Pharmacokinetics-Pharmacodynamics of Pyrazinamide in a Novel In Vitro Model of Tuberculosis for Sterilizing Effect: a Paradigm for Faster Assessment of New Antituberculosis Drugs

Abstract

There are currently renewed efforts to develop drugs that could shorten the duration of antituberculosis therapy. This is best achieved by optimizing the sterilizing effect. However, the current pathway for the development of new molecules with the potential to have a sterilizing effect is inefficient. We designed an in vitro pharmacokinetic-pharmacodynamic model in which Mycobacterium tuberculosis replicating slowly at pH 5.8 was exposed to pyrazinamide by use of the concentration-time profiles encountered in patients. The sterilizing effect rates and the time to the emergence of drug resistance were examined. Daily pyrazinamide dosing for 28 days accurately achieved (i) the pyrazinamide pharmacokinetic parameters, (ii) the lack of early bactericidal activity, (iii) a sterilizing effect rate of 0.10 log 10 CFU/ml per day starting on day 6 of therapy, and (iv) a time to the emergence of resistance of the from 2 to 3 weeks of monotherapy encountered in patients with tuberculosis. Next, dose-scheduling studies were performed. Current therapy for tuberculosis (TB) consists of rifampin (rifampicin), isoniazid, and pyrazinamide (5). In order to improve therapy, several studies have examined the pharmacokinetic (PK)-pharmacodynamic (PD) relationship between isoniazid and rifampin treatment and the response of Mycobacterium tuberculosis (22,25,29,30). However, those studies were of short duration and mainly reflected the bactericidal activities of these agents, defined as the killing of bacilli in log-phase growth. No similar studies have examined the sterilizing activities of anti-TB drugs. An anti-TB drug is considered to have a sterilizing effect when it is able to kill one of two subpopulations of M. tuberculosis: slowly growing bacilli in an acidic environment (slowly replicating bacilli [SRB]) and nonreplicating persistent bacilli (5, 26). The sterilizing activity of a drug also reflects its ability to shorten anti-TB therapy duration (41). Pyrazinamide has unique sterilizing activity against SRB, which are estimated to constitute the majority of bacilli in the pulmonary cavities of patients with TB (31,35). A measure of the size of the SRB population is that the addition of pyrazinamide to isoniazid-and rifampin-containing regimens led to a one-third reduction in the duration of therapy and a two-thirds reduction in the rate of TB relapse (2, 48). Given the size of this population and the central role of pyrazinamide in eradicating it, pyrazinamide PK-PD studies could help with the further optimization of therapy.After oral administration, pyrazinamide is almost completely systematically absorbed and eventually enters the pulmonary cavities containing M. tuberculosis. Pyrazinamide works in these cavities under acidic conditions (38). There is conflicting evidence as to whether pyrazinamide enters the bacilli by simple diffusion or by active uptake (44, 56). However, once the bacilli are in the cell, bacillary nicotinamidase deaminates the pyrazinamide to pyrazinoic acid (POA), which is transported to the extrace...

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

“…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. The theory was that directly observing the patients swallowing the pills, and using one drug to prevent resistance to another, would solve the acquired drug resistance problem.…”

“…418 (B) System of quadratic functions explaining the size of the drug-resistant subpopulation with time versus exposure, based on the model by Gumbo and colleagues. 419,420 At time t1, there is a decline in the size of the resistant subpopulation with increasing exposure, until a nadir is reached after which, paradoxically, increasing exposure leads to an increase in the drug-resistant subpopulation towards baseline. This shows suppression of acquired drug resistance over time.…”

“…More data about drug exposure targets that would minimise therapy failure is available. 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.…”

Probing the architecture of the Mycobacterium marinum arylamine N-acetyltransferase active site

“…Treatment of latent TB is an important TB control strategy but is usually complicated by the insensitivity of the dormant bacilli to antibiotics, the lack of means to ascertain the success of treatment, and the increased risk of drug resistance (Dooley and Sterling, 2005). Treatment of TB with chemotherapeutic agents is likely to remain as the cornerstone of patient management for the foreseeable future, necessitating the development of novel, non-toxic antituberculosis agents with potent sterilizing activity (Rivers and Mancera, 2008;Brown et al, 2009;Gumbo et al, 2009;Makarov et al, 2009).…”

Current status and opportunities for therapeutic drug monitoring in the treatment of tuberculosis

“…For most anti-TB drugs, the AUC 0-24 h /MIC ratio is the best parameter to predict efficacy. [10,17,68] To determine the AUC 0-24 h , conventionally 10-15 sample points are needed to cover 80% of the total AUC. [11] A significant amount of blood samples are taken from the patients before-and at several time points after intake of the anti-TB drug.…”