J Infect Chemother xxx (2017) 1e8

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Journal of Infection and Chemotherapy

journal homepage: http://www.elsevier.com/locate/jic

Original Article

Population pharmacokinetics of teicoplanin in hospitalized elderly

patients using cystatin C as an indicator of renal function
Hidefumi Kasai a, b, Yasuhiro Tsuji a, *, Yoichi hiraki c, Moeko Tsuruyama c, Hideto To a,
Yoshihiro Yamamoto d
a
Department of Medical Pharmaceutics, Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, Toyama, 930-0194, Japan
b
Certara G.K., 4-2-12, Minato-ku, Tokyo, 105-0001, Japan
c
Department of Pharmacy, National Hospital Organization Beppu Medical Center, 1473 Uchikamado, Beppu, Oita, 874-0011, Japan
d
Department of Clinical Infectious Diseases, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani,
Toyama, Toyama, 930-0194, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Objective: Serum cystatin C (CysC) has recently been proposed as an alternative marker to serum
Received 30 August 2017 creatinine (SCR) for estimating renal clearance. In the present study, we performed a population phar-
Received in revised form macokinetic analysis of teicoplanin (TEIC), which is mainly eliminated through the kidneys, using CysC as
20 November 2017
a predictor for renal clearance.
Accepted 4 December 2017
Available online xxx
Methods: Thirty-six patients with MRSA infections who were administrated to the National Hospital
Organization Beppu Medical Center between January 2012 and December 2013 were enrolled and gave
123 sets of blood TEIC concentration data. Renal clearance was estimated by the Hoek equation using
Keywords:
Cystatin C
CysC, by creatinine clearance predicted by the Cockcroft-Gault equation using SCR, or directly by CysC.
Hoek equation One compartment open model with inter-individual variabilities for renal clearance and the volume of
Methicillin-resistant Staphylococcus aureus distribution as well as an additional residual error model was used to estimate population pharmaco-
Pharmacokinetics kinetic parameters for TEIC.
Teicoplanin Results: The model with the best predictability was that with CysC as a predictor for renal clearance; it
showed better significance than the models using estimated the glomerular filtration rate by the Hoek
equation or CLcr. The final model was as follows: CL (L/hr) ¼ 0.510  (CysC/1.4)0.68  Total body weight/
600.81, omega (CL) ¼ 19.8% CV, VC (L) ¼ 78.1, omega (V) ¼ 42.7% CV.
Conclusion: The present results show the usefulness of CysC to more accurately predict the pharmaco-
kinetics of drugs mainly eliminated through the kidneys, such as TEIC. However, since the sample size in
this study was relatively small, further investigations on renal clearance predictability using CysC are
needed.
© 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases.
Published by Elsevier Ltd. All rights reserved.

1. Introduction glycopeptide class of antimicrobial agents. Glycopeptides are nat-

Methicillin-resistant Staphylococcus aureus (MRSA) represents a
predominant pathogen associated with serious infections, which
have become a major therapeutic issue because of the high rates of
morbidity and mortality as well as length of hospital stay [1, 2].
MRSA infections are a serious and constantly growing public health
concern. Teicoplanin and vancomycin are members of the
* Corresponding author.
E-mail address: ytsuji@pha.u-toyama.ac.jp (Y. Tsuji).
ural products that have been separated and purified from sub-
stances produced by the cultivation of Actinoplanes teichomyceticus
[3]. Teicoplanin shares many chemical and microbiological prop-
erties with vancomycin, and exhibits strong antibacterial activity
against aerobic Gram-positive cocci (GCP) and MRSA [4,5]. Teico-
planin is not approved for use in the United States, but has been
extensively used in Europe since 1988 and is approved for use in
more than 60 countries.
Teicoplanin is not absorbed orally and, thus, is administered by
the parenteral route (intravenously or intramuscularly). It mainly

https://doi.org/10.1016/j.jiac.2017.12.002
1341-321X/© 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Kasai H, et al., Population pharmacokinetics of teicoplanin in hospitalized elderly patients using cystatin C as
an indicator of renal function, J Infect Chemother (2017), https://doi.org/10.1016/j.jiac.2017.12.002
2 H. Kasai et al. / J Infect Chemother xxx (2017) 1e8

binds to albumin and is predominantly eliminated by the kidneys
[6]. Dosing adjustments of teicoplanin are considered necessary for
patients at any stage of renal dysfunction, including hemodialysis,
and teicoplanin concentrations were found to be significantly
higher in patients with renal function impairment than in those
without [7]. Teicoplanin has a longer elimination half-life than
vancomycin [6,7]. Thus, some loading doses according to the renal
function and weight of a patient have been recommended for the
rapid achievement of an effective therapeutic range after initial
teicoplanin therapy is started [8e10].
In adult patients in Japan, teicoplanin is typically administered
at a dose of 200 mg or 400 mg twice daily on Day 1, and this is
followed by a maintenance dose of 200 mg or 400 mg once daily via
intravenous infusion. After the initiation of teicoplanin, its trough
concentration is assumed to be maintained between 15 and 30 mg/
L [11e17], and the maintenance of a trough concentration of
>20 mg/L in severe and complicated infections with patients was
previously shown to be effective [18e23]. In contrast, Nakayama
et al. demonstrated that the development of hepatic function dis-
orders was more frequent in patients with a teicoplanin trough
concentration of approximately >30 mg/L [24]. Moreover, a teico-
planin trough concentration of >40 mg/L is associated with
thrombocytopenia and/or an increased risk of organ toxicity
[25,26]. Therefore, doses need to be adjusted based on teicoplanin
concentrations [7].
The treatment of MRSA infections in patients requires the
appropriate selection and dosing design of antimicrobial agents
based on the physiological function of the patient. Regarding the
administration of drugs such as teicoplanin and vancomycin, which
are excreted into the urine, accurate assessments of renal function
are needed in order to establish appropriate doses. Creatinine
clearance (CLcr) estimated from serum creatinine (SCR) levels by
the Cockcroft-Gault equation is used as a substitute for the
glomerular filtration rate (GFR) in clinical pr102actice because of its
simplicity [27]. On the other hand, The National Kidney Foundation
Kidney Disease Outcomes Quality Initiative (NKF/KDOQI)™
recently recommended a new GFR estimation method (eGFR), in
which age, gender, and blood test values are included and a racial
correction is added, and the adoption of this method to assess and
classify renal function in chronic renal diseases is becoming more
common worldwide [28, 29].
Cystatin C (CysC) is a low molecular mass protein that was
initially called inter alia g-trace, post-g-globulin, and g-CSF. CysC
has been identified as a marker of GFR and SCR in the populations
investigated [30]. The subsequent development of automated and
rapid particle enhanced immunoturbidimetric and immunone-
phelometric methods, which are rapid as well as more precise, has
allowed the large-scale use of CysC as a clinically useful GFR marker
[31]. Some equations using serum CysC levels to estimate the GFR
with or without anthropometric data have recently been reported
[32e37]. Among them, Hoek et al. reported that the strong corre-
lation between CysC and GFR permitted the calculation of a reliable
equation for eGFR from CysC data [32].
However, no studies have attempted to estimate the population
pharmacokinetic approach of teicoplanin in elderly patients with
MRSA infections using CysC as an index of renal function. Marked
variability in teicoplanin pharmacokinetics makes it difficult to
predict a priori the optimal dosage regimen for individual patients
with renal dysfunction. Therefore, it is important to assess the
pharmacokinetic behavior of teicoplanin.
The aims of this study were (i) to develop a population
pharmacokinetic model for teicoplanin in patients with MRSA
infections and (ii) to examine the influence of patient charac-
teristics based on several renal functions on teicoplanin
pharmacokinetics.
2. Patients and methods
2.1. Ethics
This study was performed in conformity with the Helsinki
Declaration after approval by the Ethical Review Board of University
of Toyama (approval number: clinical 24e94) and National Hospital
Organization Beppu Medical Center. A written explanation of the
study was provided to participants, and written informed consent
was obtained. Patient privacy and personal information was
handled such that it was not possible to identify patients.
2.2. Patients and data sources
A summary of the data for these patients is presented in
Table 1. All patients received teicoplanin via intravenous infusion
for the treatment of MRSA infections including pneumonia (24
cases), sepsis (6 cases), surgical site infection (5 cases) and skin
and soft tissue infections (1 cases) between January 2012 and
December 2013 at the National Hospital Organization Beppu
Medical Center, Oita, Japan. The usual dose of teicoplanin was
mainly scheduled to be administered in three loading intravenous
doses of 200e400 mg/12 h followed by a maintenance intrave-
nous dose of 200e400 mg/24 h, following the package insert.
Other dosage adjustments to teicoplanin were performed by
physicians' decisions based on the renal function of the patient.
Patients receiving dialysis therapy and those with disseminated
intravascular coagulation, multiple organ failure, and burns were

Table 1
Clinical data for the study population of patients receiving teicoplanin.

Gender Number Mean SD Median Minimum Maximum

Age (year) Male 16 77.1 11.4 82.0 54 90

Female 20 80.1 7.0 79.0 66 91
Total body weight (kg) Male 16 51.7 9.8 50.9 38.1 72.8
Female 20 43.8 15.2 38.4 21.5 91.5
Serum creatinine (mg/dL) Male 16 1.25 1.60 0.76 0.47 7.1
Female 20 0.76 0.56 0.56 0.24 2.38
Serum CysC (mg/L) Male 16 1.45 0.39 1.41 0.86 2.31
Female 20 1.74 0.81 1.35 0.66 3.41
CLcr (mL/min) Male 16 58.4 33.9 52.5 6 132
Female 20 57.2 34.9 60.5 16 154
eGFR Hoek (mL/min) Male 16 47.9 15.2 46.3 24.1 89.1
Female 20 38.7 18.2 39.6 14.1 82.0
Albumin (g/dL) Male 16 2.8 0.5 2.8 1.8 3.6
Female 20 2.4 0.6 2.4 1.1 3.4

SD, standard deviation; CysC, cystatin C; CLcr, creatinine clearance; eGFR Hoek, estimated glomerular filtration rate per body by the Hoek equation [32].

Please cite this article in press as: Kasai H, et al., Population pharmacokinetics of teicoplanin in hospitalized elderly patients using cystatin C as
an indicator of renal function, J Infect Chemother (2017), https://doi.org/10.1016/j.jiac.2017.12.002
 H. Kasai et al. / J Infect Chemother xxx (2017) 1e8
excluded. There were no patients with systemic inflammatory
response syndrome including augmented renal clearance in the
subject of the present study.
2.3. Assessment of teicoplanin concentrations
Blood samples were collected from each patient immediately
before the administration of teicoplanin on Day 4 of the treat-
ment in order to measure steady-state teicoplanin concentra-
tions and for hematology and biochemical testing. Serum CysC
levels were measured using a sol particle homogeneous immu-
noassay [38]. Teicoplanin concentrations were measured using a
TBA™-c16000 automatic analyzer (Toshiba Medical Systems CO.,
Japan) with the commercially available reagent “Nanopia® TDM
Teicoplanin” kit (Sekisui Medical CO., LTD., Japan). Below the
limit of quantitation was 2.0 mg/L, and the lower limit of
quantification (LLOQ) was 3.0 mg/L for total teicoplanin con-
centrations. The measurement range was between 3.0 and
100 mg/L for total teicoplanin concentrations.
 
80:35 BSA
eGFR Hoek ðmL=minÞ ¼  4:32 þ 
CysC 1:73
eGFR Larsson ðmL=minÞ ¼ 77:24  CysC 1:2623
BSA
eGFR Grubb ðmL=minÞ ¼ 86:49  CysC 1:686  ð  0:948 if femaleÞ
1:73
 
124 BSA
€ stro
eGFR Sjo € m ðmL=minÞ ¼  22:3 
CysC 1:73
eGFR Grubb 2 ðmL=minÞ ¼ 99:19  CysC 1:713 ð  0:823 if femaleÞ
2.4. Population pharmacokinetics and pharmacodynamics of
teicoplanin
A population pharmacokinetic analysis of teicoplanin was per-
formed using Phoenix NLME (version 1.3; Certara L.P., St. Louis, MO.,
USA). The first-order conditional estimation method with the h-ε
interaction option (FOCE ELS) was used during pharmacokinetic
model development. The entire procedure of executing model runs,
bootstrapping, visual predictive checks (VPC), graphical analyses,
and results management was performed in Phoenix NLME.
2.5. Population pharmacokinetics
The pharmacokinetics of teicoplanin assumed a one-
compartment distribution model with first-order elimination.
Pharmacokinetic parameters were total clearance (CL) and the
volume of the central compartment (VC). Between-subject vari-
ability in pharmacokinetic parameters was modeled with a log-
normal distribution in Eq. (1). Pi is the pharmacokinetic param-
eter for the ith individual, TVP is the population mean value of the
parameters, and hi is a normally distributed random variable with
mean zero and variance u2. An analysis of the covariance matrix in
the statistical model was attempted for this analysis.
Pi ¼ TVP  e hi
Residual unidentified variability was modeled with combined
additive errors of total concentrations in Eq. (2). Cij is the jth
measured concentration in the ith subject, CPREDij is the predicted
Please cite this article in press as: Kasai H, et al., Population pharmacokinetics of teicoplanin in hospitalized elderly patients using cystatin C as
an indicator of renal function, J Infect Chemother (2017), https://doi.org/10.1016/j.jiac.2017.12.002
3
concentration based on the model. εSD is an additive, with mean
zero and variance s2 for concentration.
Cij ¼ CPREDij þ εSD (2)
The data below the LLOQ of teicoplanin concentrations did not
exist in the data of the present study.
2.6. Covariate model
The covariates considered in CL were total body weight (TBW)
and body surface area (BSA) calculated by the Dubois equation [39]
and serum albumin (ALB) levels as indices of demographic factors;
CLcr, SCR, CysC, and some eGFR equations using the serum CysC
level as an index of renal function. CLcr was calculated by the
Cockcroft-Gault formula [27]. Five equations to estimate eGFR for
adult patients have been published by Hoek et al. [32], Larsson et al.
€ stro
[33], Grubb et al. [34], Sjo €m et al. [35], Grubb 2 et al. [36] as
follows.
The covariates considered in VC were age, gender, TBW, BSA, and
serum albumin levels as indices of demographic factors. TBW was
standardized to a standard body weight of 60 kg. Covariates were
modeled with a power form and centered around a patient's me-
dian values.
2.7. Model evaluation and validation
In order to test the significance of various factors that may in-
fluence pharmacokinetic parameters, the value of the objective
function (OFV) assessed in Phoenix NLME was used. OFV was
calculated as a minus twice log likelihood (-2LL) value for each
model. Covariates were searched by forward selection and
confirmed in the final model. The difference in OFV (DOFV) ob-
tained by comparing each model was asymptotically distributed
according to the chi-squared test with the degree of freedom being
equal to the difference in the number of parameters between the
two models. The significance level was set to 0.05 (DOFV: 3.84). The
goodness of fit (GOF) of the final model was evaluated by checking
the plots of observed, population predicted, and individually pre-
dicted concentrations and conditional weighted residuals.
The bootstrap resampling method was used to evaluate the
stability of the final model [40]. The final model was fit repeatedly
to 200 additional bootstrap datasets. The mean, standard deviation
(1)
(SD), and relative standard error (RSE%) were calculated from the
empirical bootstrap distribution and compared estimates from the
original dataset. A prediction-corrected VPC (pcVPC) was used to
check the distribution of observed and predicted percentiles [41].
4 H. Kasai et al. / J Infect Chemother xxx (2017) 1e8

Fig. 1. Observed plasma teicoplanin concentrations vs time since the first dose A) and since the last dose B) (123 samples from 36 patients).

The VPC was evaluated by comparing the observed concentrations CLcr and eGFR were added in the CL, in turn, to the base model and
with 95% percentile intervals (PIs) simulated from the final changes in the OFV were noted. These OFV were significantly
parameters. reduced. In the final forward step (full model), the modeling of the
The population model was also evaluated by the leave-one-out CL with CysC and TBW most significantly improved the estimates of
cross validation method [42]. Briefly, one subject was sequentially teicoplanin CL from the basic model (DOFV ¼ 19.221, df ¼ 2, P < .01).
dropped from the original data set and the population model was The final pharmacokinetic model parameters are shown in Eq. (3).
applied. The parameter estimates obtained from each of the 36
   
patient datasets were compared to investigate for outliers. CysC 0:68 TBW 0:81
CL ðL=hÞ ¼ 0:510  
1:4 60
3. Results
VC ðLÞ ¼ 78:1 (3)
3.1. Population pharmacokinetics of teicoplanin
Between-subject variabilities in CL and VC were 19.8% and 42.7%
as the coefficients of variation, respectively. Residual unidentified
A total of 123 blood total teicoplanin trough concentrations from
variability was 2.49 mg/L as the standard deviation.
36 patients were available to develop the population pharmacoki-
netic model (Fig. 1). A preliminary pharmacokinetic analysis was
3.2. Model evaluation and validation
conducted to estimate the parameters of the basic model without
any covariates. CysC, TBW or ALB was then included in the CL, and
GOF plots in the final model are shown in Fig. 2, and the
ALB was included in the VC on the basic model in Table 2. In the
observed concentrations were consistent with the population
next forward step, each candidate covariate for the equations of
predicted concentrations and individual predicted concentrations
(Fig. 2A and B). GOF was also evaluated graphically by the good
Table 2 distribution of points on conditional weighted residual versus
Summary of covariate model building of teicoplanin with forward addition. population predicted concentrations and the time after adminis-
Model OFV tration (Fig. 2C and D). Most of these plots were distributed close to
the trend line at y ¼ x and its value ranged from ±3 unit range
Basic model CL (L/h) ¼ q1, VC (L) ¼ q2 707.1555
Basic model þ CysC on CL 702.7953 relative to the reference zero line.
Basic model þ TBW on CL 697.6997 Pharmacokinetic parameter estimates from original data and
Basic model þ ALB on CL 706.3235 the bootstrap distribution are presented in Table 3, showing the
Basic model þ ALB on VC 707.1461 results of parameter estimates of the final model and the 100%
Basic model þ eGFR Filler on CL 692.6635
Basic model þ eGFR Hoek on CL 692.8391
successful computation from 200 bootstrap resampling. The mean
Basic model þ eGFR Larsson on CL 697.7002 values of the final model estimates were very similar to the esti-
Basic model þ eGFR Grubb on CL 694.2747 mates from bootstrapping. The RSE in CL and VC were small (<10%)
Basic model þ eGFR Sjostrom on CL 694.9255 for pharmacokinetic parameters. Other bootstrap RSE were slightly
Basic model þ eGFR Grubb 2 on CL 697.6037
large (14.9%e62.6%).
Basic model þ CLcr on CL 690.8173
Final model (Full model) Basic model þ CysC þ TBW on CL 687.9341 pcVPC results showed that the median prediction of simulated
data matched the observed plots (Fig. 3).
OFV, the minimum value of the objective function (2 log likelihood) in each
NONMEM run; CL, total clearance; VC, volume of the central compartment; Cys C;
Fig. 4 shows the parameter estimates from the population
Cystatin C, TBW, total body weight; ALB, albumin; eGFR, estimated glomerular pharmacokinetic analysis performed by fitting the population
filtration rate; CLcr, creatinine clearance; model to the data set generated by a leave-one-out method (one

Please cite this article in press as: Kasai H, et al., Population pharmacokinetics of teicoplanin in hospitalized elderly patients using cystatin C as
an indicator of renal function, J Infect Chemother (2017), https://doi.org/10.1016/j.jiac.2017.12.002
 H. Kasai et al. / J Infect Chemother xxx (2017) 1e8 5

Fig. 2. Goodness-of-fit plots for the final population pharmacokinetic model. Top left: observed vs population predicted, top right: observed vs individual predicted teicoplanin
concentrations. Bottom left: CWRES vs population prediction, bottom right: CWRES vs time since the last dose.

Table 3
Population pharmacokinetic parameters estimates for the final model with estimates from 200 bootstrap samples.

Parameter Description Units Final model estimate Bootstrap sample estimates

Mean SE Mean SD RSE%

Population mean for pharmacokinetics

CL Total clearance L/h 0.51 0.04 0.49 0.04 8.8%
VC Volume of the central compartment L 78.1 6.54 77.0 6.49 8.4%
KTBWCL Total body weight parameter for CL 0.81 0.22 0.71 0.27 37.3%
KCysCCL Cystatin C parameter for CL 0.68 0.18 0.67 0.26 38.1%
Between-subject variability (BSVa)
CL 0.038 0.027 0.039 0.024 62.6%
VC 0.18 0.12 0.20 0.12 58.1%
CL-VC 0.054 (r ¼ 0.54) 0.018 0.046 (r ¼ 0.62) 0.025 45.3%
Residual unidentified variability (RUVb)
RUVADD Additive residual unidentified variability of concentration mg/L 2.49 0.42 2.39 0.36 14.9%

Successful ratio ¼ 100% (200/200).

SE, standard error; SD, standard deviation; RSE, relative standard error.
a
BSV calculated from sqrt (OMEGA).
b
RUV estimated using THETA.

Please cite this article in press as: Kasai H, et al., Population pharmacokinetics of teicoplanin in hospitalized elderly patients using cystatin C as
an indicator of renal function, J Infect Chemother (2017), https://doi.org/10.1016/j.jiac.2017.12.002
6 H. Kasai et al. / J Infect Chemother xxx (2017) 1e8

The population pharmacokinetics of teicoplanin were previ-

Fig. 3. Prediction-corrected visual predictive checks (pcVPC) for teicoplanin concen-
trations. Prediction-corrected scatterplot of measurements with simulated 5th, 50th,
and 95th percentiles.
subject was sequentially dropped from the original data set). Visual
evaluations of the graph indicated that the estimated values of
qCysC, uCL2, and uCL-VC from the data set excluding subject No.
445 had deviated.
4. Discussion
The present study attempted to apply a population pharmaco-
kinetic approach to predict teicoplanin concentrations associated
with CysC as a predictor for renal clearance after the intravenous
infusion of teicoplanin to elderly patients with MRSA infections. By
identifying the influence of CysC as the most significant predictor
for renal clearance in teicoplanin, we hope to help clinicians un-
derstand how to manage teicoplanin dosing in elderly patients with
MRSA.
ously described using a multicompartmental model regardless of
adults and children [43e48]. Serum teicoplanin concentrations in
the present study were measured in blood samples collected in the
elimination phase near the trough. Thus, blood samples were not
collected at the distribution phase to fulfill the terms of the multi-
compartment model analysis. Hence, the pharmacokinetic analysis
of the present study was performed using a one-compartment
model with first-order elimination.
The accuracy of the equation for the estimation of renal function
may affect the prediction of serum teicoplanin concentrations
because teicoplanin is excreted by the kidneys via glomerular
filtration [6]. The use of population pharmacokinetic parameters
and the precise estimation of renal function are considered to be
very important when deciding the initial teicoplanin dose. Candi-
dates for covariates in the present study were composed of de-
mographic data, and some blood tests of renal function. We did not
incorporate these covariates into the present model because the
calculation formulas for CLcr and eGFR involved age, gender, and/or
TBW. Five eGFR equations and the Cockcroft-Gault formula were
not selected for CL as a significant covariate in the present study. In
contrast, CL was influenced by CysC and TBW. This result is
consistent with a previous study showing that CysC exhibited su-
perior diagnostic sensitivity for detecting impaired GFR over SCR
[31,49,50]. Our group previously reported the predictive accuracy of
teicoplanin concentrations using the Hoek equation with CysC was
similar to that of CLcr using the Cockcroft-Gault equation [51].
However, we could not find a significant difference with these two
methods. The present result clearly demonstrated the important
role of the renal elimination of teicoplanin. After accounting for the
effects of size and renal function, we found that renal clearance
decreased with increases in CysC, and renal clearance increased
with elevations in TBW.
A comparison of our estimates of pharmacokinetic parameters
with those reported in the literature is shown in Table 4. No sig-
nificant differences were observed in CL between the present study
and previous population pharmacokinetic analyses. A direct com-
parison of estimated final population pharmacokinetic parameters
in this study with previous findings was not possible because the
previous analysis has included in patients with children or neo-
nates. VC and the elimination half-life (T half) of the present study

Fig. 4. Dot plots of pharmacokinetic parameters (CL, VC, qTBW, and qCysC), inter-individual variability (uCL2, uVC2, and uCL-VC), and residual variability (s) obtained from the final
population model in a leave-one-out method. The horizontal axis represents each patient's ID, and the horizontal line in each plot shows the original estimate for each parameter.
CL, total clearance; VC, volume of the central compartment; OM calculated from sqrt (OMEGA); SG estimated using THETA.

Please cite this article in press as: Kasai H, et al., Population pharmacokinetics of teicoplanin in hospitalized elderly patients using cystatin C as
an indicator of renal function, J Infect Chemother (2017), https://doi.org/10.1016/j.jiac.2017.12.002
 H. Kasai et al. / J Infect Chemother xxx (2017) 1e8 7

Table 4
Comparison of pharmacokinetic parameters (Mean, BSV%) of teicoplanin estimated in this study with those in the literature on non-used cystatin C.

Publication date Type of subject patient (Number) CL (L/h) VC (L) VP (L) Q (L/h) T half (h)

This study: Adults (36) 0.51 (3.9) 78.1 (18.2) 106.1

Literature studies:
Lortholary et al. [43] 1996 Adults (30) 0.93 (32.0) 5.0 (29.0) 42.7 5.55 35.5
Soy et al. [44] 2006 Adults (79) 0.57 (35.0) 3.1 47.1 4.00 FIXED 37.3
Ogawa et al. [45] 2013 Adults (116) 0.70 (30.8) 12.2 (58.5) 74.1 (26.2) 4.01 (33.2) 85.5
Ramos-Martin et al. [46] 2014 Children (39) 1.04 (37.6) 7.9 (184.9) 60.7 9.34 45.8
Zhao et al. [47] 2015 Children (85) 0.63 (31.8) 28.6 (22.2) 55.8 0.62 (14.8) 93.4
Ramos-Martin et al. [48] 2016 Neonates (18) 0.40 (20.0) 0.8 (48.0) 1.4 1.17 3.8

Literature estimates of parameters were corrected based on TBW of 60 kg and/or CLcr of 6 L/h where possible; Between-subject variability (BSV%) was calculated from
100  sqrt (OMEGA); CL, total clearance; VC, volume of the central compartment; VP, volume of the peripheral compartment; Q, inter-compartment clearance; T half,
elimination half-life.
T half was calculated as Ln [2]*(VC þ VP)/CL.

corrected based on TBW 60 kg were 78.1 L and 106.1 h, respectively,
indicating slightly larger values than those reported by others. One
of the reasons for these differences is that most of the patients
included in the present study were elderly, namely, older than
seventy-five years of age. Studies including elderly subjects may be
expected to have a longer T half; however, there was no evidence
for this because physiology of elderly patients were not evaluated
in previously reported models.
The constructed population model was evaluated by three
methods: GOF plots, a bootstrap method, and leave-one-out
cross validation method. The GOF plots of the concentrations
predicted by the final model correlated strongly with the
observed concentrations, which did not show a marked deviation
in the observed concentrations versus the predicted and indi-
vidual predicted concentrations (Fig. 2). Furthermore, conditional
weighted residuals were nearly uniformly distributed within an
acceptable range [52]. These results suggested that the optimal
model was selected as the final model. The bootstrap method
was used to evaluate the accuracy and robustness of the general
model. The mean and SD values of the bootstrap procedure were
similar to parameter estimates from the original data set
(Table 3). These results suggest that the accuracy and robustness
of the general model were acceptable. The pcVPC of teicoplanin
concentrations (Fig. 3) showed that predictions matched
observed concentrations from the time since the last dose to
32 h. Model validation using pcVPC also confirmed an acceptable
agreement between the observed data and model-based simu-
lated values. Most of the observed values lay within the 90% PIs
at individual time points. The influences of teicoplanin concen-
tration data from each subject on parameter estimates were
estimated using the leave-one-out cross validation method. This
approach allows the model to be assessed for its descriptive and
predictive ability with a split sample or cross validation tech-
nique. As a result, the blood concentration data from subject No.
445 was shown to affect the parameter estimates of qCysC, uCL2,
and uCL-VC.
Several limitations of this study warrant mention. The present
dataset was limited with only 123 samples from 36 patients.
However, the prediction of teicoplanin concentrations using CysC
as an index of renal function had not yet been evaluated. Therefore,
this study appears to be important due to its novelty. It may be
possible to obtain a clearer understanding of the prediction of
teicoplanin concentrations using CysC as an index of renal function.
Furthermore, most of the subjects in this study were elderly pa-
tients. The Cockcroft-Gault formula is not correct for the elderly
because SCR is affected by age [53]. In contrast, CysC is not affected
by age [31]. The present study suggested and reaffirmed that the
predictive performance of teicoplanin concentrations using CysC is
better than using SCR for elderly patients. Therefore, CysC for
assessing the renal function of elderly patients is the most effective
method for adjusting the dosage of teicoplanin. Finally, MRSA in-
fections exhibit various symptoms including pneumonia, sepsis,
surgical site infection and skin and soft tissue infections, and
criteria of its effect are differently determined by type of infection
diseases. Thus, it was difficult to investigate the exposure-efficacy
and toxicity relationships of teicoplanin in the patient population.
We herein described the influence of CysC as a renal function
marker and TBW on the pharmacokinetics of teicoplanin. The
population pharmacokinetic parameters shown in the present
study are considered to be clinically valid from the viewpoint of
pharmacokinetics, medicine, and physiology.
Authorship statement
All authors meet the ICMJE authorship criteria.
Competing interests
All authors have completed the Unified Competing Interest and
declare no support from any organization for the submitted work,
no financial relationships with any organizations that may have an
interest in the submitted work in the previous 3 years, and no other
relationships or activities that may appear to have influenced the
submitted work.
Author contributions
HK and YT contributed to the acquisition of data, analyzed and
interpreted data, participated in the study design, and drafted the
manuscript. HK analyzed and interpreted data and revised the
manuscript. YH, MT, YY, and HT contributed to study conception
and design and the interpretation of data. YH and MT contributed to
plasma concentration measurements. All authors approved the
final version to be published.
Conflicts of interest
The authors declare that they have no competing interests.
Acknowledgment
This work was supported by MEXT KAKENHI Grant Number
17K08438.
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