title: Pharmacokinetic Modeling and Limited Sampling Strategies Based on Healthy Volunteers for Monitoring of Ertapenem in Patients with Multidrug-Resistant Tuberculosis.
abstract: Ertapenem is a broad-spectrum carbapenem antibiotic whose activity againstMycobacterium tuberculosisis being explored. Carbapenems have antibacterial activity when the plasma concentration exceeds the MIC at least 40% of the time (40%TMIC). To assess the 40%TMICin multidrug-resistant tuberculosis (MDR-TB) patients, a limited sampling strategy was developed using a population pharmacokinetic model based on data for healthy volunteers. A two-compartment population pharmacokinetic model was developed with data for 42 healthy volunteers using an iterative two-stage Bayesian method. External validation was performed by Bayesian fitting of the model developed with data for volunteers to the data for individual MDR-TB patients (in which the fitted values of the area under the concentration-time curve from 0 to 24 h [AUC0-24, fitvalues] were used) using the population model developed for volunteers as a prior. A Monte Carlo simulation (n= 1,000) was used to evaluate limited sampling strategies. Additionally, the 40%TMICwith the free fraction (f40%TMIC) of ertapenem in MDR-TB patients was estimated with the population pharmacokinetic model. The population pharmacokinetic model that was developed was shown to overestimate the area under the concentration-time curve from 0 to 24 h (AUC0-24) in MDR-TB patients by 6.8% (range, -17.2 to 30.7%). The best-performing limited sampling strategy, which had a time restriction of 0 to 6 h, was found to be sampling at 1 and 5 h (r2= 0.78, mean prediction error = -0.33%, root mean square error = 5.5%). Drug exposure was overestimated by a mean percentage of 4.2% (range, -15.2 to 23.6%). When a free fraction of 5% was considered and the MIC was set at 0.5 mg/liter, the minimumf40%TMICwould have been exceeded in 9 out of 12 patients. A population pharmacokinetic model and limited sampling strategy, developed using data from healthy volunteers, were shown to be adequate to predict ertapenem exposure in MDR-TB patients.
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.
authors.forename: S P
authors.initials: SP
authors.lastname: van Rijn
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.
authors.forename: M A
authors.initials: MA
authors.lastname: Zuur
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: van Altena
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands.|University of Groningen, University Medical Center Groningen, Tuberculosis Center Beatrixoord, Haren, The Netherlands.
authors.forename: O W
authors.initials: OW
authors.lastname: Akkerman
authors.affiliation: University of Groningen, Groningen Research Institute of Pharmacy, Section Pharmacokinetics, Toxicology and Targeting, Groningen, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Proost
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands.|University of Groningen, University Medical Center Groningen, Tuberculosis Center Beatrixoord, Haren, The Netherlands.
authors.forename: W C M
authors.initials: WC
authors.lastname: de Lange
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands.
authors.forename: H A M
authors.initials: HA
authors.lastname: Kerstjens
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.|University of Groningen, Groningen Research Institute of Pharmacy, Section Pharmacokinetics, Toxicology and Targeting, Groningen, The Netherlands.
authors.forename: D J
authors.initials: DJ
authors.lastname: Touw
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands.|University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, The Netherlands.
authors.forename: T S
authors.initials: TS
authors.lastname: van der Werf
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.|University of Groningen, Department of Pharmacy, Section Pharmacotherapy and Pharmaceutical Care, Groningen, The Netherlands.
authors.forename: J G W
authors.initials: JG
authors.lastname: Kosterink
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands j.w.c.alffenaar@umcg.nl.
authors.forename: J W C
authors.initials: JW
authors.lastname: Alffenaar
mesh_terms: D000293:Adolescent; D000328:Adult; D000995:Antitubercular Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001499:Bayes Theorem; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D000077727:Ertapenem; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D015233:Models, Statistical; D009010:Monte Carlo Method; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy / Q000382:microbiology; D047090:beta-Lactams / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000995:Antitubercular Agents; D047090:beta-Lactams; D000077727:Ertapenem
keywords: ertapenem; limited sampling; multidrug resistance; pharmacokinetic model; pharmacokinetics; tuberculosis