobbled" as the duration of therapy increased, so that by the fourth week the r(2) was 0.88 for AUC/MIC, 0.78 for %TMIC, and 0.72 for peak/MIC. This "wobble" has implications on general pharmacokinetic/pharmacodynamic theory, whereby efficacy is linked to only one of the three PDIs in deterministic models. The potency changed 8.9-fold from the first to the fourth weeks. The non-protein-bound AUC/MIC associated with maximal kill at the end of therapy was 50.53 (protein binding = 99.5%). This thioridazine exposure was calculated to extinguish all three M. tuberculosis metabolic populations in human lungs in only 42.9 days of monotherapy. However, this concentration exceeds the 2- to 8-mg/liter thioridazine concentration in serum known to be lethal to humans. Therefore, the way forward for phenothiazine monotherapy that also reduces therapy duration is via synthesis of less toxic congeners.
authors.affiliation: Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Sandirai
authors.initials: S
authors.lastname: Musuka
authors.forename: Shashikant
authors.initials: S
authors.lastname: Srivastava
authors.forename: Chandima Wasana
authors.initials: CW
authors.lastname: Siyambalapitiyage Dona
authors.forename: Claudia
authors.initials: C
authors.lastname: Meek
authors.forename: Richard
authors.initials: R
authors.lastname: Leff
authors.forename: Jotam
authors.initials: J
authors.lastname: Pasipanodya
authors.forename: Tawanda
authors.initials: T
authors.lastname: Gumbo
mesh_terms: D014150:Antipsychotic Agents / Q000493:pharmacokinetics* / Q000633:toxicity; D000995:Antitubercular Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D015169:Colony Count, Microbial; D003198:Computer Simulation; D004334:Drug Administration Schedule; D015195:Drug Design; D058492:Drug Repositioning; D024881:Drug Resistance, Bacterial; D006801:Humans; D007262:Infusions, Intravenous; D007538:Isoniazid / Q000493:pharmacokinetics / Q000494:pharmacology; D055985:Latent Tuberculosis / Q000188:drug therapy / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D015233:Models, Statistical; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D011718:Pyrazinamide / Q000493:pharmacokinetics / Q000494:pharmacology; D012293:Rifampin / Q000493:pharmacokinetics / Q000494:pharmacology; D013881:Thioridazine / Q000493:pharmacokinetics* / Q000633:toxicity; D013997:Time Factors
chemical_list: D014150:Antipsychotic Agents; D000995:Antitubercular Agents; D011718:Pyrazinamide; D013881:Thioridazine; D007538:Isoniazid; D012293:Rifampin
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