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Population Pharmacokinetic Model and Limited Sampling Strategies for Personalized Dosing of Levofloxacin in Tuberculosis Patients.

Abstract：

:Levofloxacin is an antituberculosis drug with substantial interindividual pharmacokinetic variability; therapeutic drug monitoring (TDM) could therefore be helpful to improve treatment results. TDM would be more feasible with limited sampling strategies (LSSs), a method to estimate the area under the concentration curve for the 24-h dosing interval (AUC0-24) by using a limited number of samples. This study aimed to develop a population pharmacokinetic (popPK) model of levofloxacin in tuberculosis patients, along with LSSs using a Bayesian and multiple linear regression approach. The popPK model and Bayesian LSS were developed using data from 30 patients and externally validated with 20 patients. The LSS based on multiple linear regression was internally validated using jackknife analysis. Only clinically suitable LSSs (maximum time span, 8 h; minimum interval, 1 h; 1 to 3 samples) were tested. Performance criteria were root-mean-square error (RMSE) of <15%, mean prediction error (MPE) of <5%, and r2 value of >0.95. A one-compartment model with lag time best described the data while only slightly underestimating the AUC0-24 (mean, -7.9%; standard error [SE], 1.7%). The Bayesian LSS using 0- and 5-h postdose samples (RMSE, 8.8%; MPE, 0.42%; r2 = 0.957) adequately estimated the AUC0-24, with a mean underestimation of -4.4% (SE, 2.7%). The multiple linear regression LSS using 0- and 4-h postdose samples (RMSE, 7.0%; MPE, 5.5%; r2 = 0.977) was internally validated, with a mean underestimation of -0.46% (SE, 2.0%). In this study, we successfully developed a popPK model and two LSSs that could be implemented in clinical practice to assist TDM of levofloxacin. (This study has been registered at ClinicalTrials.gov under identifier NCT01918397.).

journal_name

Antimicrob Agents Chemother

journal_title

Antimicrobial agents and chemotherapy

authors

van den Elsen SHJ,Sturkenboom MGG,Van't Boveneind-Vrubleuskaya N,Skrahina A,van der Werf TS,Heysell SK,Mpagama S,Migliori GB,Peloquin CA,Touw DJ,Alffenaar JC

doi

10.1128/AAC.01092-18

subject

Has Abstract

pub_date

2018-11-26 00:00:00

issue

eissn

0066-4804

issn

1098-6596

pii

AAC.01092-18

journal_volume

pub_type

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Population Pharmacokinetic Model and Limited Sampling Strategies for Personalized Dosing of Levofloxacin in Tuberculosis Patients.