Evaluation of fluoroquinolone reduced dosage regimens in elderly patients by using pharmacokinetic modelling and Monte Carlo simulations

Abstract

Fluoroquinolones are widely used in geriatric patients, but elderly patients are known to be at increased risk of decline in renal function. As fluoroquinolones usually exhibit a dominant renal elimination pathway, reduced dosage regimens are often used in geriatric patients. Our objective was to assess the capability to reach a pharmacokinetic-pharmacodynamic target of efficacy with such reduced dosage regimens of ofloxacin, levofloxacin and ciprofloxacin in elderly patients. Using Monte Carlo simulations, 1000 simulated elderly patients were created, based on published pharmacokinetic and pharmacodynamic data, and measured demographic data. Three usually proposed drug regimens taking renal function into account were evaluated using compartmental models. The probability of reaching an fAUC/MIC >100 was calculated for each regimen. For MICs <1 mg/L, all simulated patients reach the efficacy target. However, with higher values of MIC, the proposed regimens were inefficient for patients with moderate or severe renal impairment: 3.4% and 30.2% of patients with moderate renal impairment reached the efficacy target for ciprofloxacin and ofloxacin, respectively, for an MIC of 2 mg/L. For ciprofloxacin, more than 80% of patients with severe renal impairment were unable to reach the target fAUC/MIC with an MIC as low as 1 mg/L, whereas for levofloxacin, all simulated patients reached the efficacy target until an MIC of 4 mg/L. This suggests that the proposed dosage reduction does not allow the same exposure to be achieved in elderly patients with renal impairment, eventually leading to treatment failure or development of resistant strains.