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  • Title: Comparative pharmacokinetics, pharmacodynamics, and tolerability of ertapenem 1 gram/day administered as a rapid 5-minute infusion versus the standard 30-minute infusion in healthy adult volunteers.
    Author: Wiskirchen DE, Housman ST, Quintiliani R, Nicolau DP, Kuti JL.
    Journal: Pharmacotherapy; 2013 Mar; 33(3):266-74. PubMed ID: 23400916.
    Abstract:
    STUDY OBJECTIVE: To compare ertapenem pharmacokinetics, pharmacodynamics, and tolerability when administered as a rapid 5-minute infusion to the standard 30-minute infusion. DESIGN: Prospective, randomized, crossover pharmacokinetic study. SETTING: Clinical research center. SUBJECTS: Twelve healthy adult volunteers. INTERVENTION: Each subject received ertapenem 1 g intravenously, administered either as a rapid 5-minute infusion or the standard 30-minute infusion, every 24 hours for 3 days (first phase); after a 4-day washout period, each subject then received the other infusion every 24 hours for 3 days (second phase). MEASUREMENTS AND MAIN RESULTS: Plasma samples were collected after the first and third (steady-state) doses of each study phase, and protein binding was assessed by use of ultrafiltration. Pharmacokinetic analyses were conducted using noncompartmental and compartmental methods. A 5000-subject Monte Carlo simulation was used to assess the probability of target attainment for free drug concentration remaining above the minimum inhibitory concentration (MIC) for 40% or greater of the dosing interval (40% fT > MIC) over an MIC range. Ertapenem was well tolerated and adverse events were similar for both infusions. The ertapenem steady-state mean ± SD maximum concentrations were 193.3 ± 43.3 and 165.7 ± 20.4 mg/L for the 5- and 30-minute infusions, respectively; the mean ± SD areas under the concentration-time curves from 0-24 hours were 561.2 ± 77.0 and 531.3 ± 56.9 μg · hr/ml (geometric mean ratio 1.008, 90% confidence interval 0.999-1.017), respectively. Protein binding was concentration dependent (range 87.9-98.9%). A two-compartment model best described ertapenem pharmacokinetics with the following parameter estimates: clearance 1.89 ± 0.19 L/hr, volume of central compartment 5.04 ± 0.56 L, and transfer constants k12 0.43 ± 0.08/hr and k21 0.44 ± 0.07/hr. The probabilities of target attainment for 5- and 30-minute infusions were 97.0% and 97.9% at an MIC of 0.25 mg/L and 1.7% and 2.8% at an MIC of 0.5 mg/L, respectively. CONCLUSION: Ertapenem administered as a rapid 5-minute infusion provides a well tolerated, bioequivalent, and pharmacodynamically equivalent regimen to the 30-minute infusion at clinically relevant MICs.
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