title: Limited-sampling strategies for therapeutic drug monitoring of moxifloxacin in patients with tuberculosis.
abstract: BACKGROUND
  Moxifloxacin (MFX) is a potent drug for multidrug resistant tuberculosis(TB) treatment and is also useful if first-line agents are not tolerated. Therapeutic drug monitoring may help to prevent treatment failure. Obtaining a full concentration-time curve of MFX for therapeutic drug monitoring is not feasible in most settings. Developing a limited-sampling strategy based on population pharmacokinetics (PK) may help to overcome this problem.
  
  
  METHODS
  Steady-state plasma concentrations after the administration of 400 mg of MFX once daily were determined in 21 patients with TB, using a validated liquid chromatography-tandem mass spectrometry method. A one-compartment population model was generated and crossvalidated. Monte Carlo data simulation (n=1000) was used to calculate limited-sampling strategies. The correlation between predicted MFX AUC0-24h (area under the concentration-time curve 0 to 24 hours) and observed AUC0-24h was investigated by Bland-Altman analysis. Finally, the predictive performance of the final model was tested prospectively using MFX profiles from patients with TB receiving 400, 600, or 800 mg once daily.
  
  
  RESULTS
  Median minimum inhibitory concentration of Mycobacterium tuberculosis isolates was 0.25 mg/L (interquartile range: 0.25-0.5 mg/L). The geometric mean AUC0-24h was 24.5 mg·h/L (range: 8.5-72.2 mg·h/L), which resulted in a geometric mean AUC0-24h/minimum inhibitory concentration ratio of 72 (range: 21-321). PK analysis, based on PK profiles of 400 mg of MFX once daily, resulted in a crossvalidated population PK model with the following parameters: apparent clearance (Cl) 18.5±8.6 L/h per 1.85 m, Vd 3.0±0.7 L/kg corrected lean body mass, Ka 1.15±1.16 h, and F was fixed at 1. After the Monte Carlo simulation, the best predicting strategy for MFX AUC0-24h for practical use was based on MFX concentrations 4 and 14 hours postdosing (r=0.90, prediction bias=-1.5%, and root mean square error=15%).
  
  
  CONCLUSIONS
  MFX AUC0-24h in patients with TB can be predicted with acceptable accuracy for clinical management, using limited sampling. AUC0-24h prediction based on 2 samples, 4 and 14 hours postdose, can be used to individualize treatment.
authors.affiliation: Department of Hospital and Clinical pharmacy, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Arianna D
authors.initials: AD
authors.lastname: Pranger
authors.forename: Jos G W
authors.initials: JG
authors.lastname: Kosterink
authors.forename: Richard
authors.initials: R
authors.lastname: van Altena
authors.forename: Rob E
authors.initials: RE
authors.lastname: Aarnoutse
authors.forename: Tjip S
authors.initials: TS
authors.lastname: van der Werf
authors.forename: Donald R A
authors.initials: DR
authors.lastname: Uges
authors.forename: Jan-Willem C
authors.initials: JW
authors.lastname: Alffenaar
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D001372:Aza Compounds / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D016903:Drug Monitoring / Q000379:methods*; D024841:Fluoroquinolones; D006801:Humans; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D009169:Mycobacterium tuberculosis / Q000302:isolation & purification; D011804:Quinolines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D017211:Treatment Failure; D018088:Tuberculosis, Multidrug-Resistant / Q000097:blood* / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D000077266:Moxifloxacin