title: 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.
authors.affiliation: Clinical Pharmacology, Advanced PK/PD Modeling and Simulation, Johnson & Johnson Pharmaceutical Research & Development, LLC, Titusville, NJ 08560, USA.
authors.forename: Mahesh N
authors.initials: MN
authors.lastname: Samtani
authors.forename: Robert
authors.initials: R
authors.lastname: Flamm
authors.forename: Koné
authors.initials: K
authors.lastname: Kaniga
authors.forename: Partha
authors.initials: P
authors.lastname: Nandy
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015780:Carbapenems / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003404:Creatinine / Q000378:metabolism; D016638:Critical Illness; D000077726:Doripenem; D004334:Drug Administration Schedule; D024901:Drug Resistance, Multiple, Bacterial; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000378:metabolism* / Q000382:microbiology; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology; D006801:Humans; D007262:Infusions, Intravenous; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D009010:Monte Carlo Method
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D003404:Creatinine; D000077726:Doripenem
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