Feasibility of a Fixed-Dose Regimen of Pyrazinamide and Its Impact on Systemic Drug Exposure and Liver Safety in Patients with Tuberculosis

Abstract

bHistorically, dosing regimens for the treatment of tuberculosis (TB) have been proposed in an empirical manner. Dose selection has often been the result of efficacy trials in which drugs were administered regardless of the magnitude of the effect of demographic factors on drug disposition. This has created challenges for the prescription of fixed-dose combinations with novel therapeutic agents. The objectives of this investigation were to evaluate the impact of body weight on the overall systemic exposure to pyrazinamide (PZA) and to assess whether the use of one fixed dose, without adjustment according to weight, would ensure target exposure and safety requirements across the overall patient population. Using a population pharmacokinetic model, simulation scenarios were explored based on population demographics from clinical trials in TB patients and on historical hepatotoxicity data. The systemic drug exposure (area under the concentration-time curve [AUC]), peak concentrations (the maximum concentration of drug in serum [C max ]), the time above the MIC (t > MIC), and the risk of hepatotoxicity were evaluated for the current weight-banded regimen and compared to fixed doses under the assumption that pharmacokinetic differences are the primary drivers of toxicity. Evaluation of the standard weight banding reveals that more than 50% of subjects in the weight range of 45 to 55 kg remain below the proposed target exposure to PZA. In contrast, the use of a fixed 1,500-mg dose resulted in a lower proportion of subjects under the target value, with a 0.2% average overall increase in the risk of hepatotoxicity. Our results strongly support the use of a fixed-dose regimen for PZA in coformulation or combination with novel therapeutic agents.

Pharmacokinetics of Pyrazinamide and Optimal Dosing Regimens for Drug-Sensitive and -Resistant Tuberculosis

“…Doses higher than those currently recommended may result in high levels of 5-hydroxypyrazinoic acid, which is responsible for pyrazinamide induced hepatotoxicity (16). On the other hand, there exist discrepancies in exposure between the weight bands; patients in the lower weight bands achieve lower drug exposures (17,18).…”

Liver Fatty Acid Binding Protein Deficiency Provokes Oxidative Stress, Inflammation, and Apoptosis-Mediated Hepatotoxicity Induced by Pyrazinamide in Zebrafish Larvae

“…yrazinamide (PZA) is an important first-line drug in tuberculosis (TB) combination chemotherapy and is used during the initial 2 months of treatment for its remarkable sterilizing activity (1). Hepatotoxicity is the major adverse effect of PZA and usually occurs in the first 2 months of treatment (2).…”

Social, Historical and Cultural Dimensions of Tuberculosis

“…For example, rifampicin is administered in doses of 600 mg because the cost of the drug was prohibitively expensive when it was first introduced (Van Ingen et al, 2011), but should this economic argument find continuation today? Shifting our critical gaze to other TB drugs, we may also ask why pyrazinamide is weight-banded when a simplified fixed-dose regimen has been shown to be feasible (Sahota & Pasqua, 2012). In a climate of desperate need for TB treatment, how much evidence-based decision-making has been bypassed?…”