Feasibility of a fixed-dose regimen of pyrazinamide and its impact on systemic drug exposure and liver safety in patients with tuberculosis

Abstract

Historically, 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.

Fig 1

One-compartment PK model of PZA with first-order absorption and first-order elimination data from Wilkins et al. (48). In this model, body weight is a covariate on clearance (CL), while sex and body weight were found to influence the volume of distribution (V). Most of the variability in drug absorption was characterized by interoccasion variability in the absorption rate constant (KA).

Fig 2

A skewed distribution of the exposure (AUC_0–168 in mg · h/liter) to PZA is observed across the TB patient population despite dosing according to the currently recommended weight-banded regimen, i.e., from an 18.2 to a 26.3 mg/kg nominal dose. The AUC_0–168 distributions include rounding to a whole-tablet dose (500 mg). The data illustrate pharmacokinetics in African TB patients. The shaded area represents the target exposure range between the 25th and 90th percentiles.

Fig 3

(Left) Predicted AUC_0–168 (mg · h/liter) distribution after a fixed dose of 1,500 mg PZA (blue) compared to that of the currently recommended weight-banded regimen (pink), including rounding to a whole-tablet dose (500 mg). The data illustrate pharmacokinetics in African TB patients. (Right) Overview of the changes in AUC_0–168 following the administration of a fixed-dose regimen. The arrows indicate the direction of changes in individual exposure relative to the target range (shaded area) and the proportion (%) of patients affected by the administration of a fixed dose of 1,500 mg. The shaded area represents the target exposure range (i.e., between the 25th and 90th percentiles).

Fig 4

Aggregation of the clinical trial data in which treatment duration, drug combinations, demographic covariates, and incidence rates of hepatotoxicity were available (n = 4,490). (A) Overview of the dosing regimens and the corresponding incidence rates in each individual study (10, 17, 18, 28, 29, 31, 37, 48). (B) Logistic model. The dots represent the predicted individual exposures, expressed as AUC_0–168s (mg · h/liter). Hepatotoxicity is shown as an event at probability P (1), and all patients with no hepatotoxicity are shown at P (0). (C) Predicted increase in the risk of hepatotoxicity for TB patients taking a fixed dose of 1,500 mg PZA compared to that of those taking the standard dosing regimen by weight band. Hepatotoxicity was linked to PZA exposure based on the assumption that these adverse events were entirely driven by increasing drug exposure.