Disposition, Metabolism, and Excretion of [ ¹⁴ C]Doripenem after a Single 500-Milligram Intravenous Infusion in Healthy Men

Abstract

In this open-label, single-center study, eight healthy men each received a single 500-mg dose of Doripenem is a new parenteral carbapenem antibiotic with broad-spectrum activity against gram-negative and gram-positive pathogens, including strains resistant to multiple antibiotic classes (1, 6, 7). It is indicated for adults in the treatment of complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis. Doripenem exhibits in vitro activity against contemporary strains of gram-negative bacteria that are often responsible for serious, hospital-acquired infections, including Pseudomonas aeruginosa and extended-spectrum betalactamase-and AmpC beta-lactamase-producing Enterobacteriaceae (10-12, 15, 19). In addition, doripenem is less likely than meropenem or imipenem to select for carbapenem-resistant strains of Pseudomonas aeruginosa (17). Because carbapenems produce time-dependent bactericidal activity, the ability to deliver doripenem via prolonged infusion increases the time that drug concentrations are likely to remain above the MIC for the infecting pathogen (2, 5). This may be of critical importance for difficult-to-treat pathogens that are not susceptible to other carbapenems or for which the MICs are near the susceptibility limits of the drug.The present study was designed to characterize the disposition, metabolism, and excretion of doripenem in healthy men following a single 500-mg dose administered as a 1-h intravenous infusion, which is the standard doripenem dose indicated for treatment of subjects with serious bacterial infections. On the basis of clinical-trial data, the proposed dose of doripenem for treatment of moderate to severe infections is 500 mg administered by a 1-h or 4-h infusion (C. Lucasti, A. Jasovich, O. Umeh, J. Jiang, and K. Kaniga, presented at the 17th European Congress of Clinical Microbiology and Infectious Diseases, 2007; O. Malafaia, O. Umeh, and J. Jang, presented at the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, 2006; K. Naber, R. Redman, P. Kotey, L. Lorens, and K. Kaniga, presented at the 17th European Congress of Clinical Microbiology and Infectious Diseases, 2007). MATERIALS AND METHODSThe study protocol was reviewed and approved by an independent ethics committee. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and in compliance with good clinical practices and all applicable regulatory requirements. All subjects participating in the study provided written informed consent.Subjects. Eight healthy men characterized by a screening physical examination, medical history, vital signs, 12-lead electrocardiogram, laboratory testing, and normal renal function were enrolled. The study cohort had a median age of 20.5 years (range, 18 to 45 years), a median weight of 87.5 kg (range, 55 to 93 kg), and a median body mass index of 22.9 kg/m 2 (range, 19 to 28 kg/m 2 ); all were Caucasian. Eligible patients had not smoked for at least 6 months and agreed to refrain ...

Population Pharmacokinetics of Doripenem in Critically Ill Patients with Sepsis in a Malaysian Intensive Care Unit

“…However, this estimate is notably lower than that previously described in healthy volunteers (0.22 to 0.25 liters/kg/h) (34,35) and noncritically ill patients (0.16 to 0.25 liters/kg/h) (8,(36)(37)(38). The differences were expected, as the noncritically ill population would presumably have better end-organ function than our patient cohort.…”

“…Typical V (V 1 ϩ V 2 ) of doripenem in our cohort was 0.47 liters/kg (range, 0.14 to 1.7 liters/kg), which is generally consistent with other reports in critically ill patients with conserved renal function (0.30 to 0.54 liters/kg) (7,9,18,33). This estimate is considerably larger than that previously described in healthy volunteers (0.22 to 0.24 liters/kg) (34,35) and noncritically ill patients (0.18 to 0.24 liters/kg) (17,(36)(37)(38). This was anticipated, as the V of hydrophilic antibiotics, such as aminoglycosides (39,40) and beta-lactams (12), is often reported to be 2-fold greater in critically ill patients.…”

“…Consistent with previous data (4,33,36,38), estimated Cockcroft-Gault CL CR , a surrogate measure for renal function in our analysis, albeit less accurate than the measured CL CR , was a key predictor of doripenem CL. This relationship is highly predictable, since doripenem is extensively cleared via renal elimination; approximately 75%, and in some reports up to 90%, of doripenem is cleared via the renal route (35). Based on equation 1, a 30-ml/min increase in the estimated CL CR would increase doripenem CL by 52%.…”

Graphene and Polyaniline Composite Modified Glassy Carbon Electrode for Electrochemical Determination of Doripenem and Meropenem Metabolites

“…detected only one metabolite in the urine, the ring-open lactam. Iolanda Cirillo et al [23] reported the metabolism of doripenem in urine. In this work, the electrochemical behaviour of the metabolites of DPM and MPM has been studied, the reduction mechanism has been suggested on the modified electrode and differential pulse voltammetry method have been offered and applied to the determination of DPM and MPM in human urine and serum samples [24].…”

Pharmacokinetic/Pharmacodynamic Analysis for Doripenem Regimens in Intensive Care Unit Patient

“…10) Therefore, the importance of individualized approaches to dosing of drugs, especially renally excreted drugs, in critical ill patients has been highlighted. Doripenem is excreted renally, 11) and is frequently used for critically ill patients in ICU. However, there is a lack of studies validating the dosage regimen based on PK/PD index of DRPM for these patients.…”