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

Abstract

Pyrazinamide is used in the treatment of tuberculosis (TB) because its sterilizing effect against tubercle bacilli allows the shortening of treatment. It is part of standard treatment for drug-susceptible and drug-resistant TB, and it is being considered as a companion drug in novel regimens. The aim of this analysis was to characterize factors contributing to the variability in exposure and to evaluate drug exposures using alternative doses, thus providing evidence to support revised dosing recommendations for drug-susceptible and multidrug-resistant tuberculosis (MDR-TB). Pyrazinamide pharmacokinetic (PK) data from 61 HIV/TB-coinfected patients in South Africa were used in the analysis. The patients were administered weight-adjusted doses of pyrazinamide, rifampin, isoniazid, and ethambutol in fixed-dose combination tablets according to WHO guidelines and underwent intensive PK sampling on days 1, 8, 15, and 29. The data were interpreted using nonlinear mixed-effects modeling. PK profiles were best described using a one-compartment model with first-order elimination. Allometric scaling was applied to disposition parameters using fat-free mass. Clearance increased by 14% from the 1st day to the 29th day of treatment. More than 50% of patients with weight less than 55 kg achieved lower pyrazinamide exposures at steady state than the targeted area under the concentration-time curve from 0 to 24 h of 363 mg · h/liter. Among patients with drug-susceptible TB, adding 400 mg to the dose for those weighing 30 to 54 kg improved exposure. Average pyrazinamide exposure in different weight bands among patients with MDR-TB could be matched by administering 1,500 mg, 1,750 mg, and 2,000 mg to patients in the 33-to 50-kg, 51-to 70-kg, and greater than 70-kg weight bands, respectively.KEYWORDS NONMEM, population pharmacokinetics, HIV/TB coinfection, fat-free mass, AUC, weight band dosing P yrazinamide is a prodrug converted to its active form, pyrazinoic acid, by hepatic microsomal deamidase (1) and is active against dormant and semidormant Mycobacterium tuberculosis bacilli, especially in acidic environments (2, 3). It is currently part of a four-drug fixed-dose combination (FDC), which includes isoniazid, ethambutol, and rifampin, an inducer of a number of cytochrome P450 enzymes via the pregnane X receptor (PXR) (4). Pyrazinamide is currently being considered as a companion drug in novel tuberculosis (TB) treatment regimens (5-7), including for multidrug-resistant tuberculosis (MDR-TB).Interest in the drug derives from its potent sterilizing activity, which confers the ability to shorten treatment duration. Pyrazinamide exposures have been correlated with favorable treatment outcomes in patients on standard doses (5, 8-13). A pyrazi-

Current research toward optimizing dosing of first-line antituberculosis treatment

“…Dosing guidelines for antituberculosis drugs typically advocate a uniform milligram per kilogram of body weight (mg/kg) dose, and the drugs are typically dosed by weight band to achieve a narrow mg/kg range using the available formulations [40,41]. A consistent finding of pharmacokinetic studies in adults and children dosed in this way is that lower weight patients have lower drug exposures [5,10,13,18,33,37,[42][43][44]. This can be attributed to the nonlinear relationship between clearance and size whereby smaller people need higher maintenance doses per kilogram of body weight [45].…”

“…Weight band doses should be optimized accordingly. Moreover, fat-free mass is frequently more closely related to clearance and volume of distribution than total body weight [7,[9][10][11][12][13][14]. For these drugs (including rifampin, isoniazid, and pyrazinamide), wasted or stunted individuals have lower drug exposures due to a higher proportion of their total body weight being accounted for by fat-free mass.…”

“…fixed dose combination(FDC) tablets [5,10,13,37,32]. The pharmacokinetic models for rifampin and pyrazinamide were published previously [10,13]. The models for isoniazid and ethambutol are presented as supplementary material.…”

“…Reduced antituberculosis drug exposures have also been described in males compared to females [1,12]. Confounding by increased clearance per kilogram of fat-free mass [7,[9][10][11][12][13][14], may contribute to the association of low drug exposures with HIV infection and male sex in some cohorts. Among Tanzanian tuberculosis patients with HIV infection, nutritional supplementation during the first 2 months of treatment improved the bioavailability of rifampin [7].…”

“…Many antituberculosis drugs exhibit wide pharmacokinetic variability in patient cohorts [1][2][3][4][5][6][7][8][9][10][11][12][13]. Studies in patients with drug-susceptible tuberculosis (DS-TB) on a standard regimen of rifampin and isoniazid for 6 months with pyrazinamide and ethambutol for the first 2 months, suggest that such variability is clinically important.…”