Nemonoxacin Dosage Adjustment in Patients with Severe Renal Impairment Based on Population Pharmacokinetic and Pharmacodynamic Analysis

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) against S. 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.

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Population Pharmacokinetics of Peramivir in Healthy Volunteers and Influenza Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00799-15 ◽

2015 ◽

Vol 59 (11) ◽

pp. 6755-6762 ◽

Cited By ~ 4

Author(s):

Yumiko Matsuo ◽

Toru Ishibashi ◽

Alan S. Hollister ◽

Toshihiro Wajima

Keyword(s):

Renal Function ◽

Plasma Concentration ◽

Renal Impairment ◽

Severe Renal Impairment ◽

The United States ◽

Volume Of Distribution ◽

Elderly Subjects ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Concentration Data

ABSTRACTPeramivir is an intravenous anti-influenza agent that inhibits viral growth by selectively inhibiting neuraminidase in human influenza A and B viruses. To characterize its pharmacokinetics, a population pharmacokinetic analysis of peramivir was performed using 3,199 plasma concentration data samples from 332 subjects in six clinical studies in Japan and the United States, including studies with renal impairment subjects, elderly subjects, and influenza patients. A three-compartment model well described the plasma concentration data for peramivir, and creatinine clearance was found to be the most important factor influencing clearance. Age and body weight were also found to be covariates for clearance and the volume of distribution, respectively. No difference in pharmacokinetics was found between genders or between Japanese and U.S. subjects. Small differences in pharmacokinetics were observed between uninfected subjects and influenza patients (clearance was 18% higher and the volume of distribution was 6% lower in influenza patients). Monte Carlo simulations indicated that single adjusted doses of 1/3- and 1/6-fold for patients with moderate and severe renal impairment, respectively, would give areas under the curve comparable to those for patients with normal renal function. The population pharmacokinetic model developed for peramivir should be useful for understanding its pharmacokinetic characteristics and for dose adjustment on the basis of renal function.

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Considerations in the Selection of Renal Dosage Adjustments for Patients with Serious Infections and Lessons Learned from the Development of Ceftazidime-Avibactam

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02105-19 ◽

2020 ◽

Vol 64 (4) ◽

Author(s):

Jianguo Li ◽

Mark Lovern ◽

Todd Riccobene ◽

Timothy J. Carrothers ◽

Paul Newell ◽

...

Keyword(s):

Renal Function ◽

Renal Impairment ◽

Severe Renal Impairment ◽

Complicated Urinary Tract Infection ◽

Development Program ◽

Lessons Learned ◽

Total Daily Dose ◽

Population Pharmacokinetic ◽

Phase 3 ◽

Two Phase

ABSTRACT An extensive clinical development program (comprising two phase 2 and five phase 3 trials) has demonstrated the efficacy and safety of ceftazidime-avibactam in the treatment of adults with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), and hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP). During the phase 3 clinical program, updated population pharmacokinetic (PK) modeling and Monte Carlo simulations using clinical PK data supported modified ceftazidime-avibactam dosage adjustments for patients with moderate or severe renal impairment (comprising a 50% increase in total daily dose compared with the original dosage adjustments) to reduce the risk of subtherapeutic drug exposures in the event of rapidly improving renal function. The modified dosage adjustments were included in the ceftazidime-avibactam labeling information at the time of initial approval and were subsequently evaluated in the final phase 3 trial (in patients with HAP, including VAP), providing supportive data for the approved U.S. and European ceftazidime-avibactam dosage regimens across renal function categories. This review describes the analyses supporting the ceftazidime-avibactam dosage adjustments for renal impairment and discusses the wider implications and benefits of using modeling and simulation to support dosage regimen optimization based on emerging clinical evidence.

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Pioglitazone concentrations are reduced in patients with severe renal impairment but dosage adjustment is probably not necessary,

Inpharma Weekly ◽

10.2165/00128413-200313880-00048 ◽

2003 ◽

Vol &NA; (1388) ◽

pp. 20

Author(s):

&NA;

Keyword(s):

Renal Impairment ◽

Dosage Adjustment ◽

Severe Renal Impairment

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Population Pharmacokinetics of Piperacillin in Non-Critically Ill Patients with Bacteremia Caused by Enterobacteriaceae

Antibiotics ◽

10.3390/antibiotics10040348 ◽

2021 ◽

Vol 10 (4) ◽

pp. 348

Author(s):

Vicente Merino-Bohórquez ◽

Fernando Docobo-Pérez ◽

Adoración Valiente-Méndez ◽

Mercedes Delgado-Valverde ◽

Manuel Cameán ◽

...

Keyword(s):

Kidney Disease ◽

Renal Impairment ◽

Critically Ill ◽

Critically Ill Patients ◽

Severe Renal Impairment ◽

Bloodstream Infections ◽

Population Pharmacokinetic ◽

Loading Dose ◽

Serum Samples ◽

Drug Concentrations

This study analyzes the pharmacokinetic variability of piperacillin in non-critically ill patients with Enterobacteriaceae bloodstream infections (EBSI) and explores predicted clinical outcomes and piperacillin-related neurotoxicity under different renal conditions. Hospitalized, non-critically ill patients treated with piperacillin–tazobactam for EBSI were included. Four serum samples per patient were collected and analyzed. A population pharmacokinetic model was developed using the Pmetrics package for R. Monte Carlo simulations of various dosage regimens of 4 g piperacillin, administered q8 h or q12 h by short (0.5 h) or long (4 h) infusion, following the different glomerular filtration rate (GFR) categories used to classify chronic kidney disease (Kidney Disease: Improving Global Outcomes, KDIGO) to determine the probability of target attainment (PTA) using a free drug concentrations above the minimal inhibitory concentration (fT > MIC) of 50% for efficacy and targets for piperacillin-associated neurotoxicity. Twenty-seven patients (102 samples) were included. Extended piperacillin infusions reached a PTA > 90% (50%fT > MIC) within the susceptibility range, although a loading dose did not greatly improve the expected outcome. Long infusions reduced the expected toxicity in patients with severe renal impairment. The study supports the use of extended infusions of piperacillin in non-critically ill patients with EBSI. No benefits of a loading dose were expected in our population. Finally, extended infusions may reduce the risk of toxicity in patients with severe renal impairment.

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