title: 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 (Cmax) of >35 μg/ml or an area under the concentration-versus-time curve (AUC) of >363 μg · 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])Cmaxwas 30.8 (7.4) μg/ml, and the mean (SD) AUC from time zero to 24 h (AUC0-24) was 307 (83) μg · 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) andV/Fincreased with body weight. Our simulations show that higher doses of PZA (>50 mg/kg of body weight) are needed to achieve the therapeutic target of an AUC/MIC of >11.3 in >80% of patients, while doses of >80 mg/kg are needed for target attainment in 90% of patients, given specific assumptions about MIC determinations. For the therapeutic targets of aCmaxof >35 μg/ml and/or an AUC of >363 μg · h/ml, doses in the range of 30 to 40 mg/kg are needed to achieve the therapeutic target in >90% of the patients. Further clinical trials are needed to evaluate the safety and efficacy of higher doses of PZA.
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.|University of Florida, College of Pharmacy, Department of Pharmacotherapy and Translational Research, Gainesville, Florida, USA.|Emerging Pathogens Institute, University of Florida, Gainesville, Florida, USA.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Alsultan
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Rada
authors.initials: R
authors.lastname: Savic
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Dooley
authors.affiliation: VA Medical Center San Antonio and UT Health, San Antonio, Texas, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Weiner
authors.affiliation: Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: William
authors.initials: W
authors.lastname: Whitworth
authors.affiliation: Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Mac Kenzie
authors.affiliation: University of Florida, College of Pharmacy, Department of Pharmacotherapy and Translational Research, Gainesville, Florida, USA peloquin@cop.ufl.edu.|Emerging Pathogens Institute, University of Florida, Gainesville, Florida, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Peloquin
mesh_terms: D000328:Adult; D000368:Aged; D000995:Antitubercular Agents / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011718:Pyrazinamide / Q000627:therapeutic use*; D014376:Tuberculosis / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide
keywords: pharmacokinetics; pyrazinamide; simulation; tuberculosis