Population Pharmacokinetics of Levofloxacin and Moxifloxacin, and the Probability of Target Attainment in Ethiopian Patients with Multidrug-Resistant Tuberculosis

Abstract

Objective: This study aimed to explore the population pharmacokinetic modeling (PopPK) of levofloxacin (LFX) and moxifloxacin (MXF), as well as the percent probability of target attainment (PTA) as defined by the ratio of the area under the plasma concentration-time curve over 24 h and the in vitro minimum inhibitory concentration (AUC0-24/MIC) in Ethiopian multidrug resistant tuberculosis (MDR-TB) patients.

Methods: Steady state-plasma concentration of the drugs in MDR-TB patients were determined using optimized liquid chromatography-tandem mass spectrometry. PopPK and simulations were run at various doses, and pharmacokinetic parameters were estimated. The effect of covariates on the PK parameters and PTA for maximum mycobacterial kill and resistance prevention was also investigated.

Results: LFX and MXF both fit in a one-compartment model with adjustments. Serum-creatinine (Cr) influenced (p = 0.01) the clearance of LFX, whereas body mass index (BMI) influenced (p = 0.01) the apparent volume of distribution (V) of MXF. The PTA for LFX maximal mycobacterial kill at the critical MIC of 0.5 mg/L with the simulated 750 mg, 1000 mg, and 1500 mg doses were 29%, 62%, and 95%, respectively, whereas the PTA for resistance prevention at 1500 mg was only 4.8%, with none of the lower doses achieving this target. At the critical MIC of 0.25 mg/L, there was no change in the PTA for maximum bacterial kill when the MXF dose was increased (600 mg, 800 mg, and 1000 mg), but the PTA for resistance prevention was improved.

Conclusion: The standard doses of LFX and MXF may not provide adequate drug exposure. PopPK of LFX is more predictable for maximum mycobacterial kill, whereas MXF's resistance prevention target increases with dose. Cr and BMI are likely important covariates for dose optimization in Ethiopian patients.

Keywords: Ethiopia; MDR-TB patients; levofloxacin; moxifloxacin; population pharmacokinetics; probability of target attainment.

Figure 1

Goodness-of-fit plots for the final population pharmacokinetics of LFX (A) and MXF (B): conditional weighted residuals versus time (CWRES versus IVAR) (a); conditional weighted residuals versus population predicted concentrations (CWRES versus PRED) (b); observed versus individual predicted concentrations (DV versus IPRED) (c); observed versus population predicted concentrations (DV versus PRED) (d). The red lines in the panels represent smoothed regression lines.

Figure 2

Visual predictive checks (a) and WRES versus Standard Normal Quantiles (b) for the final model of LFX (A) and MXF (B): red lines represent the 5th, 50th, and 95th percentiles of the observed concentrations; the shaded areas represent the 90% confidence intervals of the 5th, 50th, and 95th percentiles of the simulated concentrations, respectively; the dots represent the observed data; DV represents observed concentration; DV0, observed concentration at zero time; IVAR, time; WRES, weighted residuals.

Figure 3

Box plot for simulated C_max (a) and AUC0-24 (b) of LFX (A) and MXF (B): the dashed line indicates the minimum threshold for C_max and AUC0-24.

Figure 4

Percent probability of target attainment, PTA (%) for the maximal mycobacterial kill (AUC0-24/MIC ≥146) (A) and resistance suppression (AUC0-24/MIC ≥360) (B) of the simulated doses of LFX (750 mg, 1000 mg, and 1500 mg) against the assumed MIC values in Ethiopian MDR-TB patients (n=21).

Figure 5

Percent probability of target attainment, PTA (%) for the maximal mycobacterial kill (AUC0-24/MIC≥53) (A) and resistance suppression (AUC0-24/MIC ≥100) (B) of the simulated doses of MXF (600 mg, 800 mg, 1000 mg) against the assumed MIC values in Ethiopian MDR-TB patients (n=18).