An Oracle: Antituberculosis Pharmacokinetics-Pharmacodynamics, Clinical Correlation, and Clinical Trial Simulations To Predict the Future

Abstract

Antimicrobial pharmacokinetic-pharmacodynamic (PK/PD) science and clinical trial simulations have not been adequately applied to the design of doses and dose schedules of antituberculosis regimens because many researchers are skeptical about their clinical applicability. We compared findings of preclinical PK/PD studies of current first-line antituberculosis drugs to findings from several clinical publications that included microbiologic outcome and pharmacokinetic data or had a dose-scheduling design. Without exception, the antimicrobial PK/PD parameters linked to optimal effect were similar in preclinical models and in tuberculosis patients. Thus, exposure-effect relationships derived in the preclinical models can be used in the design of optimal antituberculosis doses, by incorporating population pharmacokinetics of the drugs and MIC distributions in Monte Carlo simulations. When this has been performed, doses and dose schedules of rifampin, isoniazid, pyrazinamide, and moxifloxacin with the potential to shorten antituberculosis therapy have been identified. In addition, different susceptibility breakpoints than those in current use have been identified. These steps outline a more rational approach than that of current methods for designing regimens and predicting outcome so that both new and older antituberculosis agents can shorten therapy duration.Advances in the treatment of tuberculosis (TB) have suffered from a lack of scientific imagination. A century ago, TB research was the true cutting edge of medical innovation (65,90,97). Unfortunately, while scientific knowledge for the therapy of most diseases virtually exploded, we and others in the TB world still use dated paradigms and language. In the meantime, the pandemic shows no signs of subsiding. In 2008, there were 8.9 to 9.9 million incident cases of TB; prevalence was 9.6 to 13.3 million cases, and 1.8 million people died from TB (107). "Short-course chemotherapy" is actually long. Longterm mortality, morbidity, relapse, and resistance emergence are still problems even after "successful" therapy (20,77,78,93). Indeed, while it often said that the therapy has a 95% success rate under directly observed therapy (DOTS) programs, a look at high-TB-burden countries with good DOTS programs reveals cure rates for pulmonary TB of only 34 to 76%, and those are under study conditions (1, 103). Recently, the efficacy of DOTS itself has been challenged (14, 103). Clearly, the traditional approaches have not succeeded in eradicating TB. It is time to take a different road.

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…421 The pharmacokinetic-pharmacodynamic exposure patterns or indices important in preventing or amplifying acquired drug resistance have been established for several agents in preclinical models, and at least in the case of first-line antituberculosis drugs and quinolones, they have been validated in clinical studies. 380,426,419 Table 11 shows the pharmacokineticpharmacodynamic exposure and pharmacokineticpharmacodynamic index associated with the sup pression of acquired drug resistance for several drugs that are used in clinical practice; these often differ from those associated with opti mal microbial kill for the same drug. 173,180,191,192,196,380,395,417,[419][420][421][422][423][424][425][426][427][428][429][430][431] Mistakenly, many regi mens were designed for the treatment of tuberculosis with a focus on microbial kill, ignoring the problem of acquired drug resistance.…”

“…Most data about acquired drug resistance was collected from preclinical models, 380,419,420,[426][427][428][429][430][431] except for one analysis of clinical studies in which all acquired drug resistance was preceded by low drug concentrations. 191,426 Drug concentrations are also likely to be lower than the optimal concentration in some anatomical compartments, such as the meninges and pericardial fluid, because of poor penetration of drugs into those compartments. Thus, to choose the most effective therapy for different anatomical locations, having an idea of drug penetration indices is crucial.…”

Pharmacokinetics and Pharmacodynamics of TMC207 and Its N -Desmethyl Metabolite in a Murine Model of Tuberculosis

“…However, optimization of dosing strategies for investigational and companion drugs is a critical obstacle. Pharmacokinetic and pharmacodynamic (PK-PD) analyses should play a vital role in the rational development of dosing regimens for new anti-TB drugs and combination regimens (3,15). Dose fractionation studies have been performed in the murine model of tuberculosis in order to identify the PK-PD index that correlates with bactericidal activity (1,8,9,17).…”

Antitubercular In Vitro Drug Discovery: Tools for Begin the Search

“…Thus, in vitro models offer a safer and more ethical way of assessing the PK/PD relationships of antibiotics compared to animal or human studies. More recently, Gumbo et al (2007) have published several reports using hollow fiber bioreactors (diffusion models) as in vitro models for testing antibacterial activity against M. tuberculosis (Gumbo et al, 2007;Gumbo et al, 2009;Pasipanodya & Gumbo, 2011). There are severe limitations associated with the use of hollow fiber bioreactors for in vitro culturing of bacteria.…”

“…As these bioreactors are complex and difficult to sterilize between experiments, new hollow fiber cartridges are recommended for every study which makes a broad-based application of these experiments cost-prohibitive. However, preclinical antimicrobial PK/PD data have great clinical relevance to the treatment of TB, thus, as new drugs are created, it would be advantageous to have them undergo rigorous PK/PD studies (Pasipanodya & Gumbo, 2011).…”