Abdullah Alsultan, Guohua An, Charles A Peloquin

There is an urgent need to improve and shorten the treatment of tuberculosis (TB) and multi-drug resistant tuberculosis (MDR-TB). Levofloxacin, a newer generation fluoroquinolone, has potent activity against TB both in vitro and in vivo. Levofloxacin dosing can be optimized to improve the treatment of both TB and MDR-TB. Levofloxacin efficacy is linked primarily to fAUC/MIC. Since obtaining a full time concentration profile is not feasible in the clinic, we developed a limited sampling strategy (LSS) to estimate the AUC. We also utilized Monte Carlo simulations to evaluate the dosing of levofloxacin. Pharmacokinetic data were obtained from ten Brazilian TB patients. The pharmacokinetic data were fit with a one compartment model. LSS were developed using two methods: linear regression and Bayesian approaches. Several LSS predicted levofloxacin AUC with good accuracy and precision. The most accurate were two samples collected at four and six hours (R(2) = 0.91 using linear regression and 0.97 using Bayesian approaches), or at two and six hours (R(2) = 0.90 using linear regression and 0.96 using Bayesian approaches). The two and six hour approach also provides a good estimate of Cmax. Our target attainment analysis showed that higher doses (17-20 mg/kg) of levofloxacin might be needed to improve its activity. Doses in the range of 17-20 mg/kg showed good target attainment for MIC values from 0.25-0.50. At an MIC of 2, poor target attainment was observed across all doses. This LSS for levofloxacin can be used for therapeutic drug monitoring, and for future pharmacokinetic/pharmacodynamic studies.