Population Pharmacokinetics of Daptomycin

Article (PDF Available)inAntimicrobial Agents and Chemotherapy 48(8):2799-807 · September 2004with30 Reads
DOI: 10.1128/AAC.48.8.2799-2807.2004 · Source: PubMed
Abstract
Data from subjects in nine phase 1 (n = 153) and six phase 2/3 (n = 129) clinical trials were combined to identify factors contributing to interindividual variability in daptomycin pharmacokinetics (PK). Over 30 covariates were considered. A two-compartment model with first-order elimination provided the best fit for data on daptomycin concentrations in plasma over time. In the final population PK model, daptomycin plasma clearance (CL) was a function of renal function, body temperature, and sex. Of these factors, renal function contributed most significantly to interindividual variability. CL varied linearly with the estimated creatinine clearance. CL among dialysis subjects was approximately one-third that of healthy subjects (0.27 versus 0.81 liter/h). CL in females was 80% that in males; however, in clinical trials, the outcome was not affected by sex and therefore this effect is not considered clinically meaningful. The relationship with body temperature should be interpreted cautiously since the analysis included only a limited number of subjects who were hyperthermic. The volume of distribution of the peripheral compartment (V2) and intercompartmental clearance (Q) were linearly related to body weight. V2 increased approximately twofold in the presence of an acute infection. No factors were identified that significantly impacted V1. This analysis supports the dosing of daptomycin on a milligram-per-kilogram-of-body-weight basis and suggests that modified dosing regimens are indicated for patients with severe renal disease and for those undergoing dialysis.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Aug. 2004, p. 2799–2807 Vol. 48, No. 8
0066-4804/04/$08.000 DOI: 10.1128/AAC.48.8.2799–2807.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.
Population Pharmacokinetics of Daptomycin
Barry Dvorchik,
1
* Robert D. Arbeit,
1
Julia Chung,
2
Susan Liu,
2
William Knebel,
2
and Helen Kastrissios
2
Cubist Pharmaceuticals, Inc., Lexington, Massachusetts 02421,
1
and GloboMax
Holdings LLC, Hanover, Maryland 21076
2
Received 9 November 2003/Returned for modification 26 January 2004/Accepted 4 April 2004
Data from subjects in nine phase 1 (n 153) and six phase 2/3 (n 129) clinical trials were combined to
identify factors contributing to interindividual variability in daptomycin pharmacokinetics (PK). Over 30
covariates were considered. A two-compartment model with first-order elimination provided the best fit for
data on daptomycin concentrations in plasma over time. In the final population PK model, daptomycin plasma
clearance (CL) was a function of renal function, body temperature, and sex. Of these factors, renal function
contributed most significantly to interindividual variability. CL varied linearly with the estimated creatinine
clearance. CL among dialysis subjects was approximately one-third that of healthy subjects (0.27 versus 0.81
liter/h). CL in females was 80% that in males; however, in clinical trials, the outcome was not affected by sex
and therefore this effect is not considered clinically meaningful. The relationship with body temperature should
be interpreted cautiously since the analysis included only a limited number of subjects who were hyperthermic.
The volume of distribution of the peripheral compartment (V
2
) and intercompartmental clearance (Q) were
linearly related to body weight. V
2
increased approximately twofold in the presence of an acute infection. No
factors were identified that significantly impacted V
1
. This analysis supports the dosing of daptomycin on a
milligram-per-kilogram-of-body-weight basis and suggests that modified dosing regimens are indicated for
patients with severe renal disease and for those undergoing dialysis.
Daptomycin (N-decanoyl-L-tryptophyl-L-asparaginyl-L-aspar-
tyl-
L-threonylglycyl-L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-
D-seryl-threo-3-methyl-L-glutamyl-3-anthraniloyl-L-alanineε
1
-lac-
tone) is a novel cyclic lipopeptide antibiotic derived from the
fermentation of Streptomyces roseosporus. Daptomycin was re-
cently approved for the treatment of complicated skin and skin
structure infections (cSSSI) caused by aerobic gram-positive bac-
teria, including those caused by methicillin-resistant Staphylococ-
cus aureus and methicillin-susceptible S. aureus. In vitro, dapto-
mycin demonstrates a rapid concentration-dependent bactericidal
activity against most clinically relevant gram-positive pathogenic
bacteria, including bacterial isolates that are resistant to methi-
cillin, vancomycin, and linezolid (9). The MICs for daptomycin at
which 90% of isolates tested are inhibited are typically 1 g/ml
for staphylococci and streptococci and 2 to 4 g/ml for entero-
cocci, including vancomycin-resistant isolates (7). Although the
mechanism of action has not been fully defined, it is distinct from
those of other antibiotics and appears to be mediated by the
disruption of multiple aspects of membrane function (5, 17). In
phase 3 trials for the treatment of cSSSI caused by susceptible
gram-positive bacteria, clinical and microbiological outcomes of
patients treated with daptomycin were comparable to those for
patients receiving conventional antibiotic therapy, such as pencil-
linase-resistant penicillins or vancomycin (1, 18).
Studies of healthy human subjects have demonstrated linear
pharmacokinetics after single (20) and multiple (8) intrave-
nous daptomycin doses up to 6 mg/kg of body weight over 14
days. After once-daily doses of 4 mg/kg, the average steady-
state trough daptomycin concentration in plasma was 5.89
g/ml and varied by 27% among individuals (8). Daptomycin is
90% bound to plasma proteins and has a low steady-state
volume of distribution, averaging 0.06 to 0.15 liter/kg (8, 19,
20), consistent with distribution into extracellular fluid. Elim-
ination is primarily achieved by renal excretion of unchanged
drug. In healthy adult subjects, the mean urinary recovery over
a 24-h period is 50 to 60% of the administered dose (8, 19). In
phase 1 studies involving healthy adult subjects and subjects
with graded renal insufficiencies, including end-stage renal dis-
ease, daptomycin plasma clearance (CL) was significantly re-
duced among subjects with creatinine clearances (CL
CR
)of
40 ml/min or who were on dialysis (D. A. Sica, T. Gehr, and
B. Dvorchik, Abstr. 42nd Intersci. Conf. Antimicrob. Agents
Chemother., abstr. 2257, 2002).
For the present analysis, data from 15 clinical trials were
combined and a population analysis approach was used to
evaluate possible sources of interindividual variability in dap-
tomycin pharmacokinetics. The specific objectives were to de-
velop a model to describe the pharmacokinetics of daptomycin
in both healthy volunteers and subjects with acute bacterial
infections who were representative of the target patient pop-
ulation and to identify clinical characteristics that impact dap-
tomycin pharmacokinetics. The factors examined included age,
sex, weight, and the presence of bacterial infection, end-organ
dysfunction, comorbidities, and concomitant medications.
MATERIALS AND METHODS
Study design. The analysis included data collected from 282 subjects enrolled
in 15 phase 1, 2, and 3 clinical trials of daptomycin (Table 1). Frequent blood
samples were collected from each of 153 subjects in nine phase 1 clinical trials.
The subjects received single or multiple doses of 4 to 8 mg of daptomycin/kg
administered by a 30-min intravenous infusion every 24 h. Blood samples for
* Corresponding author. Present address: Barry Dvorchik & Asso-
ciates, Inc., 5809 Piney Lane Dr., Suite 105, Tampa, FL 33625. Phone:
(813) 951-2789. Fax: (832) 213-2008. E-mail: bdvorchi@tampabay.rr
.com.
† Present address: Paratek Pharmaceuticals, Boston, MA 02111.
2799
pharmacokinetic analysis were collected from a subset of 129 subjects with
gram-positive bacterial infections from six phase 2 and/or 3 clinical trials who
received various regimens of intravenous daptomycin. All subjects included in
the population pharmacokinetic analysis received at least one dose of daptomy-
cin, had at least one measured daptomycin concentration from plasma, and had
accurate documentation of the dates and times of the dose and concentration
measurements. Subject and study design details are shown in Table 1.
A validated high-performance liquid chromatography (HPLC) method was
used for an analysis of daptomycin concentrations in plasma for 13 studies (8).
The lower limit of quantitation was 3 g/ml and the interassay coefcient of
variation was 3.51%. A validated LC/MS/MS method (Cubist Pharmaceutical,
internal report) was used for the quantication of daptomycin concentrations in
plasma for a study of the pharmacokinetics of daptomycin in healthy and renally
impaired subjects. There was a close linear relationship (correlation coefcient,
0.965) between concentrations in plasma obtained by the LC/MS/MS and HPLC
methods. However, the LC/MS/MS assay was more sensitive than the HPLC
assay (lower limits of quantitation, 0.1 and 3 g/ml, respectively). For one study
of the use of daptomycin in healthy male volunteers, a microbiological assay was
used to quantify daptomycin concentrations in plasma (19). The interassay co-
efcient of variation and the limit of quantitation were 6.3% and 2 g/ml,
respectively. The results of the assay correlated well with those of the HPLC
assay, as evidenced by the fact that the pharmacokinetic parameters for dapto-
mycin for this group of subjects were in excellent agreement with data obtained
in other studies with healthy volunteers (8).
The covariates explored as possible sources of interindividual variability in
daptomycin pharmacokinetics are listed in Table 2. Body surface area was cal-
culated by the following formula (R. D. Mosteller, Letter, N. Engl. J. Med.
317:1098, 1987):
Body surface area (m
2
)
weight (kg) height (cm)
3,600
CL
CR
was estimated for nondialysis subjects by use of the Cockcroft-Gault
equation (6):
CL
CR
(ml/min)
[140 age (years)] weight (kg)
S
CR
(mg/dl)
x
in which x 1 for males and 0.85 for females. For single-dose studies with
healthy subjects, hepatically impaired subjects, obese subjects, and healthy geri-
TABLE 1. Study designs
Clinical
phase
Study
no.
Subject characteristic(s)
c
Dosing regimen
a
No. of
subjects
No. of samples/
subject
Sample collection period (h)
b
1 1 Healthy 4 mg/kg every 24 h for 7 days (n 6);
6 mg/kg every 24 h for 7 days (n
6), or 8 mg/kg every 24 h for 7 days
(n 6)
18 2731 24 (1st dose), 72 (last dose),
trough samples
1 2 Healthy 4 mg/kg 7 1214 24
1 3 Healthy 4 mg/kg i.v. aztreonam (crossover) 17 15 24.5
1 4 Healthy, 1830 yr old (n 12); or
healthy, 75 yr old (n 12)
4 mg/kg 23 13 24
1 5 Healthy (BMI, 25 kg/m
2
)(n
12), moderately obese (BMI,
2539.9 kg/m
2
)(n 6), or
extremely obese (BMI, 40
kg/m
2
)(n 7)
4 mg/kg 25 13 24
1 6 Healthy (n 10), or hepatic
impairment, child pugh B (n
9)
6 mg/kg 19 15 48
1 7 Healthy (n 5), mild renal
failure (n 6), moderate to
severe renal failure (n 7), on
hemodialysis (n 6), or on
peritoneal dialysis (n 5)
Healthy subjects, 4 mg/kg p.o.
probenecid (crossover design); all
other subjects, 4 mg/kg
29 1214 7296
1 8 Moderate renal impairment 4 mg/kg every 24 h for 14 days (n
4) or 6 mg/kg every 24 h for 14
days (n 4)
8 26 24 (1st and last doses),
trough samples
1 9 On hemodialysis 4 mg/kg, then six doses of 3 mg/kg
every 48 h (n 6), or 6 mg/kg,
then six doses of 4 mg/kg every
48h(n 1)
7 26 36 (1st dose), 48 (last dose),
trough samples
2 10 Subjects with bacteremic
infections due to gram-positive
bacteria
6 mg/kg every 24 h for 7 to 14 days (n
13), 4 mg/kg every 24 h for 7 to
14 days (n 14), 6 mg/kg followed
by 3 mg/kg every 12 h for 7 to 14
days (n 13), or other regimen (n
1)
41 5 6 (on 5th day of dosing)
2 11 Subjects with infections due to
gram-positive bacteria resistant
to vancomycin or otherwise
refractory to or contraindicated
for currently available therapy
6 mg/kg every 24 h for 7 to 14 days 27 5 6 (on 5th to 7th day of
dosing)
3 12 Subjects with moderate to severe
community-acquired acute
bacterial pneumonia due to
Streptococcus pneumoniae or
other gram-positive cocci
4 mg/kg every 24 h for 5 to 10 days 6 4 12 (on 5th day of dosing)
3 13 Subjects with moderate to severe
community-acquired acute
bacterial pneumonia due to S.
pneumoniae or other gram-
positive cocci
4 mg/kg every 24 h for 5 to 10 days 12 4 12 (on 5th day of dosing)
3 14 Subjects with cSSSI due to gram-
positive bacteria
4 mg/kg every 24 h for 7 to 14 days 16 5 6 (on at least 3rd day of
dosing)
3 15 Subjects with cSSSI due to gram-
positive bacteria
4 mg/kg every 24 h for 7 to 14 days 27 5 6 (on at least 3rd day of
dosing)
a
Administered by intravenous infusion for 30 min.
b
Period following dose administration.
c
BMI, body mass index.
2800 DVORCHIK ET AL. ANTIMICROB.AGENTS CHEMOTHER.
atric subjects, creatinine levels in serum and body weights were determined at
screening, on the morning of dose administration, and prior to discharge from
the clinical research unit. For each study, intraindividual differences in these
parameters were within 10% and estimated CL
CR
values for these subjects were
considered stable. For subjects in the single-dose graded renal study (excluding
those undergoing dialysis), entry criteria required that CL
CR
be determined from
two separately measured 24-hour CL
CR
values performed within 21 days of
dosing. Subjects with CL
CR
values within 30% of each other were considered to
have a stable CL
CR
and were enrolled in the study. Creatinine levels in serum
and body weights were also obtained prior to dosing and prior to discharge from
the clinical research unit. Intraindividual estimates of CL
CR
were within the
protocol criteria for a stable CL
CR
. For subjects in multiple-dose renal studies
(excluding those undergoing dialysis), creatinine levels in serum were deter-
mined at screening, predose, and every other day from day 3 to discharge (day
15) from the clinical research unit. No clinically signicant change was observed
in the intraindividual values over time. For phase 2 and/or 3 clinical studies,
creatinine levels in serum and body weights were determined at various times
throughout the duration of the study. Estimated CL
CR
values were calculated by
using creatinine levels in serum obtained on the day of the pharmacokinetic
blood draw and the day closest to the pharmacokinetic day and the mean of the
highest and lowest creatinine levels in serum obtained over the course of the
entire study. No clinically signicant intraindividual differences were observed,
regardless of the value chosen. To maintain consistency with single-dose studies,
we calculated the estimated CL
CR
values used in the nal analysis by using the
creatinine level in serum and the actual body weight measured closest to the
pharmacokinetic day. The weight used was the actual body weight on the day of
the pharmacokinetic draw or the day closest to the pharmacokinetic day. Indi-
vidual CL
CR
values were estimated to be 150 ml/min for 38 subjects and were
all set to 150 ml/min. These subjects represented multiple different studies; their
median body weight was 85.3 kg (range, 52 to 153 kg). Sixty-three percent had
normal creatinine levels in serum, with actual body weights ranging from 72.6 to
152.8 kg; the remaining 37% had creatinine levels in serum ranging from 0.2 to
0.6 mg/dl, with actual body weights ranging from 56.3 to 130.6 kg. The lowest
estimated CL
CR
for subjects was 14 ml/min. Body temperature was evaluated
only for subjects in phase 2 and/or 3 studies. Concomitant medications examined
for possible pharmacokinetic interactions with daptomycin included acidic drugs
that are actively secreted in the renal tubule and drugs that are highly (95%)
bound to albumin (3, 13, 15). Comorbidities included diseases producing uid
TABLE 2. Subject characteristics
Characteristic
Median (continuous variables)
or no. (categorical variables)
Range (continuous variables)
or % (categorical variable)
Continuous variables
Body weight (kg) 75.1 48.2152.8
Body surface area (m
2
)
1.9 1.52.8
Age (yr) 51 1893
Body temp on day of pharmacokinetic study (°C)
a
37.2 36.140.1
Baseline serum albumin (g/dl)
b
4.2 2.85.0
Baseline alkaline phosphatase (IU/liter) 81 27730
Baseline ALT (IU/liter) 21 3176
Baseline AST (IU/liter) 21 4292
Baseline total bilirubin (mg/dl) 0.5 0.215.7
Baseline BUN (mg/dl) 15 4115
Baseline blood glucose (mg/dl) 98 41382
Baseline serum creatinine (mg/dl)
c
1.0 0.218.2
Baseline creatinine clearance (ml/min)
d,e
91.2 14.0150.0
Average serum creatinine (mg/dl)
c,f
1.0 0.215.5
Average creatinine clearance (ml/min)
d,g
92.2 14.0150.0
Categorical variables
Study (phase 1, phase 2/3) 153, 129 54, 46
Sex (male, female) 166, 116 59, 41
Race (Caucasian, African-American, other) 163, 51, 68 58, 18, 24
Dialysis (yes, no) 21, 26 7, 93
Renal function 5 categories (80 ml/min, 50 to 80 ml/min,
30 to 50 ml/min, 30 ml/min, on dialysis)
165, 64, 24, 8, 21 59, 23, 9, 3, 7
Renal function 4 categories (80 mL/min, 40 to 80 ml/min,
40 ml/min, on dialysis)
165, 80, 16, 21 59, 28, 6, 7
Elevated baseline BUN (ULN 25 mg/dl) 52 18
Elevated baseline serum creatinine (ULN 1.4 mg/dl) 40 14
Elevated baseline blood glucose (ULN 109 mg/dl) 55 20
Hyperthermic (38°C) 14 14
Has diabetes 47 17
Has hypertension 52 18
Has congestive heart failure 19 7
Has uid accumulation (edema or ascites) 22 8
Has gram-positive bacterial infection 129 46
Taking concomitant aztreonam 17 6
Taking concomitant metronidazole 0 0
Taking concomitant medication that is secreted in the renal
tubule (including probenecid)
93 33
Taking concomitant medication that is 95% bound to albumin 64 23
a
On day of blood samples obtained for pharmacokinetics (n 100). Data are missing for all phase 1 studies and for 29 subjects in phase 2/3 studies.
b
n 164 (data are missing for ve phase 2/3 studies).
c
n 282.
d
n 261 (excludes subjects on dialysis).
e
Includes 38 subjects (14.6%) for whom the estimated creatinine clearance was set to 150 ml/min.
f
Average of minimum and maximum values recorded over the period of the pharmacokinetic study.
g
Includes 34 subjects (13.0%) for whom the estimated creatinine clearance was set to 150 ml/min.
VOL. 48, 2004 POPULATION PHARMACOKINETICS OF DAPTOMYCIN 2801
accumulation (e.g., ascites and edema), the presence of infection, diabetes,
hypertension, and congestive heart failure. All covariates were values recorded at
baseline, with the exception of body temperature, which was the value recorded
on the day of pharmacokinetic sampling. Missing continuous covariates were
replaced with the median value of the covariate for subjects of the same sex in the
same study.
Pharmacokinetic analysis. Population pharmacokinetic models were built by a
nonlinear mixed-effects modeling approach and rst-order conditional maximum
likelihood estimation with eta-epsilon interaction in the NONMEM program
(double precision, version V, level 1.1) (2).
(i) Base model selection. One-, two-, and three-compartment structural mod-
els were t to the data for concentrations in plasma over time; graphical displays
of the data were also evaluated. Hypothesis testing to discriminate among alter-
native hierarchical structural models was performed by using the likelihood ratio
test (16). For comparisons of alternative models, the difference in the NONMEM
objective function was approximately chi-square distributed, with n degrees of
freedom, where n was the difference in the number of parameters between the
hierarchical models. A decrease of 3.84 in the value of the NONMEM objec-
tive function, which is less than twice the maximum logarithm of the likelihood
of the data, is signicant in the likelihood ratio test (n 1; P 0.05). The
goodness of t was evaluated by using diagnostic scatter plots (not shown).
The duration of infusion (D
1
) was estimated for a subset of 108 subjects
included in the phase 3 clinical trials for whom the date and time of the start of
daptomycin infusion and the time of the rst pharmacokinetic blood draw for
concentration measurements, but not the time of cessation of the infusion, were
recorded. All estimates were consistent with the protocols, which specied an
infusion time of 30 min. Interindividual variability in D
1
could not be estimated
and was not included in the model.
All pharmacokinetic parameters were assumed to be logarithmically normally
distributed, and exponential interindividual variability terms were included in the
pharmacokinetic parameters in the model. Various residual error models were
tested, including an evaluation of possible systematic differences between phase
1 and phase 2/3 studies and among studies that used different assay methods.
(ii) Population pharmacokinetic model building. Exploratory analyses were
used to guide the model building process. Relationships between individual
covariates and Bayesian estimates of the pharmacokinetic parameters were ex-
plored graphically. Generalized additive models were used to evaluate both
linear and nonlinear relationships between parameters and covariates (14). In
addition, measures of body size and renal function markers were tested as
possible sources of interindividual variability for each pharmacokinetic param-
eter. All possible covariate-parameter relationships thus selected were tested,
with the exception that possible drug interactions and the effect of the dapto-
mycin dose were examined only for CL and the volume of the central compart-
ment (V
1
), as appropriate.
Continuous covariates were entered into the population pharmacokinetic
model according to the following equation:
P
1
2
(COV COV)
where P is the individual estimate of the parameter, COV is the value of the
covariate, and C
OV is the median value of the covariate in the study population.
1
is the typical value of the parameter (when COV COV) and
2
is the slope
of the effect of the covariate on the parameter.
Categorical covariates were included in the model by using indicator variables,
as shown in the following equation:
P
1
2
IND
where P is the individual estimate of the parameter,
1
is the typical value of the
parameter when the covariate is not present (IND 0), and
2
is the fractional
change in the value of P when the covariate is present (IND 1).
The statistical signicance of each covariate-parameter relationship was
screened individually in NONMEM, and the model was built by stepwise addi-
tions to obtain a full model. Stepwise deletions were used to obtain the nal
(reduced) model. The likelihood ratio test was used for hypothesis testing to
discriminate among alternative hierarchical models. A strict inclusion criterion
(P 0.001) corresponding to a change in the value of the NONMEM objective
function of 10.83 (n 1 degrees of freedom) was used to account for multiple
hypothesis testing. At each stage of the analysis, the goodness of t was evaluated
by using diagnostic scatterplots.
(iii) Pharmacokinetic parameter calculations. The terminal half-life (t
1/2
),
volume of distribution at a steady state (V
ss
), and area under the curve from time
zero to innity [AUC
(0-)
] were calculated from individual pharmacokinetic
parameter estimates obtained by Bayesian estimation from the nal population
pharmacokinetic model. For a two-compartment model (10), the following equa-
tions were used:
1
2
CL
V
1
Q
V
1
Q
V
2
CL
V
1
Q
V
1
Q
V
2
2
4
CL
V
1
Q
V
2
t
1/2
ln2
V
ss
V
1
V
2
AUC
(0)
Infused dose
CL
where is the terminal phase rate constant (per hour), CL is the daptomycin
plasma clearance (liters per hour), Q is the intercompartmental clearance (liters
per hour), V
1
is the volume of the central compartment (liters), V
2
is the volume
of the peripheral compartment (liters), and t
1/2
is the terminal phase half-life
(hours). All calculations were performed in NONMEM.
(iv) Statistics. Individual Bayes estimates and calculated pharmacokinetic
parameter values were grouped according to four renal function categories.
Three categories were dened by using the estimated CL
CR
values: the groups
were values of 80 ml/min, 40 to 80 ml/min, and 40 ml/min. These ranges
were chosen based on an analysis of phase 1 studies with renally impaired
subjects (Sica et al., 42nd ICAAC). Subjects on dialysis comprised a fourth
category (thus, the categories were CL
CR
values of 80 ml/min, 80 to 40
ml/min, and 40 ml/min and subjects on dialysis). Differences between groups
were evaluated by analysis of variance with Scheffes test (S-PLUS Professional;
Insightful Corp., Seattle, Wash.). P values of 0.05 were considered signicant.
RESULTS
Data. Measurements of daptomycin concentrations over
time were available for 3,325 plasma specimens collected from
282 adult subjects. Two outlying concentrations, one for a
specimen reported as a trough plasma with a daptomycin con-
centration of 106 g/ml (sixfold higher than the average trough
value) and one for a specimen reported as obtained 0.58 h after
dose administration with a daptomycin concentration of 309
g/ml (vefold higher than the average plasma concentration
at 0.58 h), were excluded from the analysis.
Imputed covariate values were generated for a total of 37
subjects; laboratory tests of hepatic function were the most
frequently missing values. Height, used in the calculation of
body surface area, was imputed for 3 subjects; baseline creat-
inine values in serum were imputed for 13 subjects. Albumin
levels in serum were not recorded in one phase 1 study and
three phase 2/3 studies and were considered to be missing for
all subjects in those studies. Missing body temperature values
on the day of pharmacokinetic sampling were not imputed for
29 subjects from the phase 2/3 studies. The population phar-
macokinetic model was coded to remove the effect of missing
covariates in the model.
Descriptive statistics for all covariates are presented in Table
2.
Pharmacokinetic analysis. (i) Base model. Plots of data for
concentrations in plasma versus time (not shown) showed a
biphasic disposition of daptomycin. A review of the minimum
objective function and diagnostic plots showed that the data
for daptomycin concentrations in plasma over time were best
described by using a two-compartment open model with rst-
order elimination. The structural pharmacokinetic model used
the following parameters: clearance (CL), the volume of the
central compartment (V
1
), intercompartmental clearance (Q),
and the volume of the peripheral compartment (V
2
). In addi
-
tion, the duration of infusion (D
1
) was estimated for several
2802 DVORCHIK ET AL. ANTIMICROB.AGENTS CHEMOTHER.
phase 3 subjects. Estimates of D
1
were consistent with the
duration of infusion specied in the clinical protocols.
The median daptomycin clearance for the study population
was estimated to be 0.688 liter/h (11.5 ml/min) and the volume
of the central compartment was 4.8 liters. Median estimates for
the intercompartmental clearance and volume of distribution
of the peripheral compartment were 3.6 liters/h and 3.6 liters,
respectively. All pharmacokinetic parameters were precisely
estimated, with relative standard errors (RSEs) of 3%. The
estimated median duration of infusion for 108 subjects en-
rolled in phase 2/3 trials was 0.402 h (24 min), with an RSE of
23.8%.
Interindividual variabilities were estimated to be 52.1% for
CL, 60.6% for the volume of the central compartment, 31.9%
for the volume of the peripheral compartment, and 74.4% for
intercompartmental clearance. A simple additive residual er-
ror model based on diagnostic plots provided the best t for
the data. A further evaluation of diagnostic plots indicated that
there was a larger degree of mist of model predictions for
observations collected in phase 2/3 studies; therefore, different
error structures were evaluated for phase 1 versus phase 2/3
studies. On the basis of the likelihood ratio test, the nal
residual error model was described by a combination of addi-
tive errors, reecting the different assay methods used to de-
termine daptomycin concentrations in plasma. The residual
error was slightly lower for the study in which daptomycin
concentrations in plasma were assayed by LC/MS/MS than for
studies assayed by HPLC (2.08 versus 4.72 g/ml, respectively),
consistent with the higher sensitivity of the former method.
(ii) Population model. Exploratory graphical analyses re-
vealed a direct correlation between daptomycin clearance and
various markers of renal function, including estimated creati-
nine clearance, renal function category, and laboratory mark-
ers of renal function. Intercompartmental clearance (in liters
per hour) and the volume of the peripheral compartment (in
liters) were correlated with body weight. There were no obvi-
ous relationships between V
1
and any of the tested covariates
and no signicant association between daptomycin pharmaco-
kinetics and either the concomitant medications or the con-
comitant diseases evaluated in this patient population.
The nal model for daptomycin clearance was determined to
be the following:
CL [CL
R
0.14 (TEMP 37.2)] y in which CL
R
0.269 in dialysis subjects
0.807 0.00514 (CL
CR
91.2) in others
where CL daptomycin clearance (liters per hour), CL
R
daptomycin clearance as a function of renal function only (li-
ters per hour), CL
CR
estimated creatinine clearance (milli
-
liters per minute), TEMP body temperature (
o
C), and y
0.8 for females and 1 for males.
Both intercompartmental clearance and the volume of the
peripheral compartment were determined to be functions of
body weight, as follows:
Q 3.46 0.0593 (WT 75.1)
V
2
3.13 0.0458 (WT 75.1)] z
where WT body weight (kilograms) and z 1.93 for subjects
with a bacterial infection and 1 for noninfected subjects.
The median value for V
1
was estimated to be 4.80 liters.
Although the interindividual variability in V
1
was 57%, none of
the covariates investigated, including body weight, was identi-
ed as a signicant source of variability in V
1
.
Additional exploratory analyses were performed to evaluate
whether any other covariate could explain the effect of sex on
daptomycin clearance or the effect of the presence of infection
on V
2
. A review of the covariate graphics indicated that body
weight, body surface area, and race differed by sex. Each of
these covariates was substituted into the clearance model to
determine if it could be substituted for sex in the model, but
none produced a signicant change in the objective function
value. Consequently, the clearance model including sex repre-
sented the nal model.
Infections were only present in subjects in the phase 2 and/or
3 clinical trials. Therefore, in the model the presence of infec-
tion could be a marker for an unmonitored covariate that
differed between the phase 1 and phase 2/3 clinical trials. In a
graphical evaluation, age and serum albumin were determined
to differ between the two groups. Each of these covariates, as
well as body temperature, was substituted into the V
2
model,
and none produced a signicant change in the objective func-
tion value. The V
2
model including infection represented the
nal model.
Parameter estimates for the nal population pharmacoki-
netic model are presented in Table 3. Pharmacokinetic param-
eters were precisely estimated and diagnostic plots showed a
good tofthenal model to the observed daptomycin con-
centrations in plasma (Fig. 1).
Based on the nal population pharmacokinetic model, the
apparent V
ss
for a typical healthy subject with a median body
weight of 75 kg was estimated to be 7.9 liters. In comparison,
the V
ss
was increased 37%, to 10.8 liters, if the subject had an
acute bacterial infection. The median terminal elimination t
1/2
of daptomycin was determined to be 7.07 h in a typical nor-
mothermic male with normal renal function. The median ter-
minal elimination t
1/2
for a male subject with a creatinine
clearance of 40 ml/min was 10.36 h, and for a male subject
receiving dialysis, the median terminal elimination t
1/2
was
20.68 h.
Individual estimates of CL and V
1
were obtained from the
nal population pharmacokinetic model by Bayesian estima-
tion. These were used to calculate individual estimates of the
t
1/2
, V
ss
, and AUC
(0-)
for a single 4-mg/kg intravenous dose
from the individual parameter estimates and were summarized
by renal function category. Summary statistics for these esti-
mates are presented for all subjects (Table 4) and separately
for phase 1 and phase 2/3 subjects (Table 5).
These analyses indicated that the daptomycin CL, t
1/2
, and
AUC
(0-)
for a single 4-mg/kg intravenous dose were depen
-
dent on renal function. An analysis of variance indicated
that compared with subjects with CL
CR
values of 40 ml/
min, subjects whose CL
CR
values were 40 ml/min or who
were on dialysis had signicantly larger volumes of the cen-
tral compartment. This factor was not signicant in the
population pharmacokinetic analysis, most likely because of
the large variation in V
1
and the relatively small number of
VOL. 48, 2004 POPULATION PHARMACOKINETICS OF DAPTOMYCIN 2803
subjects on dialysis. V
ss
was not dependent on renal func
-
tion.
Relative to that in subjects with normal renal function
(CL
CR
values of 80 ml/min), the daptomycin half-life was
increased 2.3-fold in subjects with CL
CR
values of 40 ml/min
and 3.5-fold in subjects who were on dialysis; changes in dose-
normalized AUC
(0-)
values were 1.8-fold and 3-fold, respec
-
tively (Table 5). In comparison, median half-life and dose-
normalized AUC
(0-)
values in subjects with CL
CR
values of
80 ml/min and in subjects with CL
CR
values of 80 and 40
ml/min differed 10%. These differences, although statistically
signicant, were not considered clinically meaningful.
FIG. 1. Diagnostic plots for daptomycin population pharmacokinetic model. Observed versus predicted daptomycin concentrations in plasma
(left), observed versus individual predicted daptomycin concentrations in plasma (middle), and weighted residuals versus predicted daptomycin
concentrations in plasma (right panel) are shown. Circles represent individual data points. Dashed lines represent regression lines. Solid lines
represent unity.
TABLE 3. Population pharmacokinetic parameter estimates for daptomycin
b
Structural model parameter
Median value
(RSE [%])
% Interindividual
CV (RSE [%])
CL (liter/h) for male subject with median creatinine clearance (91.2 ml/min) 0.807 (2.9) 30.6 (10.5)
Change in CL (liter/h) for each 10 ml/min that creatinine clearance differs from the median value 0.0514 (10.9)
CL (liter/h) for subject on dialysis 0.269 (6.1)
Fractional change in CL for female subject 0.801 (4.0)
Change in CL (liter/h) for each °C that temp differs from the median value (37.2°) 0.14 (32.1)
V
1
(liters)
4.80 (4.2) 56.7 (26.8)
Q (liter/h) for subject with median body weight (75 kg) 3.46 (6.3) 65.2 (39.5)
Change in Q (liter/h) for each 10 kg that body weight differs from the median value 0.593 (20.4)
V
2
(liters) for subject with median body weight (75 kg)
3.13 (2.7) 19.1 (27.4)
Change in V
2
(liters) for each 10 kg that body weight differs from the median value
0.458 (12.0)
Fractional change in V
2
for subject with infection
1.93 (9.5)
Duration of infusion (h) 0.384 (27.3) NE
a
a
NE, not estimated.
b
For the residual error parameter
2
add
for studies that used the LC/MS/MS assay, the estimated value was 4.28, with an RSE of 23.1% and an intraindividual error
SD of 2.07 g/ml. For the parameter
2
add
for studies that used the HPLC assay, the estimated value was 22.4, with an RSE of 20.3% and an intraindividual error SD
of 4.73 g/ml.
2804 DVORCHIK ET AL. ANTIMICROB.AGENTS CHEMOTHER.
DISCUSSION
Daptomycin is a novel lipopeptide antibiotic which was re-
cently approved for the treatment of cSSSI caused by suscep-
tible gram-positive microorganisms. It has a unique mechanism
of action, and in vitro it demonstrates rapid, concentration-
dependent bactericidal activity against drug-resistant clinical
isolates of gram-positive microorganisms, a long postantibiotic
effect, and a low rate of spontaneous resistance (4, 9, 11, 17).
In vivo, daptomycin exhibits linear pharmacokinetics after both
single and multiple once-daily doses (8, 20). Pharmacodynamic
studies using a model of S. aureus thigh infections in neutro-
penic mice indicated that bacterial eradication best correlates
with the ratio of AUC
24 h
to the MIC (12).
This report represents the rst population pharmacokinetic
TABLE 4. Summary of pharmacokinetic parameters sorted by estimated CL
CR
and obtained by Bayesian estimation from the nal model
Pharmacokinetic parameter
Value for subjects in CL
CR
group
80 ml/min
(n 165)
80 to 40 ml/min
(n 80)
40 ml/min
(n 16)
On dialysis
(n 21)
CL (liter/h)
Median 0.86 0.64
b
0.37
b,c
0.24
b,c
Minimum 0.41 0.23 0.21 0.17
Maximum 2.19 1.64 0.70 0.58
V
1
(liters)
Median 4.44 4.41 6.05
c
6.60
b,c
Minimum 0.63 0.20 3.27 3.76
Maximum 24.93 14.95 29.93 13.15
V
ss
(liters)
Median 9.73 8.75 10.36 10.44
Minimum 5.10 3.77 6.19 6.84
Maximum 32.77 19.24 34.89 17.63
AUC
(0⫺⬁)
(g h/ml)
a
Median 400.77 436.54
b
716.24
b,c
1,205.60
b,c,d
Minimum 160.60 151.68 297.72 367.01
Maximum 1,143.70 1,181.00 1,677.00 1,906.00
t
1/2
(h)
Median 8.28 9.07
b
18.96
b,c
29.32
b,c,d
Minimum 4.64 5.17 8.84 14.69
Maximum 48.01 71.16 58.83 41.80
a
Calculated for a single 4-mg/kg dose.
b
Signicantly different from 80-ml/min group.
c
Signicantly different from 80- to 40-ml/min group.
d
Signicantly different from 40-ml/min group.
TABLE 5. Summary of pharmacokinetic parameters by study phase and estimated CL
CR
of individual parameters obtained by Bayesian
estimation from the nal model
Pharmacokinetic
parameter
Value for phase 1 subjects in CL
CR
group
Value for phase 2/3 subjects in CL
CR
group
80 ml/min
(n 79)
80 to 40 ml/min
(n 48)
40 ml/min
(n 8)
On dialysis
(n 18)
80 ml/min
(n 86)
80 to 40 ml/min
(n 32)
40 ml/min
(n 8)
On dialysis
(n 3)
CL (liter/h)
Median 0.78 0.63 0.35 0.23 0.98 0.64 0.57 0.31
Minimum 0.48 0.29 0.21 0.17 0.41 0.23 0.22 0.29
Maximum 1.33 1.1 0.58 0.43 2.19 1.64 0.7 0.58
V
1
(liters)
Median 4.02 3.87 6.05 6.66 5.33 5.26 6.77 6.20
Minimum 2.14 1.89 3.27 3.76 0.63 0.20 3.51 6.14
Maximum 8.51 9.90 7.27 13.15 24.93 14.95 29.93 7.72
V
ss
(liters)
Median 7.52 6.88 10.01 9.98 12.38 10.81 11.66 11.42
Minimum 5.10 3.77 6.19 6.84 6.10 5.91 9.86 11.32
Maximum 13.12 13.94 11.04 17.63 32.77 19.24 34.89 12.00
AUC
(0-)
(g h/ml)
a
Median 443.79 453.18 987.02 1,310.05 338.84 394.28 527.05 849.95
Minimum 247.12 206.12 477.08 772.29 160.60 151.68 297.72 367.01
Maximum 802.04 1,181.00 1,677.00 1,906.00 1,143.70 1,151.1 1,139.5 866.09
t
1/2
(h)
Median 7.08 8.08 20.71 30.51 9.89 12.45 14.61 25.64
Minimum 4.64 5.17 8.84 22.25 5.03 7.49 12.74 14.69
Maximum 12.30 26.11 34.17 41.80 48.01 71.16 58.83 27.25
a
Calculated for a single 4-mg/kg i.v. dose.
VOL. 48, 2004 POPULATION PHARMACOKINETICS OF DAPTOMYCIN 2805
analysis of daptomycin and includes subjects from all three
phases of the clinical development program. The increased use
of population pharmacokinetic analysis has generated a num-
ber of newer software programs that, like NONMEM, have
advantages and disadvantages. One topic of discussion has
been the ability and ease of use of NONMEM to detect the
presence of a nonnormal distribution, especially within a sub-
population. The intelligent use of any pharmacokinetic pro-
gram is a prerequisite for a meaningful analysis. NONMEM,
when used by trained personnel, does allow one to detect a
distribution that is substantially nonnormal.
Among healthy subjects, the estimated pharmacokinetics
were consistent with those previously reported for a phase 1
study in which single doses of 0.5 to 6 mg of daptomycin/kg
were administered intravenously to healthy volunteers (20).
The population analysis dened quantitatively the decrease in
daptomycin CL associated with reduced renal function, a re-
lationship that was suggested by earlier phase 1 studies. New
ndings included the increase in the volume of the peripheral
compartment (V
2
) in subjects with bacterial infections relative
to healthy subjects as well as the associations between weight
and both intercompartmental clearance (Q) and V
2
.
Renal function, sex, and body temperature accounted for
21.5% of the interindividual variability in daptomycin clear-
ance, with renal function being the single most signicant ex-
planatory variable. During the screening of covariates, adding
just renal function (i.e., CL
CR
in nondialysis subjects and a ag
for subjects on dialysis) to the clearance model reduced the
interindividual variability by 18.9%, from 52.1% in the base
model (no covariates) to 33.2% (with the addition of renal
function markers) (data not shown). This nding is consistent
with the fact that daptomycin, like other hydrophilic antibiot-
ics, is cleared primarily by renal excretion (20).
The median estimated daptomycin clearance for a normo-
thermic male with an estimated CL
CR
of 91.2 ml/min was 0.807
liter/h (13.5 ml/min). Among subjects on dialysis, the median
daptomycin clearance was estimated to be 0.269 liter/h (4.5
ml/min), or approximately one-third that of nondialysis sub-
jects. Among subjects who were not on dialysis, daptomycin
clearance was a linear function of CL
CR
. For example, for an
increase or decrease in the estimated CL
CR
of 10 ml/min, the
daptomycin clearance increased or decreased by 0.05 liter/h
(0.8 ml/min).
The dose of daptomycin recommended for the treatment of
cSSSI is 4 mg/kg administered by intravenous infusion once
every 24 h for subjects with CL
CR
of 30 ml/min and once
every 48 h for subjects with lower CL
CR
values, including those
who are on dialysis. These recommendations are based on
several observations in addition to the data presented in this
report. Sica et al. (42nd ICAAC) determined mean C
max
and
AUC
ss
values among 44 subjects with graded renal impairment
or who were undergoing dialysis. The C
max
was consistent for
all subjects and the AUC
ss
was similar in all subjects who had
an estimated CL
CR
of 40 ml/min. For subjects with an esti
-
mated CL
CR
of 40 ml/min, the AUC was increased 2.33-fold
compared to that for subjects with a CL
CR
of 80 ml/min. The
two phase 3 trials for the treatment of cSSSI included a limited
number of subjects with estimated CL
CR
values between 30
and 40 ml/min. There was no increase in adverse events attrib-
uted to daptomycin among these subjects; none participated in
the pharmacokinetic studies reported here. Additional studies
of the pharmacokinetics and safety of daptomycin in renally
impaired subjects and in those undergoing dialysis are in
progress.
Daptomycin clearance was inuenced to a lesser extent by
sex and body temperature. Clearance in females was estimated
to be approximately 80% that of male subjects with similar
renal function. Among subjects with cSSSI treated with dap-
tomycin in two recent large phase 3 trials, there were no clin-
ically or statistically signicant differences between the success
rates for males (n 230) and females (n 192) (74.8 versus
77.1%, respectively; 95% condence intervals, 7.2 and 8.3)
(data on le, Cubist Pharmaceuticals). Thus, although the dif-
ference in daptomycin clearance related to sex was statistically
signicant, it does not appear to be clinically meaningful.
The observation that daptomycin clearance increased with
elevated body temperatures (37.2°C) should be interpreted
cautiously since the analysis was limited to data obtained from
100 subjects in the phase 2/3 clinical studies, of whom only 14%
were hyperthermic (body temperature of 38°C).
Comorbidities, including diseases producing uid accumu-
lation (e.g., ascites and edema), diabetes, hypertension, and
congestive heart failure, were not signicantly correlated with
daptomycin clearance. Medications that were tested for possi-
ble pharmacokinetic interactions with daptomycin included
acidic drugs that are actively secreted in the renal tubule and
drugs that are highly (95%) bound to albumin (3, 13, 15).
These had no effect on daptomycin pharmacokinetics.
The estimated increases in Q and V
2
for daptomycin with
increased body weights were consistent with the physicochem-
ical properties of daptomycin and the physiologic effects of
weight. Daptomycin appears to be restricted to the extracellu-
lar space which increases with body weight (15). Similarly, the
extravascular distribution of daptomycin occurs via diffusion
(15), which would also be facilitated by the increased uid
(water) associated with an increased body weight.
V
2
was estimated to be approximately twofold larger in sub
-
jects with acute bacterial infections than in uninfected subjects.
This is consistent with the pathophysiology of acute bacterial
infections, which is characterized by an inammatory response
associated with increased vascular permeability and the collec-
tion of extracellular uid at the site of infection. However,
since bacterial infections were only present among subjects in
the phase 2/3 clinical trials, it is also possible that this factor
was a surrogate for another, possibly unmonitored, covariate
or an unidentied systematic difference between the phase 1
and phase 2/3 clinical trials. Currently, there is no recommen-
dation regarding increased doses of daptomycin for patients
with exceptionally severe infections or impaired host defenses.
A trial of daptomycin at 6 mg/kg intravenously once a day for
the treatment of infective endocarditis due to S. aureus is in
progress.
Although there was an appreciable variability in the esti-
mates of V
1
, none of the covariates investigated was identied
as a signicant source of this variability. In a recently reported
phase 1 study of daptomycin pharmacokinetics using subjects
with graded renal insufciencies and end-stage renal disease
(Sica et al., 42nd ICAAC), the total volume of distribution for
daptomycin was increased among subjects on hemodialysis. In
the present larger study, this relationship was extended and
2806 DVORCHIK ET AL. ANTIMICROB.AGENTS CHEMOTHER.
further dened as an increase in V
1
in subjects with CL
CR
values of 40 ml/min as well as in subjects on dialysis, but only
in a supplemental analysis of variance (Table 5). This may be
because of the relatively small proportion of subjects who were
undergoing dialysis or perhaps because the effect represents
another, possibly unmonitored, covariate. Additional studies
of daptomycin pharmacokinetics in subjects on hemodialysis
are in progress.
In conclusion, this population analysis of daptomycin phar-
macokinetics indicates that renal function is the single most
signicant factor contributing to interindividual variabilities in
daptomycin clearance. Because of their reduced daptomycin
clearance, patients on dialysis and those with severe renal
disease (CL
CR
of 30 ml/min) will require adjusted dosage
regimens to achieve systemic exposures that are clinically and
pharmacologically comparable to those seen in subjects with
higher levels of renal function. Daptomycin clearance was also
impacted by sex and body temperature. However, an analysis
of clinical outcomes suggested that the variation associated
with sex is not clinically meaningful. The relationship with body
temperature should be interpreted cautiously since the analysis
was limited to the subset of subjects from phase 2/3 clinical
studies, of which only 14% were hyperthermic. The relation-
ships between body weight and the rate and extent of extravas-
cular distribution support the dosing of daptomycin on the
basis of milligrams per kilogram of body weight.
ACKNOWLEDGMENTS
This work was supported by and conducted under the auspices of
Cubist Pharmaceuticals, Inc.
We acknowledge the cooperation and assistance of the subjects,
investigators, and study personnel who participated in these trials and
the support of our colleagues in the Cubist Clinical Department.
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VOL. 48, 2004 POPULATION PHARMACOKINETICS OF DAPTOMYCIN 2807
    • "Daptomycin is renally excreted, and dosing must be adjusted for adult subjects who have impaired creatinine clearance or who are undergoing dialysis [24]. Daptomycin has a T 1/2 of 8–9 hours (Table 2) [20,24252627. At doses of 4 mg/kg every 24 hours in children 12–17 years of age, the area under the concentration curve (AUC) of daptomycin approximated adult values shown to be therapeutically effective (375 μg/mL*h vs. 414–494 μg/mL*h, respectively)262728102]. "
    [Show abstract] [Hide abstract] ABSTRACT: Methicillin-resistant Staphylococcus aureus (MRSA) remains a significant cause of morbidity in hospitalized infants. Over the past 15 years, several drugs have been approved for the treatment of S. aureus infections in adults (linezolid, quinupristin/dalfopristin, daptomycin, telavancin, tigecycline and ceftaroline). The use of the majority of these drugs has extended into the treatment of MRSA infections in infants, frequently with minimal safety or dosing information. Only linezolid is approved for use in infants, and pharmacokinetic data in infants are limited to linezolid and daptomycin. Pediatric trials are underway for ceftaroline, telavancin, and daptomycin; however, none of these studies includes infants. Here, we review current pharmacokinetic, safety and efficacy data of these drugs with a specific focus in infants.
    Full-text · Article · Apr 2014
    • "Previous population PK-PD analyses included a combination of patient populations (n = 129) and healthy volunteers (n = 153) and observed a median (%RSE) CL of 0.807 (2.9) L/ hour that was influenced by eCLcr, sex, and body tempera- ture [6]. This previous POP-PK model also suggested that the median daptomycin CL should be 1.08 L/hour in a patient with a fever (39.2°C) that is comparable to our population esti- mates [6]. Importantly, neither model identified body weight to be a predictor of daptomycin CL. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Higher daptomycin doses are advocated for select methicillin-resistant Staphylococcus aureus (MRSA)-related infections, but the probabilities of target attainment (PTA) and toxicity of these doses have not been characterized in critically ill patients. Methods: We evaluated the plasma pharmacokinetics (PK) and clinical outcomes of a cohort of critically ill patients treated with daptomycin 6-8 mg/kg/day for primarily Staphylococcus species-related infections. Daptomycin concentrations were measured intensively over the initial 96-hour dosing period. Data were modeled by population PK analyses, and Monte Carlo simulation was used to estimate the probabilities of effect and toxicity with standard and alternate dosing regimens. Results: Fifty patients with a mean (SD) age of 69.7 (12.2) years, weight 74.5 (20.3) kg, and creatinine clearance 56.8 (38.2) mL/minute were enrolled with measurements of 12 (2.2) daptomycin samples per patient. Significantly lower daptomycin exposures were observed despite comparable doses in a subset of patients (n = 13) with augmented clearance (CL). No covariates of CL were identified, but this subset was significantly more likely to be in severe sepsis or septic shock, have higher Sequential Organ Failure Assessment scores, and MRSA bacteremia. In-hospital mortality was significantly higher (30.7% vs 10.8%) in patients with augmented daptomycin CL. Use of an empiric fixed dose of 750 mg of daptomycin is predicted to achieve a comparable PTA with a lower probability of toxicity as compared to the use of 10 mg/kg in critically ill patients. Conclusions: A reappraisal of current daptomycin dosing recommendations is needed to improve the PTA and reduce toxicity among critically ill patients.
    Full-text · Article · Sep 2013
    • "Considering that sepsis has a high mortality in critically ill patients with acute kidney injury, optimizing antibiotic dosing is crucial in this patient population. In these cases, because daptomycin is eliminated primarily by the kidneys, dose adjustments are required [12, 13]. On the other hand, drug accumulation and excessive antibiotic concentrations can result in an increased risk of adverse events, such as creatine kinase elevation with rare cases of rhabdomyolysis. "
    Full-text · Dataset · Apr 2013 · Clinical Infectious Diseases
    Falcone MFalcone MRusso ARusso ACassetta MICassetta MI+1more author...[...]
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