title: Limited sampling strategies for therapeutic drug monitoring of amikacin and kanamycin in patients with multidrug-resistant tuberculosis.
abstract: Amikacin and kanamycin are considered important and effective drugs in the treatment of multidrug-resistant tuberculosis (MDR-TB). Unfortunately, the incidence of toxicity is high and is related to elevated drug exposure. In order to achieve a balance between efficacy and toxicity, a population pharmacokinetic (PPK) model may help to optimise drug exposure. Patients with MDR-TB who had received amikacin or kanamycin as part of their treatment and who had routinely received therapeutic drug monitoring were evaluated. A PPK model was developed and subsequently validated. Using this model, a limited sampling model was developed. Eleven patients receiving amikacin and nine patients receiving kanamycin were included in this study. The median observed 24-h area under the concentration-time curve (AUC0-24h) was 77.2 mg h/L [interquartile range (IQR) 64.7-96.2 mg h/L] for amikacin and 64.1 mg h/L (IQR 55.6-92.1 mg h/L) for kanamycin. The PPK model was developed and validated using n-1 cross-validation. A robust population model was developed that is suitable for predicting the AUC0-24h of amikacin and kanamycin. This model, in combination with the limited sampling strategy developed, can be used in daily routine to guide dosing but also to assess AUC0-24h in phase 3 studies.
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands.
authors.forename: J A
authors.initials: JA
authors.lastname: Dijkstra
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.
authors.forename: O W
authors.initials: OW
authors.lastname: Akkerman
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands.
authors.forename: W C M
authors.initials: WC
authors.lastname: de Lange
authors.affiliation: University of Groningen, Groningen Research Institute of Pharmacy, Department of 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, 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, 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. Electronic address: j.w.c.alffenaar@umcg.nl.
authors.forename: J W C
authors.initials: JW
authors.lastname: Alffenaar
mesh_terms: D000328:Adult; D000583:Amikacin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000995:Antitubercular Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D056808:Biostatistics; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006801:Humans; D007612:Kanamycin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D015233:Models, Statistical; D012189:Retrospective Studies; D013048:Specimen Handling / Q000379:methods*; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D007612:Kanamycin; D000583:Amikacin
keywords: Amikacin; Kanamycin; Limited sampling; Pharmacokinetic model; Pharmacokinetics; Tuberculosis