Pharmacokinetics of imipenem in healthy volunteers following administration by 2 h or 0.5 h infusion

Sutep Jaruratanasirikul*, Nuntida Raungsri, Jarurat Punyo and Somchai Sriwiriyajan

Department of Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkla 90110, Thailand


* Corresponding author. Tel/Fax: +66-74-429385; E-mail: sutep.j{at}psu.ac.th

Received 20 June 2005; returned 4 August 2005; revised 12 September 2005; accepted 19 September 2005


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Objectives: The aim of this study was to demonstrate the t > MIC of 0.5 and 1 g of imipenem when administered by 2 h infusion every 6 h compared with 0.5 g of imipenem when administered by 0.5 h infusion every 6 h.

Methods: The study was a randomized three-way crossover study with a 30 h wash-out period in eight healthy volunteers. Each subject received imipenem in three regimens: (i) a 0.5 h infusion of 0.5 g every 6 h for three doses; (ii) a 2 h infusion of 0.5 g every 6 h for three doses; and (iii) a 2 h infusion of 1 g every 6 h for three doses.

Results: Following 0.5 h infusion of 0.5 g, the percentages of time above four times an MIC of 4, 2 and 1 mg/L were 21.5 ± 2.2%, 38.6 ± 3.5% and 57.5 ± 4% of a 6 h interval, respectively. For the 2 h infusion of 0.5 g, the percentages of time above four times an MIC of 4, 2 and 1 mg/L were 26.9 ± 8.5%, 48.0 ± 3.5% and 65.4 ± 3.2% of a 6 h interval, respectively. For the 2 h infusion of 1 g, the percentages of time above four times an MIC of 4, 2 and 1 mg/L were 51.6 ± 5.4%, 67.8 ± 4.5% and 87.8 ± 5.6% of a 6 h interval, respectively.

Conclusions: A 2 h infusion resulted in a greater t > MIC than those after a 0.5 h infusion and intermittent infusion may be a useful mode of administration of imipenem in tropical countries.

Keywords: pharmacodynamics , ß-lactams , carbapenems


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Imipenem, a carbapenem antibacterial agent, exhibits primarily time-dependent killing.13 In common with other ß-lactams, the important pharmacokinetic/pharmacodynamic (PK/PD) parameter that correlates with the therapeutic efficacy is the time that concentrations in serum are above the MIC (t > MIC). A previous study showed that bactericidal activity of ß-lactams reached a maximal value at four times the MIC.4,5 Therefore, administration by prolonging the intermittent infusion may offer the opportunity to increase the t > MIC within the limitations of stability at room temperature. A previous study showed that imipenem remained 90% stable for less than 3 h at 37°C and was degraded by up to 60% within 24 h at that temperature.6 We have therefore proposed that a 2 h infusion every 6 h may be the most effective route of administration in tropical countries. In this study, we report a comparison of the PK/PD parameter, t > MIC, of 0.5 and 1 g of imipenem when administered by 2 h infusion every 6 h and 0.5 g of imipenem when administered by 0.5 h infusion every 6 h.


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Subjects

The study was conducted in eight non-smoking, non-alcoholic, non-obese healthy volunteers. All subjects were male. Their mean age was 28.25 ± 4.98 years (range 24–39) and their mean weight was 58.75 ± 8.61 kg (range 51–75). Their mean body mass index was 20.6 ± 2.7 kg/m2 (range 17.2–25.3). The protocol for the study was approved by the Ethics Committee of Songklanagarind Hospital and written informed consent was obtained from each subject. Subjects underwent a pre-study evaluation to ensure that they had no underlying illnesses and were not currently or had not recently taken any medication. All subjects had a creatinine clearance rate ≥80 mL/min. All subjects had normal biochemical and haematological laboratory profiles. Subjects were excluded if they had a history of imipenem or any other ß-lactam intolerance.

Drugs and chemicals

Tienam® was purchased from MSD, Thailand. Imipenem was generously donated by Merck & Co, Inc., USA, as pure powder. All of the solvents were HPLC grade.

Study design

The study was a randomized three-way crossover study with a 30 h wash-out period. Imipenem was reconstituted according to the manufacturer's guidelines. It was then diluted into two preparations: 0.5 g in 50 mL of normal saline solution and 1 g in 50 mL of normal saline solution immediately prior to infusion. Each subject received imipenem in three regimens at room temperature (32–37°C): (i) a 0.5 h infusion of 0.5 g of imipenem via an infusion pump at a constant flow rate every 6 h for three doses; (ii) a 2 h infusion of 0.5 g of imipenem via an infusion pump at a constant flow rate every 6 h for three doses; and (iii) a 2 h infusion of 1 g of imipenem via an infusion pump at a constant flow rate every 6 h for three doses.

Blood sampling

Imipenem pharmacokinetic studies were carried out during the third dose of each regimen (12–18 h after the start of each regimen). Blood samples (~5 mL) were obtained by direct venepuncture at the following times: before (time 0) and 15 min, 30 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h and 6 h after the third dose of each regimen. Blood samples were added to the heparinized tube and centrifuged at 1000 g for 10 min not later than 15 min after collection. An equal volume of stabilizing solution (0.5 M MOPS/water/ethylene glycol, 2:1:1, v/v/v) was added to each plasma sample, vortexed and stored at –80°C until analysis within 1 week.

Imipenem assay

This assay was used for measuring imipenem concentrations only, not for cilastatin concentrations. The concentrations of imipenem were determined by reversed-phase HPLC. The samples were prepared by the method of Garcia-Capdevila et al.7

Briefly, 250 µL of the stabilizing solution was added to 250 µL of the sample. Mixtures were then applied to ultrafiltration, using Ultrafree®-MC units, for 10 min at 6000 g. An aliquot of the sample (10 µL) was injected, using an automated injection system (Waters 717 plus Autosampler, Waters Associates, Milford, MA, USA), onto a Nova-Pak C18 column (Waters Associates). The mobile phase was 0.2 M borate buffer, pH 7.2, at a flow rate of 1 mL/min. The column effluent was monitored by UV detection (Waters 486, Waters Associates) at 300 nm. The peaks were recorded and integrated on a Waters 746 Data Module (Waters Associates). The limit of detection of imipenem was 0.125 mg/L.

The intra-assay reproducibility values characterized by coefficients of variation (CV) were 1.84%, 0.02% and 0.95% for samples containing 1, 10 and 100 mg/L, respectively. The inter-assay reproducibility precision values, calculated by CV, were 2.60%, 4.75% and 2.18% for samples containing 1, 10 and 100 mg/L, respectively.

Pharmacokinetic and statistical analysis

The maximum plasma concentration (Cmax) and the minimum plasma concentration (Cmin) were determined by visual inspection of the individual plasma concentration–time profiles. The elimination half-life (t1/2), the elimination rate constant (kel), the area under the concentration–time curve between 0 and infinity (AUC0–{infty}), the total clearance (CLtot) and the volume of distribution (V) were determined using WinNonlin Version 1.1 (Scientific Consulting Inc, NC, USA). From the individual concentration–time curves, the time above four times the MIC was calculated for MICs of 4, 2 and 1 mg/L. Results were expressed as mean values ± standard deviation (SD) and statistical comparisons were made using the analysis of variance (ANOVA). P values of <0.05 were considered significant.


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The mean plasma imipenem concentrations for 0.5 h infusion of 0.5 g and 2 h infusion of 0.5 and 1 g are shown in Figure 1. The pharmacokinetic parameters of imipenem for the three regimens are presented in Table 1. All three regimens were well tolerated and there were no reported adverse events.



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Figure 1. Mean serum imipenem concentration–time data for eight healthy volunteers following administration of: 0.5 g, 0.5 h infusion (filled squares); 0.5 g, 2 h infusion (open circles); and 1 g, 2 h infusion (filled triangles).

 

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Table 1. Pharmacokinetic parameters (mean ± SD) of imipenem administered by 2 h and 0.5 h infusion

 

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Studies in animal infection models have shown that for most ß-lactams, concentrations do not need to exceed the MIC for 100% of the dosing interval to achieve a significant antibacterial effect.1,2 Bacteriostatic effects of carbapenems against Escherichia coli and Pseudomonas aeruginosa in a murine thigh-infection model are observed when serum drug concentrations are above the MIC for 20% of the dosing interval, whereas the t > MIC required for bactericidal activity is 40% of the dosing interval.8 An earlier study has demonstrated that free drug is available for antimicrobial activity; however, imipenem has low (<10%) protein binding3 and therefore, t > MIC for both free and total drug required for bactericidal effect are not much different.

Following the manufacturers' instructions, ß-lactams are usually administered by intermittent injection; however, with this mode of administration, the high peak concentrations do not enhance the bactericidal activity of these agents. Previous studies in healthy volunteers and patients with ventilator-associated pneumonia found that a 3 h infusion of meropenem resulted in greater t > MIC values than those seen after bolus injection, indicating that intermittent infusion may be an appropriate mode of administration of meropenem in tropical countries.9,10

Although the non-susceptible breakpoint recommended in NCCLS guidelines is >4 mg/L for imipenem, most clinical isolates have an MIC of imipenem well below 4 mg/L.3 Therefore, we have used values of 1, 2 and 4 mg/L as breakpoints in our pharmacodynamic analysis, as these give a better representation of the range of MICs seen in clinical isolates. In this study, the mean serum concentrations after a 2 h infusion of 0.5 g of imipenem were above four times the MIC of 2 mg/L for ~48% of a 6 h dosing interval. Even when a 0.5 h infusion of 0.5 g of imipenem was used, the percentages of time above four times the MIC of 2 mg/L were still 38% of the dosing interval. Therefore, from these data, it appears that either a 2 h or a 0.5 h infusion of 0.5 g of imipenem every 6 h can provide serum concentrations above four times the MIC of 2 mg/L for 40% of the dosing interval. However, a 2 h infusion seems to result in greater t > MIC values than those seen after a 0.5 h infusion. For isolated pathogens with MICs of 4 mg/L, imipenem dosage administered by 2 h infusion should be increased to a maximum of 1 g every 6 h. The mean serum drug concentrations obtained from a 2 h infusion of 1 g of imipenem every 6 h were above four times the MIC of 4 mg/L for ~51% of a 6 h period. Therefore, only a 2 h infusion of 1 g of imipenem could maintain serum drug concentrations above four times the MIC of 4 mg/L for more than 40% of the dosing interval.

In conclusion, it was found that a 2 h infusion of imipenem results in greater t > MIC values than those seen after a 0.5 h infusion, suggesting that a 2 h infusion may be an appropriate route of administration of imipenem in tropical countries where drug instability may prevent the use of continuous infusion. However, further prospective studies are still necessary to confirm these findings.


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None to declare.


    Acknowledgements
 
We thank Mr David Patterson for checking our English. This work was supported by a faculty grant from the Faculty of Medicine, Prince of Songkla University.


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1. Craig WA. Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad-spectrum cephalosporins. Diagn Microbiol Infect Dis 1995; 22: 89–96.[CrossRef][ISI][Medline]

2. Vogelman B, Gudmundsson S, Leggett J et al. Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. J Infect Dis 1988; 158: 831–47.[ISI][Medline]

3. Norrby SR, Faulkner KL, Newell PA. Differentiating meropenem and imipenem/cilastatin. Infect Dis Clin Pract 1997; 6: 291–303.[ISI]

4. Tam VH, McKinnon PS, Akins RL et al. Pharmacodynamics of cefepime in patients with Gram-negative infections. J Antimicrob Chemother 2002; 50: 425–8.[Abstract/Free Full Text]

5. Craig WA. Basic pharmacodynamics of antibacterials with clinical applications to the use of ß-lactams, glycopeptides, and linezolid. Infect Dis Clin N Am 2003; 17: 479–501.[CrossRef][ISI][Medline]

6. Viaene E, Chanteux H, Servais H et al. Comparative stability studies of antipseudomonal ß-lactam for potential administration through portable elastomeric pumps (home therapy for cystic fibrosis patients) and motor-operated syringes (intensive care units). Antimicrob Agents Chemother 2002; 46: 2327–32.[Abstract/Free Full Text]

7. Garcia-Capdevila L, Lopez-Calull C, Arroyo C et al. Determination of imipenem in plasma by high-performance liquid chromatography for pharmacokinetic studies in patients. J Chromatogr B 1997; 692: 127–32.[CrossRef][ISI]

8. Drusano GL. Prevention of resistance: a goal for dose selection for antimicrobial agents. Clin Infect Dis 2003; 36 Suppl 1: S42–S50.[CrossRef][ISI][Medline]

9. Jaruratanasirikul S, Sriwiriyajan S. Comparison of the pharmacodynamics of meropenem in healthy volunteers following administration by intermittent infusion or bolus injection. J Antimicrob Chemother 2003; 52: 518–21.[Abstract/Free Full Text]

10. Jaruratanasirikul S, Sriwiriyajan S, Punyo J. Comparison of the pharmacodynamics of meropenem in patients with ventilator-associated pneumonia following administration by 3-h infusion or bolus injection. Antimicrob Agents Chemother 2005; 49: 1337–9.[Abstract/Free Full Text]





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