Journal of Antimicrobial Chemotherapy (2002) 50, 707–712

DOI: 10.1093/jac/dkf163

Single- and multiple-dose pharmacokinetics of linezolid and

co-amoxiclav in healthy human volunteers
Olaf Burkhardt1, Klaus Borner2, Nicolas von der Höh1, Peter Köppe3, Mathias Wilhelm Pletz1,
Carl Erik Nord4 and Hartmut Lode1*
1Department
of Chest and Infectious Diseases, Chest Hospital Heckeshorn, affil. Freie Universität Berlin,
Zum Heckeshorn 33, D-14109 Berlin; 2Institute of Clinical Chemistry and Pathobiochemistry and

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3Department of Medical Physics, University Hospital Benjamin Franklin, Free University of Berlin, Berlin, Germany;
4Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden

Received 16 January 2002; returned 15 April 2002; revised 30 May 2002; accepted 24 June 2002

In an open, randomized, two-period crossover study the pharmacokinetics of linezolid and

co-amoxiclav were investigated after single- and multiple-dose administration in 12 healthy
volunteers (six females and six males). Linezolid was given in tablets of 600 mg twice a day for
7 days and co-amoxiclav in tablets of 1000 mg (875 + 125 mg) once a day for 7 days. The wash-out
period was 4 weeks between the administration of the two antibacterial agents. Blood and urine
samples were collected on days 1 and 7 before and at different time points up to 24 h after
medication. The concentrations of the antibiotics in serum and urine were measured by
validated high-performance liquid chromatography methods. Linezolid exhibited a mean Cmax of
14.5 ± 4.6 mg/L after Tmax of 47.5 ± 20.1 min on day 1, with a significant increase to 24.0 ± 6.9 mg/L
on day 7 (P < 0.01). The AUDtot (total area under the data) revealed a significant increase from
140.5 ± 28.3 mg·h/L on day 1 to 220.2 ± 42.6 mg·h/L on day 7 (P < 0.01). There were no significant
differences in terminal elimination half-life between days 1 and 7 (9.53 ± 2.87 versus 7.97 ± 3.08 h)
or in total clearance (71.6 ± 17.6 versus 81.5 ± 14.7 ml/min·1.73 m2). Results are in agreement
with the assumption of a limited accumulation of linezolid under the dosage regimen given.
Serum linezolid concentrations in females were always higher than those in males. The
volume of distribution Vss/f differed significantly between females and males (41.6 ± 4.2 versus
52.2 ± 3.3 L/70 kg; P < 0.01). Pharmacokinetic parameters of amoxicillin and clavulanic acid found
in this study were similar to previously published data. No accumulation was found with
co-amoxiclav. No serious adverse event was observed with the study drugs.

Keywords: linezolid, co-amoxiclav, pharmacokinetics, multiple dosing

Introduction Enterococcus spp. and penicillin-resistant pneumococci.2

Linezolid acts as a protein synthesis inhibitor.3 It binds to
With a worldwide increasing incidence of infections due to the 23S ribosomal RNA of the 50S ribosomal subunit on the
Gram-positive organisms, which are resistant to standard bacterial ribosome and prevents formation of an initiation
therapies, there is a need for new antimicrobial agents with a complex in protein synthesis in a fashion similar to macro-
new and different mode of action compared with currently lides, lincosamides, chloramphenicol and streptogramins.
available agents. Linezolid belongs to a new class of anti- Although linezolid has been the subject of several review
bacterial agents, the oxazolidinones,1 which are active against studies,4,5 only two reports on multiple-dose kinetics, in six
a variety of Gram-positive pathogenic bacteria, including male subjects, have been published so far.6,7 In our investi-
methicillin-resistant strains of Staphylococcus aureus and gations on the ecological effects of linezolid versus co-
Staphylococcus epidermidis, vancomycin-resistant strains of amoxiclav on the normal intestinal microflora,8 we also
..................................................................................................................................................................................................................................................................

*Corresponding author. Tel: +49-30-8002-2223; Fax: +49-30-8002-2623; E-mail: [email protected]

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© 2002 The British Society for Antimicrobial Chemotherapy
 O. Burkhardt et al.

evaluated the pharmacokinetics of linezolid and co-amoxiclav before until 48 h after drug administration, the latter in order
after single and multiple oral doses in six male and six female to avoid analytical interference.
volunteers. Oral drug administration was done at 8:00 a.m. and at
8:00 p.m., in a sitting position with 100 mL of carbon dioxide-
free water at ambient temperature. The test drug was taken
Materials and methods after fasting for 12 h and in fasting conditions on days 1–7 in
the morning and 2 h after dinner for the evening administra-
Volunteers tion. Breakfast was served 2 h after drug administration on
Six male and six female healthy Caucasians, between 23 and days 1 and 7. Drug intake was observed directly in each volun-
39 years old (mean 32.2 ± 4.3 years for females and 31.3 ± 6.1 teer on day 1 and on the morning of days 2 and 7; all other
for males), average body height 166.7 ± 7.1 cm for females and medications had to be confirmed directly by telephone calls
182.3 ± 4.3 cm for males, average body weight 65.2 ± 4.5 kg from the volunteer to the responsible physician and each
for females and 82.2 ± 8.1 kg for males and average body volunteer recorded a diary protocol with the exact time of

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each medication, possible adverse event and stools, including
surface 1.73 ± 0.06 m2 for females and 2.03 ± 0.11 m2 for
the quality of faeces. All diaries were checked for possible
males, participated in the study. All had normal renal and
differences with the protocol made when receiving the
hepatic function, the mean creatinine clearance was 101.6 ±
phone calls. In the case of adverse events, the investigating
21.1 ml/min·1.73 m2. All volunteers included in the study had
physician performed a precise interview and, if necessary,
normal findings from physical examination, electrocardio-
initiated consultations or additional diagnostic or therapeutic
gram and laboratory tests (including haematological and bio-
procedures.
chemical parameters, hepatitis and human immunodeficiency
virus serological tests, tests for drug abuse, urinalysis and
Sampling
negative pregnancy test). Further exclusion criteria were
regular use of medications, abuse of alcoholic beverages, Blood samples (10 mL) were taken from a peripheral vein on
symptoms of significant illness within 3 months before the days 1 and 7 before and 30, 60, 90, 120, 180, 240, 360, 480,
study period, history of gastrointestinal, liver or kidney 720 and 1440 min (day 7) after medication through an
disease potentially interfering with absorption, metabolism or indwelling venous cannula. The samples were allowed to clot
excretion of drugs, history of central nervous system dis- at room temperature for ∼30 min. The samples were subse-
orders, allergy or hypersensitivity to the study drugs, blood quently centrifuged at 1300g for 10 min at 4°C. The serum
donation of more than 500 mL during the previous 3 months, samples were stored at –80°C until analysis.
participation in a clinical trial within 3 months before the Urine samples were collected on days 1 and 7. On both days,
study period, and pregnancy. Written informed consent was urine fractions were collected pre-dose and over the following
obtained from all volunteers prior to the study. The study was intervals: 0–3, 3–6, 6–12 and 12–24 h after administration.
approved by the Ethics Committee of University Medical The urine volumes were measured after each collection inter-
Centre Benjamin Franklin, Free University of Berlin, Berlin, val and two 5 mL aliquots were saved. The samples were
Germany. stored without preservatives in closed sterile tubes at –80°C.
Specimens were protected against light and heat during
collection, storage and analysis.
Study design and protocol
The study was performed in an open, randomized, two-period High-performance liquid chromatography (HPLC)
crossover design and was divided into two periods of 35 days. Concentrations of linezolid, amoxicillin and clavulanic acid
The treatment regimens were (i) one 600 mg linezolid tablet in serum and urine were determined by validated HPLC
(Pharmacia & Upjohn, Kalamazoo, MI, USA) in the morning methods.9,10,11 Validation of the method for linezolid gave
and one 600 mg linezolid tablet in the evening for 6 days; and the following results for serum (and urine): detection limit
(ii) one 1000 mg co-amoxiclav tablet in a new formulation 0.07 mg/L (2.4 mg/L), lower limit of quantification 0.14 mg/L
(875 mg amoxicillin and 125 mg clavulanic acid; SmithKline (4.7 mg/L), linear range 20 mg/L (500 mg/L), intra-assay
Beecham, Harlow, UK) each morning for 7 days. Each volun- variability (CV) 1.8–2.5% (0.8–1.0%), inter-assay variability
teer received first one treatment regimen and then the cross- (CV) 1.8–2.3% (0.4–2.3%), recovery 99–102% (93–103%).
over regimen. The wash-out period was 4 weeks between the Validation of the method for amoxicillin yielded the follow-
administration of the two antibiotic regimens. Strenuous ing results for serum (and urine): detection limit 0.15 mg/L
physical activity, smoking, intake of alcohol and of stimulat- (1.6 mg/L), lower limit of quantification 0.5 mg/L (15.6 mg/L),
ing beverages containing xanthine derivatives (tea, coffee and linear range 20 mg/L (1500 mg/L), intra-assay variability
soft drinks containing caffeine) were prohibited from 24 h (CV) 1.1–3.7% (0.7–1.1%), inter-assay variability (CV)

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 Pharmacokinetics of linezolid and co-amoxiclav

1.7–11.2% (1.7–2.4%), recovery 96.2–101.5% (100.7–

101.3%). Validation of the method for clavulanic acid yielded
the following results for serum (and urine): detection limit
0.06 mg/L (3.9 mg/L), lower limit of quantification 0.12 mg/L
(7.8 mg/L), linear range 5 mg/L (200 mg/L), intra-assay vari-
ability (CV) 1.5–5.9% (1.2–6.4%), inter-assay variability
(CV) 3.6–4.8% (4.5–19.6%), recovery 98.8–101% (89.5–
105.3%).

Pharmacokinetic calculations and statistical evaluations

The serum concentrations of linezolid were analysed
assuming an open two-compartment model and the data of

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amoxicillin and clavulanic acid with a one-compartment Figure 1. Mean (S.D.) serum concentrations of linezolid on days 1
model. Models were selected using the Schwarz criterion.12 and 7.
These models were used to calculate time between drug ad-
ministration and start of absorption (Tlag), terminal half-life
and total area under the curve (AUCtot) by integration of the
regression curve. The highest observed serum concentration
was taken for peak concentration (Cmax) and time to peak
concentration (Tmax). All other parameters [total area under
the data (AUDtot), volume of distribution at steady state (Vss/f),
mean residence time (MRT) and urinary recovery] were
analysed non-compartmentally. The AUD was calculated
with the trapezoidal rule. AUCtot and AUDtot of linezolid on
each day were calculated up to 12 h after administration and
on day 7 up to 24 h. Residual areas were calculated by integra-
tion of the compartmental regression line from the last data
point to infinity and added to the areas from zero to 12 or 24 h
(day 7). The dose-dependent parameters (AUCtot, AUDtot, Vss/f
and Cmax) were adjusted to a body weight of 70 kg. Clearance Figure 2. Mean (S.D.) serum concentrations of linezolid in male and
female volunteers.
values were normalized to a body surface of 1.73 m2. Recov-
eries in urine were extrapolated to infinity. The pharmaco-
kinetic determinations were made using REVOL software as
previously described.13 Student’s t-test and Wilcoxon’s rank
test were used for statistical analysis and P values <0.05 were
considered significant.

Results
Pharmacokinetics
Concentration versus time curves of linezolid, amoxicillin
and clavulanic acid are shown in Figures 1–3. The pharmaco-
kinetic data for the three drugs obtained on days 1 and 7 are
listed in Tables 1 and 2.
Figure 3. Mean (S.D.) serum concentrations of amoxicillin and clavu-
Single-dose kinetics of linezolid lanic acid on days 1 and 7.

On day 1 the linezolid absorption started after a mean Tlag of

0.16 ± 0.19 h and reached a Cmax of 14.5 ± 4.6 mg/L after Tmax 4 h and 3.62 ± 1.7 mg/L after 12 h (Figure 1). The area under
of 0.79 ± 0.34 h (Table 1). The first dose of 600 mg linezolid the serum concentration–time curve (AUCtot) was 138 ±
resulted in peak levels of 13.2 ± 3.8 mg/L after 1 h, with a 27.6 mg·h/L, the AUDtot was 140.5 ± 28.3 mg·h/L. The volume
decrease to 11.6 ± 3.6 mg/L after 2 h, 8.84 ± 3.0 mg/L after of distribution at steady state (Vss/f) was 46.9 ± 6.61 L. The

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Table 1. Pharmacokinetic parameters (mean ± S.D.) of linezolid on days 1 and 7

Day 1 Day 7

Parameters Day 1 Day 7 females males females males

Cmax (mg/L)a 14.5 ± 4.6 24.0 ± 6.9** 18.3 ± 2.5 10.7 ± 2.2 28.0 ± 5.9 20.0 ± 5.7
Cmin (mg/L)a 0 9.0 ± 4.4 0 0 11.7 ± 4.8 6.3 ± 1.5**
Tmax (h) 0.79 ± 0.34 0.96 ± 0.72 0.67 ± 0.26 0.92 ± 0.4 1.25 ± 0.9 0.67 ± 0.26
Tlag (h) 0.16 ± 0.19 0.17 ± 0.20 0.11 ± 0.15 0.21 ± 0.22 0.17 ± 0.18 0.17 ± 0.2
Terminal half-life (h) 9.53 ± 2.87 7.97 ± 3.08 8.76 ± 3.2 10.3 ± 2.9 8.10 ± 3.5 7.84 ± 2.9
MRT (h) 9.90 ± 2.28 – 9.05 ± 2.58 11.3 ± 0.52 – –
AUCtot (mg·h/L)a 138.1 ± 27.6 234 ± 55.2** 141.6 ± 37.2 134.7 ± 16.0 240 ± 42.6 227 ± 69.4
AUDtot (mg·h/L)a 140.5 ± 28.3 220.2 ± 42.6** 137.8 ± 36.2 143.2 ± 20.9 226 ± 38.1 214.5 ± 49.6

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Urinary recovery (% of dose)b 29.2 ± 6.7 47.3 ± 15.4** 31.5 ± 6.2 26.8 ± 7.0 51.3 ± 18.4 43.1 ± 11.9
CLtot (ml/min·1.73 m2) 71.6 ± 17.6 81.5 ± 14.7 72.35 ± 24.7 70.7 ± 8.1 80.3 ± 19.2 81.5 ± 14.7
CLren (ml/min·1.73 m2) 36.7 ± 9.7 55.6 ± 22.0* 41.0 ± 5.1 32.5 ± 11.7 59.5 ± 25.7 51.6 ± 19.2
Vss/f (L)a 46.9 ± 6.6 – 41.6 ± 4.2 52.2 ± 3.3** – –

*P < 0.05 day 7 versus day 1 or females versus males. **P < 0.01 day 7 versus day 1 or females versus males
aAdjusted to 70 kg body weight.
bAfter 12 h.

Table 2. Pharmacokinetic parameters (mean ± S.D.) of amoxicillin and clavulanic acid on days 1 and 7

Amoxicillin Clavulanic acid

Parameters day 1 day 7 day 1 day 7

Cmax (mg/L)a 10.01 ± 3.16 9.38 ± 3.41 2.65 ± 1.27 2.79 ± 1.32
Tmax (h) 1.83 ± 0.75 1.87 ± 0.77 1.58 ± 0.87 1.54 ± 0.89
Tlag (h) 0.48 ± 0.20 0.26 ± 0.12 0.35 ± 0.18 0.31 ± 0.16
Terminal half-life (h) 1.35 ± 0.48 1.29 ± 0.77 1.26 ± 0.75 1.01 ± 0.15
MRT (h) 2.55 ± 0.54 2.57 ± 0.55 2.53 ± 1.07 2.20 ± 0.72
AUCtot (mg·h/L)a 29.1 ± 6.89 27.9 ± 6.22 6.27 ± 1.89 7.21 ± 2.0
AUDtot (mg·h/L)a 31.0 ± 5.9 28.8 ± 6.0 6.35 ± 1.9 7.56 ± 2.0
Total urinary recovery (% of dose)b 54.3 ± 11.1 46.4 ± 11.9 27.6 ± 9.81 24.6 ± 13.7
CLtot (mL/min·1.73 m2) 466 ± 75.9 506 ± 95.3 359 ± 178 281 ± 82.1
CLren (mL/min·1.73 m2) 247 ± 39.4 233 ± 65.9 89.3 ± 19.9 75.6 ± 26.4
Vss/f (L)a 32.7 ± 10.6 40.4 ± 17.4 32.0 ± 26.4 21.6 ± 8.5

aAdjusted to 70 kg body weight.

bAfter 24 h.

pharmacokinetics of linezolid could be described by an open Multiple-dose kinetics of linezolid

two-compartment model with a terminal elimination half-life
of 9.53 ± 2.87 h. The MRT was 9.90 ± 2.28 h. The mean renal On day 7 serum peak and trough levels showed a clear accu-
clearance (CLren) of linezolid was 36.7 ± 9.7 ml/min·1.73 m2, mulation, with a linezolid concentration of 9.01 ± 4.4 mg/L
the total clearance (CLtot) 71.6 ml/min·1.73 m2. Within 12 h before medication and a maximum concentration of 21.07 ±
after the first dose of linezolid, 29.2 ± 6.7% of the dose was re- 7.3 mg/L after 1 h, with a decrease to 19.38 ± 6.6 mg/L after
covered in urine as unmodified parent drug. After intake of 2 h, 15.39 ± 5.5 mg/L after 4 h, 6.45 ± 2.6 mg/L after 12 h and
linezolid, two additional peaks were observed in chromato- 1.98 ± 1.1 mg/L after 24 h (Figure 1). Calculations of Cmax,
grams of the urine samples. These potential metabolites could AUCtot, AUDtot, CLren and urinary recovery revealed signi-
not be identified because of the lack of pure reference ficant differences (P < 0.05) between days 1 and 7. All other
materials. relevant pharmacokinetic parameters, Tmax, Tlag, CLtot and

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 Pharmacokinetics of linezolid and co-amoxiclav

terminal half-life, revealed no significant differences between drug serum concentrations higher than MICs for most clin-
days 1 and 7 (see Table 1). ically significant Gram-positive pathogens during the entire
dosing interval.
Sex-related differences in linezolid pharmacokinetics Pharmacokinetic modelling showed that the serum con-
centrations of linezolid best fitted an open two-compartment
Serum concentrations, adjusted to 70 kg body weight, were model. The single- and multiple-dose pharmacokinetics of
always higher in females than in males (Figure 2). The distri- linezolid in our study are similar to those previously reported
bution volume was accordingly significantly lower (P < 0.01) by Gee et al.6 and Slatter et al.7 After a single dose, linezolid
in females than in males (Table 1). was absorbed with a Tmax of <1 h to give a Cmax of 14.5 ±
4.6 mg/L, and an MRT of 9.90 ± 2.28 h. The AUDtot on day 1
Pharmacokinetics of amoxicillin and clavulanic acid was 140.5 ± 28.3 mg·h/L. Linezolid and the two main meta-
bolites have been reported to be predominantly eliminated by
Calculations of relevant pharmacokinetic parameters of amoxi- the kidneys, accounting for 83.9 ± 3.3% of the radioactive

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cillin and clavulanic acid revealed no significant differences label.7 In this study 29.2 ± 6.7% of the dose was recovered in
between days 1 and 7 (Table 2). The serum concentration– urine as parent compound within the first 12 h. Two potential
time curves of days 1 and 7 showed an excellent agreement metabolites could be detected in chromatograms from urine
(Figure 3). On day 7, amoxicillin had a mean Cmax of 9.38 ± samples, as has been similarly reported by Slatter et al.7
3.41 mg/L, a terminal elimination half-life of 1.29 ± 0.77 h After multiple drug administration of linezolid, Cmax,
and an AUCtot of 27.9 ± 6.22 mg·h/L. The mean Cmax of AUCtot, AUDtot, CLren and urinary recovery revealed signifi-
clavulanic acid was 2.79 ± 1.32 mg/L, the terminal half-life cant differences between days 1 and 7. The significant in-
1.01 ± 0.15 h and the AUCtot 7.21 ± 2.00 mg·h/L. No accu- crease of maximum serum concentration on day 7 could be
mulation was observed for either drug. considered as dose-dependent accumulation. When adjusted
to 70 kg body weight, serum concentrations were higher in
Safety and tolerance females than in males and resulted from the fact that the
volume of distribution Vss/f in female volunteers was signific-
The overall tolerance of linezolid and co-amoxiclav was good.
antly lower than in male volunteers (41.6 ± 4.2 versus 52.2
No severe adverse events occurred. No significant differences
± 3.3 L/70 kg; P < 0.01).
in the values of clinical parameters and safety laboratory test
Pharmacokinetic parameters of amoxicillin and clavulanic
results were found before and after the study. No volunteer
acid in the modified formulation used in this study were
was excluded during the study. The main adverse events after
similar to previously published data.10,21
linezolid administration were headaches (two subjects) and
The overall tolerance of linezolid and the other two drugs
gastrointestinal disturbances such as flatulence and diarrhoea
administered in our study was acceptable. The main adverse
(two subjects). One male volunteer complained of Candida
events were headaches, diarrhoea and candidiasis, and no
mycosis of the glans penis. Under therapy with co-amoxiclav
volunteer had to be withdrawn from the study because of
three volunteers complained of headaches. Two female
them. Furthermore, no drug-related changes in vital signs,
subjects complained of candidiasis vulvovaginalis; one
clinical chemistry, haematology or urinalysis were observed
complained of mycosis of the body and the other of cystitis.
in the study.
All adverse events were classified as mild to moderate.

Discussion Acknowledgements

Linezolid is the first of a new class of antibacterial agents, the The technical assistance of E. Borner, H. Hartwig, M. Rau and
oxazolidinones, with good activity against Gram-positive G. Schreiber is gratefully acknowledged.
bacteria, including multidrug-resistant strains. Mean trough
levels of linezolid 12 h after a single oral administration of
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