Increased Doses Lead to Higher Drug Exposures of Levofloxacin for Treatment of Tuberculosis

Saliva may be a useful alternative matrix for monitoring levofloxacin concentrations in multidrug-resistant tuberculosis (MDR-TB) patients. The objectives of this study were (i) to evaluate the correlation between plasma and salivary levofloxacin (Lfx) concentrations in MDR-TB patients and (ii) to gauge the possibility of using saliva as an alternative sampling matrix for therapeutic drug monitoring of Lfx in areas where TB is endemic. This was a prospective pharmacokinetic study that enrolled MDR-TB patients receiving levofloxacin (750-to 1,000-mg once-daily dosing) under standardized treatment regimen in Nepal. Paired blood and saliva samples were collected at steady state. Lfx concentrations were quantified using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated using noncompartmental kinetics. Lfx drug exposures were evaluated in 23 MDR-TB patients. During the first month, the median (interquartile range [IQR]) areas under the concentration-time curve from 0 to 24 h (AUC 0 -24 ) were 67.09 (53.93 to 98.37) mg · h/liter in saliva and 99.91 (76.80 to 129.70) mg · h/liter in plasma, and the saliva plasma (S/P) ratio was 0.69 (0.53 to 0.99). Similarly, during the second month, the median (IQR) AUC 0 -24 were 75.63 (61.45 to 125.5) mg · h/liter in saliva and 102.7 (84.46 to 131.9) mg · h/liter in plasma, with an S/P ratio of 0.73 (0.66 to 1.18). Furthermore, large inter-and intraindividual variabilities in Lfx concentrations were observed. This study could not demonstrate a strong correlation between plasma and saliva Lfx levels. Despite a good Lfx penetration in saliva, the variability in individual saliva-to-plasma ratios limits the use of saliva as a valid substitute for plasma. Nevertheless, saliva could be useful in semiquantitatively predicting Lfx plasma levels. (This study has been registered at ClinicalTrials.gov under identifier NCT03000517.)

Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 99%

Evaluation of Saliva as a Potential Alternative Sampling Matrix for Therapeutic Drug Monitoring of Levofloxacin in Patients with Multidrug-Resistant Tuberculosis

Ghimire

Maharjan

Jongedijk

et al. 2019

“…Similarly, “Opti-Q” was a double-blinded, randomized, dose-ranging clinical trial conducted on 101 patients with MDR-TB. The patients received LVX at 11, 14, 17, or 20 mg/kg/day and achieved median AUC 0–24 values of 109, 98, 145, and 207 mg ⋅ h/liter, respectively, suggesting that dose increase produces a relatively linear exposure increase (24). Recently, the STREAM trial has reported a higher number of patients developing QTc prolongation in the short, high-dose MOX regimen compared to the long, conventional one (31 [11%] versus 9 [6%], P = 0.14) (25).…”

Section: Discussionmentioning

confidence: 99%

Fluoroquinolones in Drug-Resistant Tuberculosis: Culture Conversion and Pharmacokinetic/Pharmacodynamic Target Attainment To Guide Dose Selection

Al‐Shaer

Alghamdi

Alsultan

et al. 2019

Self Cite

Fluoroquinolones are group A drugs in tuberculosis guidelines. We aim to compare the culture conversion between new-generation (levofloxacin and moxifloxacin) and old-generation (ciprofloxacin and ofloxacin) fluoroquinolones, develop pharmacokinetic models, and calculate target attainment for levofloxacin and moxifloxacin. We included three U.S. tuberculosis centers. Patients admitted between 1984 and 2015, infected with drug-resistant tuberculosis, and who had received fluoroquinolones for ≥28 days were included. Demographics, sputum cultures and susceptibility, treatment regimens, and serum concentrations were collected. A time-to-event analysis was conducted, and Cox proportional hazards model was used to compare the time to culture conversion. Using additional data from ongoing studies, pharmacokinetic modelling and Monte Carlo simulations were performed to assess target attainment for different doses. Overall, 124 patients received fluoroquinolones. The median age was 40 years, and the median weight was 60 kg. Fifty-six patients (45%) received old-generation fluoroquinolones. New-generation fluoroquinolones showed a faster time to culture conversion (median 16 versus 40 weeks, P = 0.012). After adjusting for isoniazid and clofazimine treatment, patients treated with new-generation fluoroquinolones were more likely to have culture conversion (adjusted hazards ratio, 2.16 [95% confidence interval, 1.28 to 3.64]). We included 178 patients in the pharmacokinetic models. Levofloxacin and moxifloxacin were best described by a one-compartment model with first-order absorption and elimination. At least 1,500 to 1,750 mg levofloxacin and 800 mg moxifloxacin may be needed for maximum kill at the current epidemiologic cutoff values. In summary, new-generation fluoroquinolones showed faster time to culture conversion compared to the old generation. For optimal target attainment at the current MIC values, higher doses of levofloxacin and moxifloxacin may be needed.

“…During February to December 2017, a convenience sample of children aged 2 to 10 years who had been on treatment for Ͼ1 month were enrolled in the pharmacokinetic study with written informed consent from parents/guardians. Venous samples (1 ml) were drawn immediately after medication administration and after 1, 2, and 6 h; in previously published studies of TB patients, maximum drug concentration (C max ) typically occurred 1 to 2 h postdose (7,11,12). Levofloxacin serum concentrations were measured at the University of Florida (Gainesville, FL), using a validated high-pressure liquid chromatography assay with tandem mass spectrometry (LC-MS/MS) detection (11).…”

mentioning

confidence: 99%

“…Venous samples (1 ml) were drawn immediately after medication administration and after 1, 2, and 6 h; in previously published studies of TB patients, maximum drug concentration (C max ) typically occurred 1 to 2 h postdose (7,11,12). Levofloxacin serum concentrations were measured at the University of Florida (Gainesville, FL), using a validated high-pressure liquid chromatography assay with tandem mass spectrometry (LC-MS/MS) detection (11). A noncompartmental pharmacokinetic analysis was performed to estimate pharmacokinetic parameters using Phoenix v7.0 (Certara LP, Princeton, NJ).…”

mentioning

confidence: 99%

Pharmacokinetics of Levofloxacin in Children Treated for Exposure to Drug-Resistant Tuberculosis

Malik

Brooks

Siddiqui

et al. 2019

Self Cite

Levofloxacin is used to treat and prevent drug-resistant tuberculosis in children. We assessed levofloxacin serum drug concentrations in 24 children aged 2 to 10 years who received levofloxacin-based tuberculosis preventive therapy in Karachi, Pakistan. Only 9 children (37.5%) achieved adequate drug exposure. Target serum drug concentration was met in 4 (26.7%) of 15 children dosed consistently with World Health Organization recommendations and 4 (80.0%) of 5 who received higher-than-recommended doses. Levofloxacin dosing recommendations may require reevaluation.