title: Pharmacokinetic Modeling and Optimal Sampling Strategies for Therapeutic Drug Monitoring of Rifampin in Patients with Tuberculosis.
abstract: Rifampin, together with isoniazid, has been the backbone of the current first-line treatment of tuberculosis (TB). The ratio of the area under the concentration-time curve from 0 to 24 h (AUC0-24) to the MIC is the best predictive pharmacokinetic-pharmacodynamic parameter for determinations of efficacy. The objective of this study was to develop an optimal sampling procedure based on population pharmacokinetics to predict AUC0-24 values. Patients received rifampin orally once daily as part of their anti-TB treatment. A one-compartmental pharmacokinetic population model with first-order absorption and lag time was developed using observed rifampin plasma concentrations from 55 patients. The population pharmacokinetic model was developed using an iterative two-stage Bayesian procedure and was cross-validated. Optimal sampling strategies were calculated using Monte Carlo simulation (n = 1,000). The geometric mean AUC0-24 value was 41.5 (range, 13.5 to 117) mg · h/liter. The median time to maximum concentration of drug in serum (Tmax) was 2.2 h, ranging from 0.4 to 5.7 h. This wide range indicates that obtaining a concentration level at 2 h (C2) would not capture the peak concentration in a large proportion of the population. Optimal sampling using concentrations at 1, 3, and 8 h postdosing was considered clinically suitable with an r(2) value of 0.96, a root mean squared error value of 13.2%, and a prediction bias value of -0.4%. This study showed that the rifampin AUC0-24 in TB patients can be predicted with acceptable accuracy and precision using the developed population pharmacokinetic model with optimal sampling at time points 1, 3, and 8 h.
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.
authors.forename: Marieke G G
authors.initials: MG
authors.lastname: Sturkenboom
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.
authors.forename: Leonie W
authors.initials: LW
authors.lastname: Mulder
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.
authors.forename: Arthur
authors.initials: A
authors.lastname: de Jager
authors.affiliation: University of Groningen, University Medical Center Groningen, Tuberculosis Centre Beatrixoord, Haren, and Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands.
authors.forename: Richard
authors.initials: R
authors.lastname: van Altena
authors.affiliation: Radboud University Medical Center, Department of Pharmacy, Nijmegen, The Netherlands.
authors.forename: Rob E
authors.initials: RE
authors.lastname: Aarnoutse
authors.affiliation: University of Groningen, University Medical Center Groningen, Tuberculosis Centre Beatrixoord, Haren, and Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands.
authors.forename: Wiel C M
authors.initials: WC
authors.lastname: de Lange
authors.affiliation: University of Groningen, Department of Pharmacy, Section Pharmacokinetics, Toxicology and Targeting, Groningen, The Netherlands.
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Proost
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: Jos G W
authors.initials: JG
authors.lastname: Kosterink
authors.affiliation: University of Groningen, University Medical Center Groningen, Tuberculosis Centre Beatrixoord, Haren, and 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: Tjip 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 j.w.c.alffenaar@umcg.nl.
authors.forename: Jan-Willem C
authors.initials: JW
authors.lastname: Alffenaar
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001499:Bayes Theorem; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D012293:Rifampin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D014376:Tuberculosis / Q000188:drug therapy* / Q000378:metabolism; D055815:Young Adult
chemical_list: D007538:Isoniazid; D012293:Rifampin