DISCUSSION
Renal excretion is the major elimination route of nemonoxacin. An important part of the clinical development is investigating the effects of renal impairment on the safety and PK profile to determine the need for dosage adjustment. In the present study, we developed a PPK model of nemonoxacin in 20 subjects with or without renal impairment to evaluate the probability of PK/PD target attainment by MIC and CFR. An optimal dosage regimen was consequently proposed through PK/PD analysis for patients with severe renal impairment. To our knowledge, this is the first clinical trial in compliance with good clinical practice guidelines to investigate the effect of renal function on nemonoxacin dosage.
The covariates in the final PK model were CrCl, age on CL, and TBW on V1. The IIV was 11.3% for CL and 14.5% for V1. The inclusion of these covariates explained 71% (approximately 65% from CrCl) and 22% of the variation in CL and V1, respectively. CrCl level was the most notable source of variability influencing CL. Compared with CrCl, age was regarded as a relatively minor factor for CL. It was concluded from the final model that the CL of nemonoxacin would be reduced by 50% when CrCl decreased by 80%. This is consistent with the PK property of nemonoxacin, i.e., mostly excreted in unchanged form via kidneys [9,11,13]. The urinary excretion study found that the renal elimination of nemonoxacin in unchanged form in healthy subjects (about 66% of the dose) was nearly triple the value in patients with severe renal impairment (about 23% of the dose). It is evident that there is a significant non-renal elimination pathway in renal impairment patients. Several in vitro and in vivo studies have investigated the mass balance and identify the major metabolite of nemonoxacin [22,23]. Although the fecal excretion was proved to be a minor pathway in healthy volunteers, the increased drug exposure and prolonged elimination half-life in the renal impairment population would probably lead to enhanced biliary and fecal elimination rates [22]. On the other hand, nemonoxacin acyl-β -D-glucuronide, a potential major phase II metabolite, was speculated to be more efficiently biotransformed with the up-regulation of UDP-glucuronosyltransferase pathways [23]. Thus, further study should be conducted to understand the details of nemonoxacin elimination routes and metabolic pathways in renal impairment patients. The PPK analysis also implied that TBW accounted for some IIV in V1. TBW was determined routinely in chronic peritoneal dialysis patients to estimate the volume of urea distribution, which was calculated by the Watson formula based on combinations of height, weight, gender, and age. Moreover, it is recommended as one of the strongest prognostic variables for assessing patients’ body composition or nutritional status and therefore included in the final model.
It would be necessary to consider reduction of nemonoxacin dose in case of more than two-fold increase of steady-state AUC. However, an improved understanding of the PK/PD characteristics of nemonoxacin in the renal impairment population is the key to maximizing its bactericidal activity and minimizing the safety risk. The information is also important for optimization of dosing regimens. S. pneumoniae and S. aureus , the most common pathogens of CAP, are generally treated with fluoroquinolones and penicillins. Nemonoxacin is a concentration-dependent antibiotic. It has been approved for treatment of CAP in adults. Reportedly, the target value for the most clinically relevant PK/PD index (f AUC0-24h/MIC) of nemonoxacin is 47.05 [16]. The MIC values of nemonoxacin against common target pathogens ranged from 0.015 to 1 mg/L. Monte Carlo simulation showed that only the dosing regimen of nemonoxacin capsule 0.5 g q48h achieved 92.7% PTA and >99% CFR at MIC ≤ 1 mg/L in patients with severe renal impairment. A marked decrease was observed both in the Cmax and PTA at MIC = 1 mg/L for 0.25 g q24h regimen. Therefore, nemonoxacin 0.5 g q48h is recommended for treatment of S. pneumoniae and S. aureus infections in patients with severe renal impairment. This dosage regimen corresponds to nemonoxacin 0.5 g q24h for CAP patients with normal renal function, guaranteeing excellent clinical efficacy.
All AEs were mild in severity and resolved spontaneously without treatment. No significant difference was observed in the total number of drug-related AEs between the two patient groups, indicating well tolerability in renal impairment patients. However, the incidence of nemonoxacin cardiotoxicity, especially at higher dose (0.75 g q24h), seems to increase in a dose-dependent manner [14]. Compared with the standard dosage (0.5 g q24h), the dosing regimen (0.5g q48h) is unlikely to increase the risk of cardiotoxicity in renal impairment patients. Nevertheless, it is necessary to monitor the adverse drug reactions of nemonoxacin since the AE data were obtained from limited number of subjects in a single-dose, open-label study.
In summary, a PPK model for nemonoxacin is built using the PK data from healthy subjects and severe renal impairment patients. Monte Carlo simulation and PK/PD analysis indicates that nemonoxacin 0.5 g q48h is the optimal dosing regimen in severe renal impairment patients, evidenced by excellent PTA (92.7%) and CFR (>99%) at nemonoxacin MIC ≤ 1 mg/L against S. pneumoniae and S. aureus .