Pharmacokinetics and pharmacodynamics of levofloxacin injection in healthy Chinese volunteers and dosing regimen optimization

Abstract

What is known and objective: The pharmacokinetics (PK) and pharmacodynamics (PD) of levofloxacin were investigated following administration of levofloxacin injection in healthy Chinese volunteers for optimizing dosing regimen.

Methods: The PK study included single-dose (750 mg/150 mL) and multiple-dose (750 mg/150 mL once daily for 7 days) phases. The concentration of levofloxacin in blood and urine was determined using HPLC method. Both non-compartmental and compartmental analyses were performed to estimate PK parameters. Taking fC(max) /MIC ≥5 and fAUC(24 h) /MIC ≥30 as a target, the cumulative fraction of response (CFR) of levofloxacin 750 mg for treatment of community-acquired pneumonia (CAP) was calculated using Monte Carlo simulation. The probability of target attainment (PTA) of levofloxacin at various minimal inhibitory concentrations (MICs) was also evaluated.

Results and discussion: The results of PK study showed that the C(max) and AUC(0-∞) of levofloxacin were 14·94 μg/mL and 80·14 μg h/mL following single-dose infusion of levofloxacin. The half-life and average cumulative urine excretion ratio within 72 h post-dosing were 7·75 h and 86·95%, respectively. The mean C(ss,max), C(ss,min) and AUC(0-τ) of levofloxacin at steady state following multiple doses were 13·31 μg/mL, 0·031 μg/mL and 103·7 μg h/mL, respectively. The accumulation coefficient was 1·22. PK/PD analysis revealed that the CFR value of levofloxacin 750-mg regimen against Streptococcus pneumoniae was 96·2% and 95·4%, respectively, in terms of fC(max) /MIC and fAUC/MIC targets.

What is new and conclusion: The regimen of 750-mg levofloxacin once daily provides a satisfactory PK/PD profile against the main pathogenic bacteria of CAP, which implies promising clinical and bacteriological efficacy for patients with CAP. A large-scale clinical study is warranted to confirm these results.

Keywords: Monte Carlo simulation; healthy volunteer; levofloxacin; pharmacodynamics; pharmacokinetics.

Fig 1

Concentration–time profiles of levofloxacin following single- or multiple-dose infusion of 750-mg levofloxacin in healthy Chinese volunteers (Mean ± SD, n = 9). The observed values and fittings obtained from two-compartment model were represented by dots and lines, whereas red and blue symbols represent single-dose PK group and multiple-dose PK group, respectively. The infusion time of single-dose levofloxacin was 1·5 h. The dosing regimen for multiple PK study was q24 h × 7 days.

Fig 2

Cumulative fraction of response of fC_max/MIC (a) and fAUC_24 h/MIC (b) for levofloxacin. The dosing regimen of levofloxacin was 500 mg or 750 mg (q.d.) for seven consecutive days, and f indicates the unbound fraction, the value of which was 0·7.

Fig 3

Distribution of CAP pathogens in terms of MIC level and the PTA of fC_max/MIC (a) and fAUC_24 h/MIC (b) for levofloxacin following multiple dosing. The dosing regimen of levofloxacin was 500 mg or 750 mg (q.d.) for 7 consecutive days, and f indicates the unbound fraction, the value of which was 0·7. Histograms and lines represent the distribution frequency of MIC and PTA values, respectively. In the graph, the distribution data of MIC for CAP pathogens were obtained from the literature.