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 .