Simulation and PK/PD Analysis
Simulations were performed on four different multiple-dose regimens of nemonoxacin (0.25 g q24h; loading dose 0.5 g on Day 1 followed by maintenance dose 0.25 g q24h; 0.5 g q24h; and 0.5 g q48h) to evaluate the effect of renal impairment on PK/PD at steady state. The daily AUCs simulated from 1000 subjects were highly dependent on CrCl. The predicted geometric mean ratio of AUS0-24h ss and 90% CI between the renal impairment and control groups were 2.08 (2.06, 2.11), suggesting a lower dosage requirement (Table 4). The exposurein vivo , i.e., daily AUCs of nemonoxacin, of the three adjusted dosing regimens (0.25 g q24h, loading dose 0.5 g followed by maintenance dose 0.25 g q24h, and 0.5 g q48h) in patients with severe renal impairment was similar to that of the standard dosing regimen of nemonoxacin (0.5 g q24h) in subjects with normal renal function (Figure 3). All the three regimens of oral nemonoxacin capsule (0.25 g q24h; loading dose 0.5 g followed by maintenance dose 0.25 g q24h; and 0.5 g q48h) achieved satisfactory PTA of 99.1% - 100% forf AUC0-24h/MIC target (47.05) at MIC ≤ 0.5 mg/L against S. pneumoniae and S. aureus in renal impairment group (Table 5). However, only 0.5 g q48h regimen achieved 92.7% PTA and >99% CFR when MIC ≤1 mg/L. Nemonoxacin 0.25 g q24h or loading-dose strategy led to a grossly inadequate PTA (≤ 17.0% at MIC = 1 mg/L). These findings suggest that clinical efficacy could be expected in an extended-interval dosing strategy (Figure 4).