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.)

Limited Sampling Strategies Using Linear Regression and the Bayesian Approach for Therapeutic Drug Monitoring of Moxifloxacin in Tuberculosis Patients

“…For these reasons, we expect the results reported here to represent the clinical practice of TDM using these LSSs very closely. The small sample size of the MFXϩRIF group can be considered a limitation as well, although comparable to previously published LSS studies (21,(37)(38)(39)(40). We consider this sample size to be sufficient for exploratory objectives, since this is the first study that…”

Population Pharmacokinetics and Limited Sampling Strategy for Therapeutic Drug Monitoring of Polymyxin B in Chinese Patients With Multidrug-Resistant Gram-Negative Bacterial Infections

“…The simple and multiple regression equations for estimating AUC 0-12h with good correlation r 2 were shown in Table 5. C 2h model and all models using two to four samples met the acceptance criteria (Van den Elsen et al, 2018;Zhang et al, 2018). With the increase of sample points, the linear correlations between predicted and measured AUC 0-12h were improved.…”

“…3) were used to evaluate the accuracy and precision of the model. The acceptance criteria of RMSE < 15 and r 2 > 0.95 (Van den Elsen et al, 2018).…”

A mobile microvolume UV/visible light spectrophotometer for the measurement of levofloxacin in saliva

“…Developed limited sampling strategies have shown that single or multiple samples collected after drug administration can be used to quantify levofloxacin exposure, which mitigates the risk of interference. 39 …”