ABSTRACT
Aims: To optimize the dosing regimen in patients with severe
renal impairment based on population pharmacokinetic/pharmacodynamic
(PPK/PD) analysis.
Methods: The pharmacokinetics and safety of nemonoxacin was
evaluated in a single-dose, open-label, nonrandomized, parallel-group
study after single oral dose of 0.5 g nemonoxacin capsule in 10 patients
with severe renal impairment and 10 healthy
controls. Both blood and urine
samples were collected within 48 hours after admission and determined
the concentrations. A PPK model was built using nonlinear mixed effects
modelling. The probability of target attainment (PTA) and the cumulative
fraction of response (CFR) againstS. Pneumoniae and S.
aureus was calculated by Monte Carlo simulation.
Results: The data best fitted to a two-compartment model, from
which the PPK parameters were
estimated, including clearance (8.55
L/h), central compartment volume
(80.8 L), and peripheral
compartment volume (50.6 L). The accumulative urinary excretion was
23.4±6.5% in severe renal impairment patients and 66.1±16.8% in
healthy controls. PPK/PD modeling and simulation of 4 dosage regimens
found that nemonoxacin 0.5 g q48h was the optimal dosing regimen in
severe renal impairment patients, evidenced by higher PTA (92.7%) and
CFR (>99%) at nemonoxacin MIC ≤ 1 mg/L against S.
pneumoniae and S. aureus . The alternative regimens (0.25 g q24h;
loading dose 0.5 g on Day 1 followed by 0.25 g q24h) were insufficient
to cover the pathogens even if MIC ≤ 0.5 mg/L.
Conclusion: An extended dosing interval (0.5 g q48h) may be
appropriate for optimal efficacy of nemonoxacin in case of severe renal
impairment.