ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 2010, p. 924–926 Vol. 54, No.

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0066-4804/10/$12.00 doi:10.1128/AAC.00836-09
Copyright © 2010, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics of Ertapenem following Intravenous and

Subcutaneous Infusions in Patients䌤
Denis Frasca,1,3 Sandrine Marchand,1,2,3 Franck Petitpas,1,3 Claire Dahyot-Fizelier,1,2,3
William Couet,1,2,3* and Olivier Mimoz1,2,3
INSERM, ERI-23, Pôle Biologie Santé, 40 Avenue du Recteur Pineau, Poitiers, France1; Université de Poitiers,
UFR Médecine-Pharmacie, 6 Rue de la Milétrie, Poitiers, France2; and CHU Poitiers, 2 Rue de la Milétrie,
Poitiers, France3
Received 22 June 2009/Returned for modification 28 July 2009/Accepted 18 November 2009

Steady-state pharmacokinetics of ertapenem were compared in patients after 1-g intravenous and subcuta-
neous (s.c.) infusions. Bioavailability was 99% ⴞ 18% after s.c. administration, but peaks were reduced by
about 1⁄2 (43 ⴞ 29 versus 115 ⴞ 28 ␮g/ml) and times to peak were delayed. Simulations based on unbound
concentrations show that time over the MIC should always be longer than 30% to 40% of the dosing interval,
suggesting that s.c. infusion could be an alternative in patients with reduced vascular access.

Ertapenem is a recent long-acting, parenteral carbapenem ment, patients were mechanically ventilated and exhibited a
antibiotic mainly indicated in the treatment of community- systemic inflammatory response syndrome. Infection sites jus-
acquired infections or hospital-acquired infections without sus- tifying ertapenem administration were early-onset ventilator-
picion of Pseudomonas or Acinetobacter (5), as an alternative associated pneumonia (n ⫽ 5) and surgical wound infection
to penicillin–␤-lactamase inhibitor combination (10, 19, 23). (patient no. 2). The microorganisms isolated at those infection
The pharmacokinetics of ertapenem has been extensively de- sites were methicillin-susceptible Staphylococcus aureus (n ⫽
scribed (2, 3, 6–8, 15, 16, 18, 21). Ertapenem may be adminis- 2), Haemophilus influenzae (n ⫽ 1), Escherichia coli (n ⫽ 1),
tered intravenously (i.v.) or intramuscularly (i.m.) for several and Klebsiella pneumoniae (n ⫽ 2). Local tolerance was as-
days (13), but for many hospitalized patients the i.m. route sessed during the 24 h following subcutaneous infusion by
might be contraindicated due to anticoagulant therapy. Sub- checking for erythema, pruritus, hematoma, or necrosis at the

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cutaneous (s.c.) administration is daily safely used with drugs insertion site. Ertapenem (Invanz) was purchased from the
and fluids mostly for dehydrated elderly patients or patients in pharmaceutical company Merck Sharp & Dohme-Chibret
palliative care when oral or i.v. administration is impossible (Paris, France) as a dry powder and reconstituted in 50 ml
(20) and could then appear as an interesting alternative. Ad- normal saline just before being infused with a pump (Orches-
vantages for the s.c. route over the i.v. route include a similar tra DPS; Fresenius Vial, Brezins, France). The administration
number of or even fewer complications, cost savings, greater sites were a central vein (i.v.) or the anterior side of a thigh
patient comfort, and less nursing time to start and maintain the (s.c.). Initially 1 g of ertapenem was administered i.v. over 30
infusion (1, 22). The aim of this study was to compare the min once daily, and blood samples for the i.v. pharmacokinetic
pharmacokinetics of ertapenem at steady state following 30- study were collected between the 4th day and the 7th day. The
min i.v. and s.c. infusions in order to determine if s.c. admin- next day, treatment was shifted to the s.c. route and a second
istration of ertapenem, which is not yet approved, could be a series of blood samples was collected during the following 24 h
viable alternative for i.v. infusion in patients with limited vas- for the s.c. pharmacokinetic study. Ertapenem administration
cular sites. was shifted back to the i.v. route until the end of therapy.
The study was conducted at the University Hospital of Poit- Blood samples were drawn via an arterial catheter in hepa-
iers (France) after its approval by the local ethics committee rinized tubes and immediately centrifuged for 10 min at
(Region Poitou-Charentes CCPPRB, protocol no. 05.12.26). 2,500 ⫻ g and 4°C to separate plasma, which was then trans-
Written informed consent was obtained from each subject or ferred to storage vials and diluted (1:1) with a stabilizing so-
their closest relative if the patient was unconscious. The study lution consisting of 1:1 ethylene glycol and 2-(4-morpholino)
enrolled 6 adult male patients suspected of having an infection ethylsulfonic acid at 0.1 mol/liter (pH 6.5). Plasma ultrafiltrates
due to ertapenem-susceptible bacteria (Table 1). Ertapenem were obtained from plasma samples collected at times 0.5 h
was the only antibiotic used, sedation was obtained with propo- and 24 h postdosing by centrifugation with a Centrifree system
fol and sufentanil, and no other drugs that could have been (CF50A model; Amicon, Molsheim, France). Samples were
suspected of interacting with ertapenem pharmacokinetics stored at ⫺80°C until analysis. Ertapenem concentrations were
such as vasopressors or midazolam were used. At study enroll- measured using a liquid chromatography method with tandem
mass spectrometry detection (12). Within- and between-day
variability of the method at various concentrations led to co-
* Corresponding author. Mailing address: INSERM, ERI-23, Pôle efficients of variation no greater than 16.4% (n ⫽ 11) and
Biologie Santé, 40 Avenue du Recteur Pineau, Poitiers, France.
Phone: (33) 5 49 45 43 79. Fax: (33) 5 49 45 43 78. E-mail: william
accuracies ranging between 98.5% and 110.9%. A compart-
[email protected]. mental pharmacokinetic analysis for total plasma concentra-
䌤
Published ahead of print on 23 November 2009. tions was conducted with WinNonLin version 4.0.1. (Pharsight

924
VOL. 54, 2010 ERTAPENEM PHARMACOKINETICS AFTER SUBCUTANEOUS INFUSION 925

TABLE 1. Patient characteristics and individual and mean ⫾ SD pharmacokinetic parameters based on total ertapenem concentrations
measured after i.v. and s.c. 30-min infusions of ertapenem (1 g/24 h) to 6 adult patients
Result for patient:
Parametera Mean ⫾ SDb
1 2 3 4 5 6

Patient characteristics
Age (yr) 67 52 19 63 55 81 56 ⫾ 19
Body wt (kg) 72 60 76 90 100 66 77 ⫾ 14
Height (m) 1.67 1.72 1.80 1.80 1.85 1.70 1.76 ⫾ 0.07
BMI (kg/m2) 25.8 20.3 23.5 27.8 29.2 22.8 24.9 ⫾ 3.0
SAPS II on admission 20 18 21 59 21 30 28 ⫾ 14
Albumin concn (g/liter) 10.0 14.4 16.8 14.3 9.5 19.6 14.1 ⫾ 3.6
Creatinine concn (␮mol/liter) 27 37 43 66 86 72 55 ⫾ 21
Total concn of proteins (g/liter) 48 57 65 49 40 58 53 ⫾ 9

Fluid balance (ml)

i.v. ⫹ 350 ⫹ 950 ⫹ 200 ⫹ 350 ⫹ 800 ⫹ 100 ⫹458 ⫾ 340
s.c. ⫹ 500 ⫹ 700 ⫹ 200 ⫹ 150 ⫹ 650 ⫹ 150 ⫹392 ⫾ 255

ICU outcome Survived Survived Survived Survived Survived Survived

Pharmacokinetics
Cmax (␮g/ml)
i.v. 94 124 104 75 148 142 115 ⫾ 28
s.c. 25 25 77 19 28 84 43 ⫾ 29*

tmax (h)
i.v. 0.5 0.5 0.5 0.5 0.5 0.5 0.5
s.c. 2.7 1.3 2.8 4.6 2.3 2.3 2.7 ⫾ 1.1*

t1/2 (h)
i.v. 3.4 2.3 4.7 3.0 4.9 5.3 3.9 ⫾ 1.2
s.c. 5.1 6.3 2.8 6.6 6.4 5.3 5.4 ⫾ 1.4*

AUC0–24 s.c./AUC0–24 i.v. 0.87 1.02 1.03 1.18 0.70 1.14 0.99 ⫾ 0.18

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CL (liters/h) i.v. 4.7 4.4 3.1 6.2 2.6 1.7 3.8 ⫾ 1.6

Vss (liters) i.v. 19.4 12.6 15.0 23.1 15.3 10.9 16.1 ⫾ 4.5

fu (%)
i.v. 45.8 ⫾ 4.4 43.4 ⫾ 4.3 40.9 ⫾ 3.9 45.8 ⫾ 3.3 51.4 ⫾ 5.5 46.8 ⫾ 4.6
s.c. 43.4 ⫾ 1.7 41.4 ⫾ 1.5 40.4 ⫾ 2.8 44.1 ⫾ 0.9 48.3 ⫾ 2.2 45.3 ⫾ 2.9
a
BMI, body mass index; SAPS, simplified acute physiology score; ICU, intensive care unit; Cmax, maximal concentration of ertapenem; tmax, time to obtain maximal
concentration; t1/2, half-life of elimination; AUC0–24, area under the curve from 0 to 24 h; CL, clearance; Vss, volume of distribution at steady state; fu, unbound fraction
of ertapenem.
b
*, P ⬍ 0.05.

Corporation, Mountain View, CA), using a two-open-compart- subject and each route of administration in order to estimate
ment model with multiple zero order infusions after i.v. ad- the percentage of dosing interval during which unbound con-
ministrations followed by a one-open-compartment model with centrations would be higher than various breakpoint values,
one zero order infusion after s.c. administration. Duration of chosen as 1, 2, 4, and 8 mg/liter, in agreement with the Clinical
infusion was set at a fixed value equal to 0.5 h after i.v. admin- Laboratory Standards Institute. Results are presented as
istrations, but estimated by the modeling after s.c. administra- means ⫾ standard deviation (SD), and nonparametric Wilcox-
tion. A 1/y weight was used for all the analysis. Unbound on’s rank test was used for statistical comparisons, with P ⬍
concentrations were derived from measured total concentra- 0.05 considered as significant.
tions using a saturable two-class binding site model with one All patients completed the study without any local or sys-
specific binding site and one nonspecific binding site, previ- temic adverse effect attributable to ertapenem administration,
ously validated for ertapenem (7). The rate constants for spe- and signs of infection had disappeared by the end of treatment.
cific and nonspecific binding sites were estimated from the 12 Ertapenem plasma concentration-time profiles were shifted to
pairs of total and unbound concentrations measured at 0.5 and the right after s.c. infusion, with an approximately 3-fold re-
24 h and using the mean concentration values of albumin (14.1 duction of peak concentrations (Cmax) and 5-fold increase of
g/liter) and the remaining proteins (38.7 g/liter) characteristic time to peak concentration (tmax) (Table 1). However, after 3 h
of these patients. The same compartmental pharmacokinetic postdosing on average, plasma concentrations became higher
analysis as for total concentrations was conducted with un- following s.c. infusion (Fig. 1), and AUCs were virtually iden-
bound concentrations, and simulations were derived for each tical after both routes of administration, attesting for complete
926 FRASCA ET AL. ANTIMICROB. AGENTS CHEMOTHER.

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