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Pharmacokinetic-pharmacodynamic-model-guided doripenem dosing in critically ill patients.

ABSTRACT: The growing number of infections caused by multidrug-resistant pathogens has prompted a more rational use of available antibiotics given the paucity of new, effective agents. Monte Carlo simulations were utilized to determine the appropriateness of several doripenem dosing regimens based on the probability of attaining the critical drug exposure metric of time that drug concentrations remain above the drug MIC (T>MIC) for 35% (and lower thresholds) of the dosing interval in >80 to 90% of the population (T>MIC 35% target). This exposure level generally correlates with in vivo efficacy for carbapenems. In patients with creatinine clearance of >50 ml/min, a 500-mg dose of doripenem infused over 1 h every 8 h is expected to be effective against bacilli with doripenem MICs of < or =1 microg/ml based on a T>MIC 35% target and MICs of < or =2 microg/ml based on lower targets. A longer, 4-hour infusion time improved target attainment in most cases, such that the T>MIC was adequate for pathogens with doripenem MICs as high as 4 microg/ml. Efficacy is expected for infections caused by pathogens with doripenem MICs of < or =2 microg/ml in patients with moderate renal impairment (creatinine clearance, 30 to 50 ml/min) who receive doripenem at 250 mg infused over 1 h every 8 h and in patients with severe impairment (creatinine clearance between 10 and 29 ml/min) who receive doripenem at 250 mg, infused over 1 h or 4 h, every 12 h. Results of pharmacokinetics/pharmacodynamics (PK/PD) modeling can guide dose optimization, thereby potentially increasing the clinical efficacy of doripenem against serious Gram-negative bacterial infections.

SUBMITTER: Samtani MN

PROVIDER: S-EPMC2876367 | biostudies-other | 2010 Jun

REPOSITORIES: biostudies-other

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Pharmacokinetic-pharmacodynamic-model-guided doripenem dosing in critically ill patients.

Samtani Mahesh N MN Flamm Robert R Kaniga Koné K Nandy Partha P

Antimicrobial agents and chemotherapy 20100412 6

The growing number of infections caused by multidrug-resistant pathogens has prompted a more rational use of available antibiotics given the paucity of new, effective agents. Monte Carlo simulations were utilized to determine the appropriateness of several doripenem dosing regimens based on the probability of attaining the critical drug exposure metric of time that drug concentrations remain above the drug MIC (T>MIC) for 35% (and lower thresholds) of the dosing interval in >80 to 90% of the pop ...[more]

PMID: 20385857

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Project description:Objectives: Teicoplanin has been extensively used in the treatment for infections caused by gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA). However, current teicoplanin treatment is challenging due to relatively low and variable concentrations under standard dosage regimens. This study aimed to investigate the population pharmacokinetics (PPK) characteristics of teicoplanin in adult sepsis patients and provide recommendations for optimal teicoplanin dosing regimens. Methods: A total of 249 serum concentration samples from 59 septic patients were prospectively collected in the intensive care unit (ICU). Teicoplanin concentrations were detected, and patients' clinical data were recorded. PPK analysis was performed using a non-linear, mixed-effect modeling approach. Monte Carlo simulations were performed to evaluate currently recommended dosing and other dosage regimens. The optimal dosing regimens were defined and compared by different pharmacokinetic/pharmacodynamic parameters, including trough concentration (Cmin), the ratio of 24-h area under the concentration-time curve to the minimum inhibitory concentration (AUC0-24/MIC), as well as the probability of target attainment (PTA) and the cumulative fraction of response (CFR) against MRSA. Results: A two-compartment model adequately described the data. The final model parameter estimates for clearance, central compartment volume of distribution, intercompartmental clearance and peripheral compartment volume were 1.03 L/h, 20.1 L, 3.12 L/h and 101 L, respectively. Glomerular filtration rate (GFR) was the only covariate that significantly affected teicoplanin clearance. Model-based simulations revealed that 3 or 5 loading doses of 12/15 mg/kg every 12 h followed by a maintenance dose of 12/15 mg/kg every 24 h-72 h for patients with different renal functions were required to achieve a target Cmin of 15 mg/L and a target AUC0-24/MIC of 610. For MRSA infections, PTAs and CFRs were not satisfactory for simulated regimens. Prolonging the dosing interval may be easier to achieve the target AUC0-24/MIC than reducing the unit dose for renal insufficient patients. Conclusion: A PPK model for teicoplanin in adult septic patients was successfully developed. Model-based simulations revealed that current standard doses may result in undertherapeutic Cmin and AUC, and a single dose of at least 12 mg/kg may be needed. AUC0-24/MIC should be preferred as the PK/PD indicator of teicoplanin, if AUC estimation is unavailable, in addition to routine detection of teicoplanin Cmin on Day 4, follow-up therapeutic drug monitoring at steady-state is recommended.

Dataset Information

Pharmacokinetic-pharmacodynamic-model-guided doripenem dosing in critically ill patients.

Publications

Pharmacokinetic-pharmacodynamic-model-guided doripenem dosing in critically ill patients.

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