Population Pharmacokinetics of Pyrazinamide in Patients with Tuberculosis

Abstract

The current treatment used for tuberculosis (TB) is lengthy and needs to be shortened and improved. Pyrazinamide (PZA) has potent sterilizing activity and has the potential to shorten the TB treatment duration, if treatment is optimized. The goals of this study were (i) to develop a population pharmacokinetic (PK) model for PZA among patients enrolled in PK substudies of Tuberculosis Trial Consortium (TBTC) trials 27 and 28 and (ii) to determine covariates that affect PZA PK. (iii) We also performed simulations and target attainment analysis using the proposed targets of a maximum plasma concentration (C max ) of Ͼ35 g/ml or an area under the concentration-versus-time curve (AUC) of Ͼ363 g · h/ml to see if higher weight-based dosing could improve PZA efficacy. Seventy-two patients participated in the substudies. The mean (standard deviation [SD]) C max was 30.8 (7.4) g/ml, and the mean (SD) AUC from time zero to 24 h (AUC 0 -24 ) was 307 (83) g · h/ml. A one-compartment open model best described PZA PK. Only body weight was a significant covariate for PZA clearance. Women had a lower volume of distribution (V/F) than men, and both clearance (CL/F) and V/F increased with body weight. Our simulations show that higher doses of PZA (Ͼ50 mg/kg of body weight) are needed to achieve the therapeutic target of an AUC/MIC of Ͼ11.3 in Ͼ80% of patients, while doses of Ͼ80 mg/kg are needed for target attainment in 90% of patients, given specific assumptions about MIC determinations. For the therapeutic targets of a C max of Ͼ35 g/ml and/or an AUC of Ͼ363 g · h/ml, doses in the range of 30 to 40 mg/kg are needed to achieve the therapeutic target in Ͼ90% of the patients. Further clinical trials are needed to evaluate the safety and efficacy of higher doses of PZA.KEYWORDS pyrazinamide, tuberculosis, pharmacokinetics, simulation T he standard regimen for drug-susceptible tuberculosis (TB) consists of rifampin, isoniazid, pyrazinamide (PZA), and ethambutol for 2 months, followed by 4 months of isoniazid and rifampin. If used properly, this regimen is highly effective, with cure rates approaching 95% within clinical trials; however, in program settings, treatment is successful in only 70 to 85% of patients (1). Despite the widespread availability of this regimen, TB is still a worldwide pandemic; it surpassed HIV as a leading cause of death from an infectious agent in 2014. Approximately 9.6 million people develop TB annually, and 1.5 million die from it (1). Also, multidrug-resistant tuberculosis (MDR-TB) and extensively drug resistant tuberculosis (XDR-TB) pose threats to public health efforts to control TB. Treatment of MDR-TB and XDR-TB requires the use of less effective and

A Systematic Review on the Effect of HIV Infection on the Pharmacokinetics of First-Line Tuberculosis Drugs

“…First, several studies lacked a comparator group, making it difficult to adequately investigate the effect of HIV infection on the PK of the FLDs [34][35][36][37][38]. Instead, these studies compared with the widely cited reference ranges published by Peloquin et al [27,57] and Alsultan et al [54,58]. However, these reference ranges are not age-, sex-, and weight-matched and often racial and regional differences are not taken into account.…”

“…However, these reference ranges are not age-, sex-, and weight-matched and often racial and regional differences are not taken into account. Studies have shown that female sex is a determinant of higher RIF, INH and PZA concentrations and lower EMB concentration [18,24], and older age is a determinant of higher drug levels of all four FLDs [24,58]. Another study reported that RIF exposure was significantly lower in people of African descent when adjusted for dose and genetic polymorphisms [59].…”

Evaluation of the Adequacy of WHO Revised Dosages of the First-Line Antituberculosis Drugs in Children with Tuberculosis Using Population Pharmacokinetic Modeling and Simulations

“…To date, several target values have been suggested to predict treatment outcomes for adults and children (18)(19)(20)(43)(44)(45). The main predictors of treatment failure have been a PZA peak concentration of Ͻ38.10 mg/liter and a RIF C max of Ͻ3.01 mg/liter in Indian children (18).…”

Predicting the Outcomes of New Short-Course Regimens for Multidrug-Resistant Tuberculosis Using Intrahost and Pharmacokinetic-Pharmacodynamic Modeling

“…For each of the included anti-TB drugs, a PK model was developed to simulate the concentration-time profiles in plasma, epithelial lining fluid (ELF; extracellular concentrations) and alveolar cells (AC; intracellular concentrations). These models have been found to best describe PK data of the respective anti-TB drugs in previous studies (14,(31)(32)(33)(34)(35)(36)(37)(38). Except for INH (for which the PK model structure included both ELF and AC compartments) (14), ELF/plasma and AC/plasma concentration ratios were used to extrapolate ELF and AC concentrations from simulated plasma concentrations.…”