Accepted Article

PROF. ASHRAF A. DAHABA (Orcid ID : 0000-0001-8513-3643)

Article type : Original Article

Location matters: overlooked ethnic-geographic effect in China and Austria on

propofol /cisatracurium sex-differences among a population pharmacokinetic
/pharmacodynamic (PopPK /PD) covariate analysis in men,
women and one transgender subject

Running head: Propofol-Cisatracurium population pharmacokinetics.

Ashraf A. Dahaba1,#,*, Zhaoyang Xiao2,3,#, Xiaoling Zhu2,

Karl Oettl4, Hailong Dong2, Lize Xiong2, Sieglinde Zelzer5,
Shuiyu Zhao6, Gilbert Reibnegger4

#Professor Zhaoyang Xiao and #Professor Ashraf A. Dahaba have both equally
contributed to the study.

1Department of Anaesthesiology and Intensive Care Medicine,

Suez Canal University, Ismailia, 41522.

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/FCP.12704
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 2Department
Accepted Article of Anesthesiology, Xijing Hospital of Fourth Military Medical University, Xi’an,
Shanxi, People’s Republic of China. CN 710032 127 Changle West Road 15th 0086 2983375337,
0086 13609283068
3Department of Anesthesiology, Second Affiliated Hospital of Dalian Medical University, 467
Zhongshan Road, Dalian, 116023 People’s Republic of China. 0086 11709873399
4Otto-Loewi Research Center for Physiological Chemistry

Medical University of Graz, Austria

5Institute for Medical and Chemical Diagnostics,

Medical University of Graz, Austria

6Shanghai Qiangshi Information Technology Co., Ltd, Shanghai, People’s Republic of China.

*Corresponding Author: Prof. Dr. Ashraf A. Dahaba

E-mail: ashraf.dahaba@medunigraz.at
E-mail: xiaozhaoy2012@163.com
E-mail: caribbean-66@126.com
E-mail: karl.oettl@medunigraz.at
E-mail: hldong6@hotmail.com
E-mail: mzkxlz@126.com
E-mail: sieglinde.zelzer@klinikum-graz.at
E-mail: Shuiyu.zhao@shcscc.com
E-mail: gilbert.reibnegger@medunigraz.at

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 HIGHLIGHTS
Accepted Article
1. Is sex differences in the commonly used anesthetic drugs propofol hypnotic and
cisatracurium neuromuscular blocking drug influenced by the ethnic–geographic
location?
2. We revealed considerable influence of ethnic–geographic region on sex
differences in our propofol and cisatracurium pharmacodynamic primary parameter
at induction of anesthesia.
3. This sex ethnic-geographic effect should be taken into consideration when dosing
the commonly used anesthetic drugs, propofol and cisatracurium.

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 ABSTRACT
Accepted Article
Background: A quick literature search using “sex/gender” versus the commonly
used hypnotic propofol or neuromuscular blocking agent cisatracurium will reveal
numerous contradictory sex–difference publications depending on the ethnic–
geographic location of where these studies were conducted.
Methods: We induced anesthesia with cisatracurium 100 g kg-1 administered
exactly 1-minute following propofol 2 mg kg-1. In 20 male and 20 female ethnic
Han-Chinese test set patients (Xi’an China), and in 20 male and 20 female ethnic
white Austrian validation set patients (Graz Austria), we quantified
propofol/cisatracurium pharmacodynamic parameters namely: propofol onset time,
lag time, plasma concentrations (Cp) at loss-of-behavioral-response (LOBR) using
bispectral index (BIS); cisatracurium onset time, lag time, and Cp at T1% (first
twitch of train-of-four) complete twitch suppression using mechanomyography
(MMG). Serial arterial blood samples were collected for population
pharmacokinetic (PopPK) analysis of all demographic and biological covariates
(region, sex, age, weight, and height) versus volume of distribution and clearance
pharmacokinetic parameters.
Results: In Chinese women (but not in white women) propofol Cp at LOBR was
33.60% lower than men and cisatracurium Cp at T1% complete twitch suppression
was 21.49% lower than men, a clear pharmacodynamic assertion. Region and
weight were significant population pharmacokinetic covariates.
Conclusion: We demonstrated that sex–differences are influenced by ethnic–
geographic location as only in Chinese women (but not in white women) propofol
Cp at LOBR and cisatracurium Cp at T1% complete twitch suppression were lower
than in men. When defining sex–differences, ethnic–geographic location should be
taken into consideration as a predictive factor for optimizing propofol/cisatracurium
initial loading recommended dosages.

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Accepted Article
Keywords: bispectral Index, electroencephalography, gender, sex,
mechanomyography, pharmacokinetic-pharmacodynamic

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 1. INTRODUCTION
Accepted Article
William Golding once said: “I think women are foolish to pretend they are equal to
men, they are far superior and always have been”. The two major classes female and
male are so different one might well be excused to think they are different species
[1]. In recent years it has become clear that there are sex differences in the dosage of
several drugs [2]. However, a quick literature search for the commonly used
hypnotic propofol or the benzylisoquinolinium non-depolarizing neuromuscular
blocking agent (NMBA) - cisatracurium - using the terms “sex /gender” will reveal
that actually these sex differences in propofol or cisatracurium seem to be dependent
on the ethnic–geographic location of where these studies were conducted. This has
far reaching implications in determining sex–based dosage adjustments. For
instance, Adamus et al. [3] in a Czech study reported no sex differences in
cisatracurium [3], and Schmith et al. [4] reported in a Norwegian study that sex
differences were not associated with any clinically significant alterations in
cisatracurium onset or recovery profiles and therefore do not warrant any sex-
specific dose recommendations [4]. Conversely, Shi et al. [5] in a Chinese language
publication reported that women were indeed more sensitive to cisatracurium than
men [5].
Regarding propofol, several sex–difference studies appearing in literature [2,
6-8] about dissimilar plasma concentrations (Cp) between males and females at
anesthesia recovery phase, all concluded that men are “more sensitive to propofol
than women” simply because men have 30-40% longer “recovery times” [2, 6-8].
This is categorically incorrect. Men are not “more sensitive to propofol” as no
clinical trial explicitly examined propofol sex–differences at the crucial phase of
“anesthesia induction”, and not only “anesthesia recovery”, which is essential for
any sex–specific dose adjustments.

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Accepted Article Among mostly mono-ethnic published literature searches we conducted, to
the best of our knowledge, this is the first “multi-ethnic study” with the aim of
investigating at “anesthesia induction” the influence of ethnicity /geographic
location on simultaneously administered propofol and cisatracurium sex–differences
among formal covariate analysis. We chose our propofol and cisatracurium study
primary parameters to be the highly clinically relevant propofol Cp required for
achieving loss-of-behavioral-response (LOBR) and cisatracurium Cp required for
reaching complete twitch suppression, as predictive factors for optimizing drug
dosages initial loading at anesthesia induction.

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 2. METHODS
Accepted Article
2.1. Subjects and Study Design
Our study was approved by Xijing Hospital of Fourth Military Medical University,
Xi’an, Shanxi, People’s Republic of China ethics committee 20110224-6 meeting
(on the 24th of February 2011) chaired by Prof. Dr. Ming Quan Li); and Medical
University of Graz, Austria ethics committee 21-329 ex 9/10 (on the 5.8.2010
meeting Chaired by the late Professor Dr. Peter H. Rehak). Our study was registered
at European Community Clinical Trials Database EudraCT (http://eudract.emea.eu)
trial registration number: 2009-017921-20 for the assessment of propofol and
cisatracurium; and was registered as a clinical study at Food and Drug
Administration Clinical Trials Database www.ClinicalTrials.gov trial registration
number: NCT02588118. A multicenter consecutive Intention-to-Treat (ITT) study
was conducted in conformity with the guidelines of the “Standards for Reporting of
Diagnostic Accuracy” (STARD)” [9], to investigate ethnic-geographic effect on
sex–differences among propofol and cisatracurium population pharmacokinetic
/pharmacodynamic (PopPK /PD) covariate analysis. After giving a written informed
consent to participate in the study, we recruited 20 male and 20 female ethnic Han-
Chinese test set in Xi’an and we recruited 20 male and 20 female ethnic white
Austrian validation set in Graz, American Society of Anesthesiologists (ASA) I-II
18-45 yr middle aged, 18-30 kg m2 body mass index (BMI) patients undergoing
general anesthesia for scheduled elective surgical procedures. Because of our ITT
design (once randomized always analyzed), one biologically female patient, who
underwent 2 years of hormonal therapy preceding gender reassignment surgery 3
years prior to our study recruitment, was not excluded from the study. Reporting one
patient from a unique group (transgender patient) is inadequate to make any
conclusions as this patient group should be of similar size to the other groups,
however because no other transgender patient was recruited during our ITT study

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 period, we report this patient’s data just as descriptive data of what we considered a
Accepted Article
secondary parameter obviously not adequately powered to be separately analyzed.

2.2. Propofol and cisatracurium pharmacodynamics

Using bispectral index monitor (BIS, Medtronic, Ireland), a BIS “Quatro” sensor
was placed on the patient’s forehead. The raw EEG signal was band-pass filtered to
2–70 Hz and processed in real time. Frontal electromyography (EMG) is displayed
in decibel (dB) units relative to 0.01 V [10]. BIS recording was started after
verifying a signal quality index (SQI) >95% and electrodes impedance <5 kΩ, while
the smoothing rate was set to 15 s. Patients were not premedicated. Anesthesia was
induced with propofol 2 mg kg-1. With a gentle prod on the shoulder once every 30
s, patients were asked whether they were awake until they reached LOBR defined as
an Observer’s Assessment of Alertness/ Sedation (OAA/S) score [11] of 1; i.e. they
lost their eyelash reflex and did not respond to verbal commands or gentle prodding
[12]. Propofol pharmacodynamic parameters: Cp at LOBR, lag and onset times (time
from beginning of propofol administration until the start of BIS decline and until
BIS maximum decline) were recorded.
Using the same Relaxometer mechanomyograph (MMG, Groningen
University, Netherlands) in Xi’an then in Graz; the MMG force transducer was
attached to patient’s thumb and the preload was maintained within 200-400 g
throughout the whole procedure [13]. After supramaximal current determination, the
ulnar nerve at the wrist was stimulated with train-of-four (TOF) stimuli (2-Hz, pulse
width 200 s, for 2 s) at 12-s intervals. First twitch of the TOF (T1%) expressed as
percentage of control response (T1: T0) was used to evaluate the neuromuscular
block. Single bolus dose of cisatracurium 100 g kg-1 (twice the 95% effective dose,
ED95) was administered exactly 1-min after propofol administration. Cisatracurium
pharmacodynamic parameters: cisatracurium Cp at T1% complete twitch

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 suppression, lag and onset times (time from beginning of cisatracurium
Accepted Article
administration until the start of T1% decline and until T1% complete twitch
suppression) were recorded. We inserted a ProSeal Laryngeal Mask Airway [14]
and after capnographic confirmation of correct positioning, the lungs were
ventilated mechanically with 40% oxygen in air and adjusted to maintain 4.0-4.6
KPa end-tidal carbon dioxide.

2.3. Blood samples acquisition, handling, processing and concentration

assays
Five ml serial arterial blood samples were collected in duplicate in EDTA-tubes for
propofol and cisatracurium assays. This represents propofol time points before
induction (t0), at 1, 3, 5, 7, 10, 13, 16, 19, 22, 25, 30, 60, 90, 120 and 150 min
following propofol administration and represents cisatracurium time points at t0, 2,
4, 6, 9, 12, 15, 18, 21, 24, 29, 59, 89, 119 and 149 min following cisatracurium
administration. Samples were immediately kept on ice for at least 5 min. Within
minutes of acquisition, plasma was isolated by 2500 g 4°C cold (4°C) centrifugation
for 10 min. Blood samples were immediately extracted, acidified and stored frozen.

2.3.1. Propofol blood sample handling and concentration assay

Propofol blood samples were acidified to prevent propofol degradation by adding
480 µL serum to 500 µL of sodium phosphate buffer (NaH2PO4, 0.1 M, pH 7.8) and
20 µL internal standard (10 µg mL-1 thymol in ethanol) in Eppendorf tubes. The
internal standard is used to rectify variations in recovery and stability among
samples. Plasma was then isolated by vortex cold roto-mixing (4°C) centrifugation
at 2500 g for 10 min, and stored at –20oC. Blood samples were assayed in duplicate,
using high performance liquid chromatograph (HPLC). The method involved
thawing the acidified serum and after adding 5 mL cyclohexane, vortex roto-mixing

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 for 10 min and centrifugation at 2500 g room temperature for 10 min, 50 µL of the
Accepted Article
supernatant was withdrawn and mixed with 50 µL tetrabutylammonium hydroxide
(TBAH) 6% (150 µl TBAH +850 µL ethanol) then evaporated under nitrogen
stream at 50°C organic phase. The residual was mixed with 300 µL acetonitrile
/phosphate buffer (700 ml acetonitrile +300 ml K2HPO4 phosphate buffer 10 mM,
pH 7.8) mobile phase, vortex roto-mixed and centrifuged at 2500 g at room
temperature for 10 min, and then 50 µL were injected into the HPLC-system.
Detection was carried out by fluorescence at 276/620 nm. Propofol intra- and inter-
assay coefficient of variation within day precision and between day precisions were
≤7% (1.4% to 4.9% and 2.3% to 7.0% respectively).

2.3.2. Cisatracurium blood sample handling and concentration assay

To prevent cisatracurium degradation we added 950 µL of plasma to 40 µL of 0.5 M
sulphuric acid and 10 µL internal standard (100 µg mL-1 verapamil) in Eppendorf
tubes on ice. Samples were carefully mixed and subsequently stored at –70oC. Blood
samples were assayed in duplicate according to Farenc et al. [15] HPLC method.
The method involved, first thawing the acidified plasma and after adding 1 mL
acetonitrile to 500 µL, vortex roto-mixing and centrifugation at 2500 g at room
temperature for 10 min, 1 mL of the supernatant was evaporated under nitrogen
stream at 30 °C. The residual was dissolved in 500 µL mobile phase and 50 µL were
injected into the HPLC-system. Detection was carried out by fluorescence at
240/320 nm. Cisatracurium inter- and intra- assay coefficient of variation was <5%.

2.4. Propofol and cisatracurium pharmacokinetic analysis

Data analysis involved fitting each patient’s plasma concentration-time decay
profiles to non-compartment and multi-compartment pharmacokinetic models.
2.4.1. Moment analysis

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 A classic non-parametric moment analysis was used to calculate the area under
Accepted Article
concentration versus time curve (AUC) using linear trapezoidal method. In a single
compartment model, mean residence time (MRT) is the time constant for 63.2% of a
dose to leave the body. The Vdss is apparent volume of distribution at steady state.
Clearance (Cl) = Dose /AUC and Vdss = Cl x MRT.

2.4.2. Multi-compartment pharmacokinetic analysis

We used Nonlinear mixed effects modelling (NONMEM, version 7.3, ICON
Development Solutions) [16] to calculate propofol and cisatracurium inter-
compartment rate constants (K12, K21), elimination rate constant (K10); central
volume of distribution (V1), peripheral volume of distribution (V2); central clearance
(Cl1 = K10 x V1) and peripheral clearance (Cl2 = K21 x V2) (Diagram 1).

2.5. Population pharmacokinetic (PopPK) analysis

2.5.1. Base model

Propofol and cisatracurium base models were created using the first-order
conditional estimation (FOCE) method with η-ε interaction. We comprehensively
compared the objective function values (OFV), model diagnosis graphs and
individual prediction results of various structural models namely; one-compartment
model, two-compartment model, three-compartment model with additive,
proportional, or combined additive and proportional residual models; that all
showed no significant improvement over the two-compartment model with
combined additive and proportional residual model, the most appropriate choice.

Proportional error models were applied in the pharmacokinetic models:

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 Our dichotomous survival type analyses main cut-off criteria was based on sex and
Accepted Article
AUC0-2min (AUC0-2min <median or AUC0-2min ≥median).

Where Cij is the jth observation for the ith subject, Cpred,ij is the jth predicted
value for the ith subject, εprop,ij is the proportional portions of intra-individual
variability with means of zero and variances of σprop2.

2.5.2. Population pharmacokinetic covariate analysis

Propofol and cisatracurium base models were created using the first-order
conditional estimation (FOCE) method with η-ε interaction. Based on likelihood
ratio tests and residual analysis; all available demographic and biological covariates
that could be meaningfully explained from both clinical and scientific perspective
(region, sex, age, weight and height) versus V1, V2, Cl1, Cl2 pharmacokinetic
parameters obtained by Bayesian estimation, were explored graphically followed by
linear regression analysis for the continuous covariates or ANOVA (Analysis of
Variance) testing for categorical covariates using R software [17]. Because other
NONMEM pharmacokinetic parameters are collinearly related and derived from
volumes of distribution and clearances, usually they are not included in the covariate
screening.
Relationships between pharmacokinetic parameters and continuous covariates were
modeled as follows:

Relationships between pharmacokinetic parameters and categorical covariates were

modeled as follows:

Where i is the individual model parameter for the ith subject; T is the typical value
of the parameter in the population; Covi is the individual value of a continuous

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 covariate for the ith subject; Covpop is the population median value of a continuous
Accepted Article
covariate for the typical population; Xi is the individual categorical covariate
indicator, where a value of one represents the population with the covariate of the
most frequent category, and kcov is the coefficient describing the strength of the
covariate effect.
After base model selection, covariates screening was conducted using
Stepwise Covariate Modelling (SCM) of Perl Speaks NONMEM (PsN, version
4.4.8 Uppsala University, Sweden) to test whether each selected covariate had
significant influence on the base model [18]. To determine the full covariate model,
potential covariates were one-at-a-time individually introduced into the base model
in the so called “forward inclusion step /forward addition method” where criterion
for a covariate to be incorporated in the model was a decrease of >3.84 in OFV (P
<0.05, X2 distribution with DF, degree of freedom =1 based on a Log Likelihood
ratio test) carrying forward to the next step only significant covariates to form the
full PopPK model until no more significant covariates were found. To confirm their
relevance, each covariate was then one-at-a-time individually removed from the full
PopPK model in the so called “backward deletion step /backward elimination
method”. An OFV increase of ≥6.63 (P <0.01, X2 distribution with DF =1) was
considered significant. In the final PopPK model, all retained covariates were
significant.

2.5.3. Propofol and cisatracurium PopPK model evaluation

To assess the final model, we used Nonparametric Bootstrap resampling internal
validation technique based on Monte Carlo repeated replacement in the sample
simulations. Once the self-sampling reaches a certain frequency it forms a statistical
distribution and the original sample statistics can then be estimated by a semi-
empirical method. We used Visual Predictive Check (VPC) [19], the most

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 commonly used approach in population model evaluation, to adequately describe
Accepted Article
and simulate data similar to the original data. The simulated concentration profiles
were graphically compared with the original data.
In addition to Nonparametric Bootstrap resampling and VPC common
approaches in population model evaluation, we used additional diagnostic goodness-
of-fit plots namely; “residual versus fitted concentrations” and “observed versus
fitted concentrations” as well as Normalized Prediction Distribution Errors (NPDE)
to further investigate the accuracy of the model predictions. Similar to the VPC and
bootstrap; the NPDE is also an evaluation tool based on Monte Carlo simulations
useful in investigating the accuracy of the model predictions that is particularly
useful when comparing the observations with their own simulated distributions.
We used relative standard error percentage (RSE%) to evaluate the precision
of the estimated parameters. Generally, RSE% <30% of fixed effects and RSE%
<40% of random effects are considered reliable. For the final model goodness-of-fit
plots, we compared both population prediction (PRED) and individual prediction
(IPRED) with the observed concentrations. We compared the conditional weighed
residuals (CWRES) scattering with the observed concentrations as an indicator of
models’ predictive power adequacy.

2.6. Statistical analysis and sample size power analysis

Our power calculation is based on our primary parameter of propofol Cp required to
achieve LOBR. A previous study in which mean ±SD propofol Cp required to reach
LOBR of 2.9 ±0.2 g·ml-1 in men and 2.7 ±0.1 g·ml-1 in women [20], showed that
a sample size projection of 10 would be required to achieve 80.05% power to reject
the null hypothesis of equal means t-test (α =0.05 significance level).
Fisher et al. [21] concluded that for intermediate NMBAs (such as
cisatracurium) the single-bolus-dose technique is the accepted method because it has

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 been established that the potency estimates by cumulative dose-response yield larger
Accepted Article
estimates than those obtained by the traditional single-bolus-dose technique. Our
cisatracurium study primary parameter of sex differences in neuromuscular block
was based on a previous study [5] that used cisatracurium single-bolus-dose
approach, in which cisatracurium 3 Effective Doses 50, 90, 95 parameters (ED50,
ED90, ED95) 22.5 ±1.3, 40.9 ±1.6, 48.7 ±1.0 µg kg-1 in women and 30.4 ±0.8, 56.7
±2.9, 67.4 ±4.4 µg kg-1 in men, [5] showed that the sample size projections required
to achieve 95.44% power to reject the null hypothesis of equal means t-test of the 3
parameters were all substantially less than 10 (α =0.05 significance level).
P <0.05 was considered statistically significant. Data were expressed as
means ±SD. Kaplan–Meier log-rank plots, a popular method showing time to event
data, was used to explore the impact of potential covariates on lag and onset times.

3. RESULTS
Patients’ demographics are presented in table 1.
3.1. Propofol pharmacokinetics and pharmacodynamics
Propofol Cp (μg ml-1) at LOBR was 33.60% lower in Chinese women (6.54 3.59)
than men (9.85 9.26) but similar in Austrian women (3.16 1.07) and men (2.99
1.55). Kaplan–Meier (figure 1) showed significantly shorter lag time (X2 =7, P
<0.01) and onset time (X2 =12.5, P <0.05) in Chinese women than men.
Figure 2 describes propofol plasma concentrations versus time decay. Chinese
women had higher (P =0.018, P =0.012) propofol Cl1 and Cl2 than men. Austrian
women and men had similar propofol Cl1 and Cl2. We report the transgender subject
as descriptive data who exhibited higher Cl1 and Cl2 than both our male and female
subjects (table 2).

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 3.2.
Accepted Article Cisatracurium pharmacokinetics and pharmacodynamics
Cisatracurium Cp (μg ml-1) at T1% complete twitch suppression was 21.49% lower
in Chinese women (603.6 292.6) than men (733.3 318.2) but similar in Austrian
women (551.2 95.3) and men (587.9 99.2). Kaplan–Meier (figure 3) showed
significantly shorter lag time (X2 =12.4, P <0.001) and onset time (X2 =14, P
<0.001) in Chinese women than men.
Figure 4 describes cisatracurium plasma concentrations versus time decay.
There were no significant differences in Cl1 or Cl2 between men and women. The
transgender subject descriptive data showed pharmacokinetic parameters not clearly
distinguishable from men or women (table 3).

3.3. Propofol and cisatracurium PopPK model

Because propofol backward one-at-a-time covariate elimination step revealed no
significant effect from removal of any covariate on the pharmacokinetic parameters;
propofol base model will be the final model (table 4).
Cisatracurium final model forward one-at-a-time covariate addition step
showed that region was a significant covariate on Cl1 and Cl2. Whereas, weight was
a significant covariate on V1, V2 and Cl1. Cisatracurium stepwise covariate fitting of
the final model is better than the base model because incorporation of covariate
effects on V1, V2, Cl1 and Cl2 decreased the OFV from –3183.878 to –3230.145
(table 4). Parameter estimates, standard error, and bootstrap confidence intervals
(CI) of propofol and cisatracurium pharmacokinetic final models are detailed in
table 5.

3.4. Propofol and cisatracurium PopPk model evaluation

The final models demonstrated strong stability as 996 propofol and 962
cisatracurium, out of 1000 bootstrap runs for each, successfully fit the bootstrap

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 estimates and highly resembled the population final model. This confirmed the
Accepted Article
precision of the robust final models and the accuracy of model predictions.
Base model goodness-of-fit plots of the “residuals versus fitted
concentrations” and “observed versus fitted concentrations” diagnostic plots of
propofol (figure 5) and cisatracurium (figure 6) showed that PRED and IPRED are
in good agreement with the observed concentrations. The CWRES showed good
scattering with most of the observed concentrations being located within ±2%;
indicating strong predictive power of the models.
In figure 7 (propofol) and figure 8 (cisatracurium) final model NPDE
analyses; the upper-left quantile-quantile plot (Q–Q plot) against theoretical
distribution with a density of N (0, 1) showed that the points were either distributed
along the line or uniformly distributed on both sides of the line. The upper-right
histogram plot of NPDE distribution against theoretical distribution with a density
of N (0, 1) exhibited normal distribution. The lower-left plot of NPDE versus time
and lower-right plot of NPDE versus predicted concentrations showed that the
scatters were distributed on both sides of y =0 indicating that the final model was
accurate and reliable.

4. DISCUSSION
4.1. Main finding of our study
We embarked upon an interesting study where our primary objective was to
investigate the effect of the ethnic–geographic location on propofol /cisatracurium
sex–differences in a manner that could be clinically utilized in daily anesthesia
practice. We provide precise data on two of the most commonly used drugs in
anesthesia practice propofol and cisatracurium sex differences as a function of
ethnic–geographic location. We discovered that sex–differences are not globally

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 uniform and we cannot assume that sex differences in ethnic white populations are
Accepted Article
similar to sex differences in ethnic Han Chinese. Our results indicate that this could
be attributed to a pharmacodynamic, rather than a pharmacokinetic, assertion. Our
primary pharmacodynamic parameters as a predictive factor for optimizing sex–
based initial dosages of propofol Cp at LOBR and cisatracurium Cp at T1% complete
twitch suppression were both lower only in Han–Chinese women than men (but
similar in white women and men).

4.2. Propofol pharmacokinetics and pharmacodynamics

In our Han–Chinese women propofol Cp at LOBR pharmacodynamic parameter was
33.60% lower than men (but similar in white women and men) with significantly
shorter lag and onset times in Chinese women than men. In Korean patients; median
(25-75%) time to LOBR in women of 16 s (10-22 s) was significantly shorter than
the 20 s (14-24 s) in men [22]. Apfelbaum et al. [7] postulated an interesting
premise that female sex hormones can cause functional changes in the γ-amino
butyric acid (GABA) receptors, site of action of most intravenous anesthetic drugs
[7]. The plausible explanation of our results in Han Chinese women is a
pharmacodynamic assertion of putative biologic increase in intrinsic propofol brain-
sensitivity in women. This means that “women are more sensitive” to propofol and
“respond more” to the same propofol dose; i.e. a true difference in potency, as
potency is stricto sensu a pharmacodynamic parameter.
Conversely numerous multicenter studies [6-8, 23] stated the exact opposite
that “men are the ones who are more sensitive” to propofol than women because
women consistently emerged from propofol anesthesia faster than men [6-8, 23].
We demonstrated that this “conclusion” is categorically incorrect; as “men are not
more sensitive” to propofol than women, rather Chinese women have significantly
higher propofol clearances than men (in our study Chinese women had significantly

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 higher propofol Cl1 and Cl2 than men, but similar Cl1 and Cl2 in white women and
Accepted Article
men) resulting in a more rapid emergence from propofol anesthesia [24] in Chinese
women than men.

4.3. Cisatracurium pharmacokinetics and pharmacodynamics

In our study cisatracurium Cp at T1% complete twitch suppression was 21.49%
lower in Han-Chinese women than men (but similar in white women and men) with
significantly shorter lag and onset times in Chinese women than men. This sex
difference could be explained by a pharmacodynamic more than a pharmacokinetic,
assertion, as women have lower plasma protein binding than men for water-soluble
NMBAs [25]; resulting in women requiring less NMBAs [2]. Shi and colleagues [5]
demonstrated in a Chinese language publication that cisatracurium ED50, ED90, ED95
were 26%, 27.9%, 27.7% significantly lower in women than men. Conversely, data
from Schmith et al. [4] Norwegian study of possible sex effects on cisatracurium
showed that sex as a variable was not associated with any clinically significant
alterations in cisatracurium predicted onset or recovery profiles [4]. Similarly
Adamus et al. [3] reported no cisatracurium sex differences in their Czech study [3].

4.4. Population pharmacokinetic /pharmacodynamic formal covariate

analysis
In 1972, Sheiner et al. [26] first proposed the PopPK approach using a classical
pharmacological mixed-effect model for covariate analysis. The PopPK /PD was
later extensively applied to clinical trials [27], to population approaches in pediatrics
[28], investigation of pharmacokinetic–pharmacodynamic drug–drug interaction
[29], and in post marketing drug dosing safety guidelines [30]. The PopPK allows
calculation of pharmacokinetic model estimates and quantification of random effects
such as within and between subject variability. Our PopPK analysis offers

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 interesting and valuable insights that could clarify our ethnic–geographic
Accepted Article
pharmacodynamics sex differences. Our observed ethnic–geographic
pharmacokinetic sex–differences could be due to differences in the amount of body
fat, muscle /fat mass as well as their respective body distributions that could
independently vary irrespective of kg body weight [31]. Women have different body
composition with larger proportion of body fat and smaller water content than men
[2], that could all considerably affect the pharmacokinetics of a lipophilic drug such
as propofol [31] and a hydrophilic drug like cisatracurium.

4.5. Study Limitations

In PopPK analysis, the number of patients required to determine the power of each
covariate depends on many factors such as the number of sampling per patient and
inter-individual variability of the pharmacokinetic parameter. With our sample size
of n=20 (correctly calculated from our primary parameter, as it should) of the effect
of ethnic–geographic location sex–differences on our clinically relevant primary
parameter; we additionally conducted extensive sampling for each individual subject
to accurately identify a covariate, obtain reliable pharmacokinetic parameters and
decrease our false positive results. Our goodness-of-fit plots, VPC and NPDE results
all highly indicate that our final model was accurate and reliable.
Our PopPK analyses revealed that pharmacokinetic sex differences might not
be specifically related to sex–differences per se, rather attributed to other
physiological parameters closely related to sex such as body weight or cardiac
output (CO). Male patients generally exhibit a higher CO and thus greater hepatic
perfusion than females [32] for a drug like propofol with its high first-pass effect
and a very high hepatic extraction ratio of 0.87 [33]. Absalom et al. [34] noted in
their “the devil in the detail” editorial that hemodynamic variations especially CO
may strongly influence propofol clearance [34].

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Accepted Article
5. CONCLUSION
We demonstrated that sex–differences are influenced by ethnic–geographic location
because in Chinese women (but not in white women) both propofol Cp at LOBR and
cisatracurium Cp at T1% complete twitch suppression were lower than men. We
believe that when defining sex differences, ethnic–geographic location should be
taken into consideration as a predictive factor for optimizing propofol and
cisatracurium initial loading recommended dosages.

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 REGISTRATION OF CLINICAL TRIALS
Accepted Article
Prior to patient enrolment our study was registered at European Community Clinical Trials
Database EudraCT (http://eudract.emea.eu), trial registration number: 2009-017921-20, and prior
to patient enrolment our study was registered at Food and Drug Administration Clinical Trials
Database www.ClinicalTrials.gov; trial registration number: NCT02588118 at 4th May 2011 by
the primary investigator Ashraf Dahaba.

ETHICS COMMITTEE APPROVAL

Prior to patient enrolment our study was approved by Xijing Hospital of Fourth Military Medical
University, Xi’an, Shanxi, People’s Republic of China ethics committee, approval number
20110224-6 (on the 24th of February 2011, chaired by Prof. Dr. Ming Quan Li) and Medical
University of Graz ethics committee approval number 21-329 ex 9/10 (on 5.8.2010 meeting
Chaired by the late Professor Dr. Peter H. Rehak).

AUTHORS' CONTRIBUTIONS

A. D. This author helped with writing the manuscript, recruited patients and administered
anesthesia.
Z. X. This author helped with writing the manuscript, recruited patients and administered
anesthesia.
X. Z. This author helped with writing the manuscript, recruited patients and administered
anesthesia.
K. O. This author helped with writing the manuscript, designed the pharmacokinetic time frame
and did the cisatracurium blood assay.
H. D. This author helped with writing the manuscript, recruited patients and administered
anesthesia.
L. X. This author helped with writing the manuscript, recruited patients and administered
anesthesia.
S. Z. This author did the propofol blood assay.

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 S. Z. This author is the statistician who built the statistical model.
Accepted Article
G. R. This author is the statistician who did the pharmacokinetic analysis.

FUNDING SECTION

The study was financed from National Natural Science Foundation of China (Beijing, People’s
Republic of China), grant No: 81471373, and the National Natural Science Foundation of China
(Beijing, People’s Republic of China), grant No: 81071052, both grants awarded to Professor Dr.
Zhaoyang Xiao.

DECLARATION OF INTEREST

All authors attest to the validity and legitimacy of the data and its interpretation and agree to its
submission. All authors have significantly contributed to the manuscript and no person or group of
persons who actively contributed were excluded from the study. All authors confirm that they
have read and approved the paper, have met the criteria for authorship as established by the
International Committee of Medical Journals Editors, believe that the paper represents honest
work, and are able to verify the validity of the results reported.
All authors state that they have absolutely no conflicts of interest (including financial,
consultant, institutional and other relationships that might lead to bias or a conflict of interest).
None of the authors received honoraria from a company or were on the speaker’s bureau for any
Organization, and there were no sources of financial support, corporate involvement or patent
holdings other than above mentioned grants from the Scientific Research Fund of Ministry of
Health - Major Plan of Science and from above mentioned departmental sources.
There was no support from a pharmaceutical company or a manufacturer in any role such
as editing of the protocol, drug supply, data analysis or writing of the paper.

ACKNOWLEDGMENTS

All authors would like to thank Victoria Helene Lirscher and Andreas Domke for the part of the
data they collected for their “Diplomarbeit” at Medical University of Graz. All authors would like

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 to thank Dr. Kun Wang and Fengyan Xu for reviewing the pharmacokinetic statistical analysis,
Accepted Article
simulations, figures and the NPDE statistical modelling. We would like to thank the late Prof. Dr.
Peter H. Rehak for the original statistical analysis and to thank the great efforts of Renate
Oberreither for her tremendous help with the propofol samples assay and Doris Payerl for her
tremendous help with the cisatracurium samples assay.

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 Table 1. Patients’ demographics
Accepted Article
China
Males Females
Age (yr) 31.7 7.7 32.6 6.8
Weight (kg) 67.5 10.2 59 8.4
Height (cm) 170 5 162 5
BMI 23.3 2.8 22.4 2.8
Austria
Males Females
Transgender
Age (yr) 34.2 6.5 36.2 6.7 39
Weight (kg) 84 17 69 10 77
Height (cm) 179 8 165 5 168
BMI 26.2 4.2 25.3 3.3 27.3
Mean SD.

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 Table 2. Propofol pharmacokinetics in Chinese Patients
Accepted Article Males Females
Moment analysis
MRT (min) 9.48 9.56 8.10 6.12
AUC (g min l-1) 57.7 33.9 40.71 11.3
Vdss (ml kg-1) 434.2 452.3 447.2 251.9
Cl (ml kg-1 min-1) 45.1 16.5 58.4 14.1
Non-linear model compartmental analysis
Micro rate constants (min-1)
K10 0.449 0.246 0.324 0.161
K12 0.316 0.159 0.340 0.168
K21 0.154 0.059 0.172 0.064
Apparent volumes of distribution (ml kg-1)
V1 190.7 246.3 233.5 190.4
V2 348.5 426.7 400.9 227.0
Clearances (ml kg-1 min-1)
Cl1 41.2 14.8 52.312.2
Cl2 38.10 22.08 61.6 30.0
Propofol Pharmacokinetics in Austrian Patients
Males Females
Transgender
Moment analysis
MRT (min) 23.7 18.5 19.5 21.9 10.1
AUC (g min l-1) 65.9 24.5 55.8 19.3 45.8
Vdss (ml kg-1) 916.6 738.1 848.6 916.3 532.6
Cl (ml kg-1 min-1) 40.8 18.0 45.3 19.9 52.6

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 Non-linear model compartmental analysis
Accepted Article
Micro rate constants (min-1)
K10 0.217 0.141 0.242 0.166 0.179
K12 0.307 0.247 0.234 0.143 0.364
K21 0.089 0.072 0.098 0.059 0.159
Apparent volumes of distribution (ml kg-1)
V1 325.3 367.8 252.8 173.7 244.2
V2 880.78747.32 827.2 1072.9 558.0
Clearances (ml kg-1 min-1)
Cl1 35.6 16.4 41.0 18.6 43.7
Cl2 52.0 38.3 43.1 21.2 88.8
Mean SD, AUC: blood propofol concentration versus time area under the curve,
MRT =mean residence time (time taken for 63.2% of a dose to leave the body), Cl
=clearance (Cl = Dose /AUC), Vdss =apparent volume of distribution at steady state
(Vdss =Cl x MRT), K10 =elimination rate constant, K12, K21 =inter-compartment rate
constants, V1 =central volume of distribution, V2 =peripheral volume of distribution,
Cl1 =central clearance (Cl1 =K10 x V1), Cl2 =rapid peripheral clearance (K21 x V2).

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 Table 3. Cisatracurium Pharmacokinetics in Chinese Patients
Accepted Article Males Females
Moment analysis
MRT (min) 15.9 6.8 18.5 9.6
AUC (g min l-1) 17.6 6.1 19.0 8.6
Vdss (ml kg-1) 64.6 38.6 71.8 47.7
Cl (ml kg-1 min-1) 4.2 2.0 4.1 1.7
Non-linear model compartmental analysis
Micro rate constants (min-1)
K10 0.059 0.022 0.060 0.033
K12 0.143 0.058 0.131 0.078
K21 0.082 0.038 0.073 0.036
Apparent volumes of distribution (ml kg-1)
V1 66.2 18.8 70.9 21.4
V2 46.1 35.6 48.9 37.0
Clearances (ml kg-1 min-1)
Cl1 3.8 1.7 3.7 1.6
Cl2 4.2 4.4 3.2 2.5
Cisatracurium Pharmacokinetics in Austrian Patients
Males Females
Transgender
Moment analysis
MRT (min) 25.5 17.5 25.1 21.9 22.9
AUC (g min l-1) 24.0 11.0 22.5 12.7 23.24
Vdss (ml kg-1) 73.4 65.5 65.9 57.3 69.6
Cl (ml kg-1 min-1) 2.7 0.7 2.9 0.7 3.0

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 Non-linear model compartmental analysis
Accepted Article
Micro rate constants (min-1)
K10 0.038 0.019 0.049 0.047 0.033
K12 0.250 0.138 0.292 0.217 0.172
K21 0.112 0.041 0.110 0.037 0.114
Apparent volumes of distribution (ml kg-1)
V1 78.5 53.2 72.7 37.0 74.3
V2 45.6 38.3 39.2 32.0 49.1
Vdss 124.1 91.0 111.9 68.8 123.4
Clearances (ml kg-1 min-1)
Cl1 2.3 0.3 2.5 0.8 2.5
Cl2 4.8 4.4 3.9 3.0 5.6
Mean SD, AUC: blood cisatracurium concentration versus time area under the
curve, MRT =mean residence time (time taken for 63.2% of a dose to leave the
body), Cl = clearance (Cl =Dose /AUC), Vdss =apparent volume of distribution at
steady state (Vdss =Cl x MRT), K10 =elimination rate constant, K12, K21, =inter-
compartment rate constants, V1 =central volume of distribution, V2 =peripheral
volume of distribution, Cl1 =central clearance (Cl1 = K10 x V1), Cl2 =peripheral
clearance (K21 x V2).

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 Table 4. Propofol candidate covariate screening
Accepted Article
Propofol Covariate screening OFV △OFV P
Base model –1730.658
Forward step
Model 1: Add weight on V2 in the base model –1734.942 4.284 >3.842 <0.05
Model 2: Add region on Cl2 as model 1 –1739.322 4.380 >3.842 <0.05
Model 3: Add age on Cl2 as model 2 –1744.012 4.690 >3.842 <0.05
Backward step
Model 4: Remove age on Cl2 as model 3 –1739.322 4.690 <6.635 >0.01

Model 5: Remove region on Cl2 as model 4 –1734.942 4.380 <6.635 >0.01

Model 6: Remove weight on V2 as model 5 –1730.658 4.284 <6.635 >0.01
Propofol covariate screening result: propofol base model is the final model.
Cisatracurium candidate covariate screening
Cisatracurium Covariate screening OFV △OFV P
Base model –3183.878 - -
Forward step
Model 1: Add region on Cl2 in the base model –3204.845 20.967 >3.842 <0.05
Model 2: Add weight on V2 as model 1 –3214.675 9.83 >3.842 <0.05
Model 3: Add region on Cl1 as model 2 –3222.642 7.967 >3.842 <0.05
Model 4: Add weight on V1 as model 3 –3230.145 7.503 >3.842 <0.05
Model 5: Add weight on Cl1 as model 4 –3235.615 5.47 >3.842 <0.05
Backward step
Model 6: Remove weight on Cl1 as model 5 –3230.145 5.47 <6.635 >0.01
Cisatracurium covariate screening result: Model 5 will be the final model.
OFV =objective function values.

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Accepted Article
Table 5. Parameter estimates, standard error and bootstrap confidence intervals of the pharmacokinetic final model
Propofol pharmacokinetic 948 successful bootstrap median
Estimate (RSE%)
Parameter (95% PI)
V1 (L) 18.1 (8.5) 18.2 (15.1 –21.2)
V2 (L) 68.3 (6.4) 68.7 (59.9 –78.9)
Cl1 (L/h) 136 (3.6) 136.0 (127.0 –145.3)
Cl2 (L/h) 153 (7.3) 153.0 (133.0 –175.0)
Inter-individual variability
V1 % 56.8 (10.0) 55.5 (41.1 –66.3)
V2 % 43.5(12.0) 42.5 (32.4 –53.2)
Cl1 % 25.2 (9.5) 24.8 (19.9 –29.3)
Cl2 % 44.8 (13.2) 43.7 (33.0 –55.4)
Residual error % 53.57 (5.45) 19.3 (17.5 –21.2)

Cisatracurium pharmacokinetic 962 successful bootstrap median

Estimate (RSE%)
Parameter (95% PI)

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Accepted Article
V1 (L) 5.51 (4.60) 5.47 (5.01 –5.99)
V2 (L) 10.9 (5.40) 10.87 (9.68 –12.48)
Cl1 (L/h) 11.3 (7.10) 11.3 (9.85 –12.96)
Cl2 (L/h) 23.3 (7.60) 23.28 (20.26 –28.64)
θCl1_region -0.276 (24.2) -0.275 (-0.399 – -0.145)
θCl2_region 0.953 (22.1) 0.96 (0.54 –1.40)
θV1_weight 0.75, FIX -
θV2_weight 0.75, FIX -
Interindividual variability
V1 % 34.4 (14.6) 33.08 (22.39 –43.26)
V2 % 37.1 (18.2) 36.99 (14.38 –48.80)
Cl1 % 37.6 (10.9) 36.71 (28.40 –44.48)
Cl2 % 35.8 (17.5) 35.00 (18.53 –61.22)
Residual error % 11.9 (4.60) 11.86 (10.78 –12.95)
RSE = relative standard error, PI = percent interval,  = the individual model parameter.

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 LEGENDS
Accepted Article
Diagram 1 Propofol and cisatracurium Pharmacokinetic /Pharmacodynamic
models.
Figure 1 Kaplan–Meier analysis of propofol lag and onset times in Chinese males
and females.
Figure 2 Propofol observed plasma concentrations versus time decay profiles.
Figure 3 Kaplan–Meier analysis of cisatracurium lag and onset times in Chinese
males and females.
Figure 4 Cisatracurium observed plasma concentrations versus time decay profiles.
Figure 5 Propofol base model goodness-of-fit plots.
The upper left represents individual predicted (IPRED) concentrations versus
observed concentrations. The upper right represents population predicted (PRED)
concentrations versus observed concentrations. The red line is the regression line.
The lower left represents conditional weighed residual (CWRES) versus time. The
lower right represents CWRES versus PRED. The red line is the position where
CWRES equals 0.
Figure 6 Cisatracurium base model goodness-of-fit plots.
The upper left represents individual predicted (IPRED) concentrations versus
observed concentrations. The upper right represents population predicted (PRED)
concentrations versus observed concentrations. The red line is the regression line.
The lower left represents conditional weighed residual (CWRES) versus time. The
lower right represents CWRES versus PRED. The red line is the position where
CWRES equals 0.
Figure 7 Propofol final model Normalized Prediction Distribution Error (NPDE)
plots.
In the upper fields: left is quantile-quantile plot (Q–Q plot) against theoretical
distribution with a density of N (0, 1) and right is plot histogram of NPDE

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 distribution against theoretical distribution with a density of N (0, 1). The red
Accepted Article
interrupted line represents the median NPDE of the observations and the semi-
transparent blue fields represent a simulation-based 95% confidence Interval (CI)
for the median. In the lower fields: left is plot of NPDE versus time and right is
NPDE versus predicted concentrations. The blue interrupted lines represent the
NPDE of the observed 5th and 95th percentiles and the semi-transparent red fields
represent a simulation-based 95% CI for the median and the semi-transparent blue
fields represent a simulation-based 95% CI for the corresponding model predicted
percentiles. The solid blue circles represent NPDE of the observations.
Figure 8 Cisatracurium final model Normalized Prediction Distribution Error
(NPDE) plots.
In the upper fields: left is quantile-quantile plot (Q–Q plot) against theoretical
distribution with a density of N (0, 1) and right is plot histogram of NPDE
distribution against theoretical distribution with a density of N (0, 1). The red
interrupted line represents the median NPDE of the observations and the semi-
transparent blue fields represent a simulation-based 95% confidence Interval (CI)
for the median. In the lower fields: left is plot of NPDE versus time and right is
NPDE versus predicted concentrations. The blue interrupted lines represent the
NPDE of the observed 5th and 95th percentiles and the semi-transparent red fields
represent a simulation-based 95% CI for the median and the semi-transparent blue
fields represent a simulation-based 95% CI for the corresponding model predicted
percentiles. The solid blue circles represent NPDE of the observations.

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Accepted Article
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