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\begin{document}

\title{Pharmacokinetics of Cefoperazone/sulbactam in Critically Ill Thrombotic
Thrombocytopenic Purpura Patients Undergoing Therapeutic Plasma Exchange}



\author[1]{Haitao Li}%
\author[2]{Chunlu Gao}%
\author[2]{Shengjin Fan}%
\author[2]{gensheng Zhang}%
\author[2]{Xin Hai}%
\author[2]{Jin Zhou}%
\affil[1]{First Affiliated Hospital of Harbin Medical University}%
\affil[2]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
AIMS The aim of this study was to investigate the~pharmacokinetics
of~CFP and SUL in critically ill thrombotic thrombocytopenic purpura
(TTP) patients undergoing TPE. METHODS Critically ill TTP patients
receiving a dose of 3 g CFP/SUL (2.0 g/1.0 g) intravenously every 8 h
were included in the study. Serial blood samples were collected at 0, 1,
2, 3, 4, 6, and 8 h at the third infusion with TPE (Session I) and the
sixth infusion without TPE (Session II). Effluent samples were also
collected at the effluent port of plasma eliminated during TPE.
Concentrations of CFP and SUL in plasma and effluent were measured using
LC/MS/MS. RESULTS Specific pharmacokinetic parameters were calculated to
evaluate the effect of TPE on CFP and SUL. The amount of drug eliminated
during TPE (QPE) were 395.75\selectlanguage{ngerman}±147.38 and 35.25±11.32 mg, respectively.
Percentage eliminated by TPE (fe\%) were 11.38±3.18\% and 2.74±1.13\%,
respectively. Calculated percentages of total drug clearance by TPE
(\%CLPE) were 27.71±10.8\% and 6.16±2.16\%, respectively. There were no
significant differences in pharmacokinetic parameters (AUC0-8, Vd,
T1/2a) between session I and session II for both CFP and SUL.
CONCLUSIONS A single plasma volume TPE does not remove clinically
significant amounts of CFP and SUL. Dosage adjustment in critically ill
TTP patients after the procedure is not necessary. CFP is more likely to
be removed than SUL during TPE due to its small Vd and high protein
binding (Pb). Elevated plasma drug concentration due to organ
dysfunction may permit more drug removal during TPE.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Pharmacokinetics ofCefoperazone/sulbactam in Critically Ill
ThromboticThrombocytopenic Purpura Patients Undergoing Therapeutic
Plasma Exchange}

Haitao Li\textsuperscript{a,1}, Chunlu Gao\textsuperscript{b}, Shengjin
Fan\textsuperscript{a}, Gensheng Zhang\emph{\textsuperscript{c}} , Xin
Hai \textsuperscript{b*}, Jin Zhou\textsuperscript{a,\emph{d} ,*}

\emph{\textsuperscript{a}} Department of Hematology, First Affiliated
Hospital of Harbin Medical University, 23 Youzheng Street, Nangang
District, Harbin, 150001, China.

\emph{\textsuperscript{b}} Department of Pharmacy, First Affiliated
Hospital of Harbin Medical University, 23 Youzheng Street, Nangang
District, Harbin, 150001, China.

\emph{\textsuperscript{c}} Department of Critical Care Medicine, Second
Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang
Road, Hangzhou, Zhejiang 310009, China.

\emph{\textsuperscript{d}} Heilongjiang Institute of Hematology \&
Oncology, 23 Youzheng Street, Nangang District, Harbin, 150001, China

* \textbf{Corresponding author:}

Xin Hai, PhD

Department of Pharmacy

The First Hospital, Harbin Medical University

NO.23 Youzheng Street, Nangang District, Harbin, 150001, China.

E-mail address: hai\_xin@163.com

Jin Zhou, MD

Department of Hematology

The First Affiliated Hospital of Harbin Medical University

NO.23 Youzheng Street, Nangang District, Harbin, 150001, China.

E-mail: zj\_hmu@163.com

\textbf{WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT}

* Patients with TTP are often at risk for multiple nosocomial infections
and need to be treated with cefoperazone/sulbactam during TPE.

* Cefoperazone is highly~protein~bound and sulbactam has a small volume
of distribution, which tend to be removed by TPE.

\textbf{WHAT THIS STUDY ADDS ABOUT THIS SUBJECT}

* We quantified~the~proportion~of~cefoperazone and sulbactam removed by
TPE. Cefoperazone is more likely to be removed than sulbactam.

* No significant differences were observed in PK when compared with and
without TPE.

* Dosage adjustment after TPE is unnecessary, and the time interval
between TPE and drug infusion is negligible.

\subsection*{Abstract}

{\label{abstract}}

\textbf{AIMS}

The aim of this study was to investigate the~pharmacokinetics of~CFP and
SUL in critically ill thrombotic thrombocytopenic purpura (TTP) patients
undergoing TPE.

\textbf{METHODS}

Critically ill TTP patients receiving a dose of 3 g CFP/SUL (2.0 g/1.0
g) intravenously every 8 h were included in the study. Serial blood
samples were collected at 0, 1, 2, 3, 4, 6, and 8 h at the third
infusion with TPE (Session I) and the sixth infusion without TPE
(Session II). Effluent samples were also collected at the effluent port
of plasma eliminated during TPE. Concentrations of CFP and SUL in plasma
and effluent were measured using LC/MS/MS.

\textbf{RESULTS}

Specific pharmacokinetic parameters were calculated to evaluate the
effect of TPE on CFP and SUL. The amount of drug eliminated during TPE
(Q\textsubscript{PE}) were 395.75\selectlanguage{ngerman}±147.38 and 35.25±11.32 mg,
respectively. Percentage eliminated by TPE (\emph{fe} \%) were
11.38±3.18\% and 2.74±1.13\%, respectively. Calculated percentages of
total drug clearance by TPE (\%CL\textsubscript{PE}) were 27.71±10.8\%
and 6.16±2.16\%, respectively. There were no significant differences in
pharmacokinetic parameters (AUC\textsubscript{0-8}, Vd,
T\textsubscript{1/2a}) between session I and session II for both CFP and
SUL.

\textbf{CONCLUSIONS}

A single plasma volume TPE does not remove clinically significant
amounts of CFP and SUL. Dosage adjustment in critically ill TTP patients
after the procedure is not necessary. CFP is more likely to be removed
than SUL during TPE due to its small Vd and high protein binding (Pb).
Elevated plasma drug concentration due to organ dysfunction may permit
more drug removal during TPE.

\textbf{Keywords:} Pharmacokinetics; Thrombotic Thrombocytopenic
Purpura; Cefoperazone; Sulbactam; Therapeutic Plasma Exchange; Removal;

\textbf{Abbreviations:} TTP, thrombotic thrombocytopenic purpura; TPE,
therapeutic plasma exchange; CFP, cefoperazone; SUL, sulbactam; PV,
plasma volume; Pb, protein binding; Vd, volume of distribution; AUC,
area under concentration-time curve; Kel, elimination rate constant; CL,
drug clearance; MOF:~multiple organ failure.

\textbf{Introduction}

Thrombotic Thrombocytopenic Purpura (TTP) is a type of
thrombotic~microangiopathy, whose typical clinical manifestations
include severe thrombocytopenic purpura, microangiopathic hemolytic
anemia, neuropsychiatric symptoms, occasionally fever or renal damage.
The main pathogenesis of TTP is associated with severe deficiency of
ADAMTS-13 (von Willebrand factor-cleaving protease). TTP is considered
as a rare and life-threatening hematologic critical illness with a
mortality rate of up to 10 to 20 percent, even if diagnosed timely and
treated properly. Currently, the first-line treatment for the acute
episode of TTP is based on daily therapeutic plasma exchange (TPE). TPE
is a therapeutic apheresis procedure for removal of pathologic
substances, including anti-ADAMTS-13 antibodies, ADAMTS-13 immune
complexes, and ultra-large VWF multimers. The replacement fluid is
usually a large volume of fresh-frozen plasma containing ADAMTS-13, in
order to maintain oncotic pressure and compensate for blood loss
{[}1{]}. The application of TPE has greatly reduced the mortality of TTP
patients and should be started as soon as possible.

The basic procedure for TPE can be performed through a highly permeable
microporous filter with hemodialysis equipment or centrifugation with an
apheresis device. According to the guidelines, one exchange procedure
requires the replacement of approximately 1 to 1.5 plasma volume (PV)
{[}2,3{]}. Similar to the mechanisms by which TPE clears pathologic
substances, drugs that do not bind to proteins are more likely to be
cleared from plasma compartment, resulting in sub-therapeutic doses and
may affect therapeutic efficacy. The amount of drug eliminated by TPE is
determined by pharmacokinetic properties of the drug and TPE-specific
factors, such as the time between initiation of TPE and infusion of
drug; plasma exchanged volume and TPE procedure frequency. The
pharmacokinetic properties, especially volume of distribution (Vd) and
protein binding (Pb), were considered to be the most dominant~factors in
determining whether a drug is susceptible to removal by TPE {[}7{]}.
Drugs that exhibit a higher Pb (\textgreater{}80\%) and smaller Vd
(\textless{}0.2 L kg\textsuperscript{-1}) are more likely to be
eliminated by TPE {[}5,6,7{]}. Amphotericin B liposomal, for instance,
with a small Vd (0.1-0.16 L kg\textsuperscript{-1}) and high Pb (95\%)
can be significantly removed by TPE. A study has shown that supplemental
doses are needed after TPE as therapeutic concentration fell below
minimum inhibitory concentration {[}8{]}.

Patients with critically ill TTP are often at high risk for
multiple~nosocomial~infections and need to be treated with a
combination~of antibiotics~during TPE in the intensive~care unit (ICU).
Beta-lactam antibiotics present similar pharmacokinetic properties and
are widely used in current clinical practice. Most \selectlanguage{greek}β-\selectlanguage{english}lactam antibiotics
including ceftazidime, cefepime, and ampicillin showed poor removal by
TPE {[}9, 10{]}. Cefoperazone/sulbactam (CFP/SUL) is a combination
containing extended spectrum beta-lactamases (ESBL) inhibitor antibiotic
widely used for the treatment of complicated several bacterial
infections, such as extended-spectrum \selectlanguage{greek}β-\selectlanguage{english}lactamase producing
Enterobacteriaceae and carbapenem resistant Acinetobacter baumannii.
Cefoperazone is highly protein bound (70-93\%) with an average Vd of
0.28L kg\textsuperscript{-1} and a T\textsubscript{1/2} of 1.7 hours,
while sulbactam has a low Pb of 40\%, a small Vd of 0.14L
kg\textsuperscript{-1}, and T\textsubscript{1/2} of 1 hour in subjects
with normal renal and hepatic function. TPE has the potential to remove
a certain amount of CFP or SUL. To the best of our knowledge, no
information is available about the amount of CFP and SUL removed or
pharmacokinetics changes during TPE. This is the first report to
evaluate the effect of TPE on the pharmacokinetics of CFP/SUL, aim to
provide relevant clinical suggestions for the optimization of antibiotic
dosing regimens.

\textbf{Materials and methods}

\textbf{Patients}

This was a prospective, single-center study conducted in the
Hemato-oncological intensive care unit of the first affiliated hospital
of Harbin Medical University between Mar 2020 and June 2021. Critically
ill TTP patients with suspected or confirmed infections who received
CFP/SUL as an empirical or targeted therapy became candidates for this
research. Patient characteristics and clinical data, including
demographic data (sex, age, high weight), type of infection, and
organ~function characteristics were collected.

TTP was diagnosed based on current expert statements regarding the ICU
management of patients with TTP {[}11{]}. The study was approved by the
ethics committee of the participant hospital, and the study was
conducted in adherence to the Declaration of Helsinki. Written informed
consent was obtained from the patient designated decision-maker.

\textbf{Therapeutic Plasma Exchange settings}

TPE was carried out via a continuous-flow centrifugation system using
the Fresenius Blood Cell Separator (Fresenius COM.TEC, Germany).
Extracorporeal blood flow was maintained at 20\textasciitilde{}40 ml
min\textsuperscript{-1}. At the end of TPE, the blood was returned with
0.9\% sodium chloride physiological solution. Fresh frozen plasma was
used as volume replacement solutions. Sodium citrate (pH 5.0\selectlanguage{ngerman}±0.5) was
used in a 1:14 v/v ratio with blood as anticoagulant therapy.

\textbf{Sample collection}

Cefoperazone/sulbactam (Sulperazon, Pfizer, New York, USA) with
cefoperazone 2.0 g/sulbactam 1.0 g in a 3-g ampoule was given to
patients. A dose of 3.0 g CFP/SUL for adults was added to 100 mL of
0.9\% normal saline solution and was administered by intravenous
injection using an infusion pump at the usual rate for 60 min every 8 h.
Each TPE session began 10 min after the end of the CFP/SUL infusion. 3
mL blood anticoagulated with EDTA were collected from median cubital
vein. To evaluate the effect of TPE on the pharmacokinetics of CFP and
SUL, whole blood~samples were collected during two sessions.

Session I, the third dose of CFP/SUL was administered on the first day
with TPE. Serial venous blood samples were collected at time 0 (trough
concentration), time 1 (peak level, 10 min before TPE), and time 2, 3,
4, 6, 8 h after the start of drug infusion. An aliquot was also taken
from the effluent port of plasma eliminated during TPE.

Session II, before the following day's TPE, a series of venous blood
samples were collected respectively at the same~time points at the sixth
CFP/SUL administration without TPE.

Whole~blood~samples were centrifuged at 4°C at 3000 rpm for 10 min, and
then the plasma~was~separated. All~plasma samples were stored at -80°C
until analysis.

\textbf{Measurement of drug concentrations}

Concentrations of CFP and SUL in plasma were simultaneously determined
by liquid chromatography method with tandem mass spectrometer detection
(LC-MS/MS). Ceftiofur was used as internal standard (IS). The plasma
samples were extracted by protein precipitation. An aliquot of 200 \selectlanguage{greek}µ\selectlanguage{english}L
plasma with 20 \selectlanguage{greek}µ\selectlanguage{english}L IS (100 \selectlanguage{greek}µ\selectlanguage{english}g mL\textsuperscript{-1}), was added with 400
\selectlanguage{greek}µ\selectlanguage{english}L acetonitrile. The mixture was then vortexed for 1 min and centrifuged
at 13,500 rpm for 5 min at 4. The supernatant was injected into the
LC-MS/MS system.

The LC-MS/MS system consisted of an AB ExionLC system and an AB SCIEX
QTRAP QUADTM 4500MD (Applied Biosystems Sciex, Ont, Canada). The
chromatographic separation was performed using a Waters Symmetry C18
column (150\selectlanguage{ngerman}×4.6 mm, 5 \selectlanguage{greek}µ\selectlanguage{english}m). The column temperature was set at 40. The
analysis was carried out using linear gradient elution with mobile phase
acetonitrile-0.1\% (v/v) formic acid in ammonium formate solution (10
mM), at a flow rate of 1 mL min\textsuperscript{-1}. The linear gradient
was as follows: 0-1 min, 10\% acetonitrile; 1-7 min, 10\% to 90\%
acetonitrile; 7-8 min, back to the initial state. The total elution time
was 8 min. The analytes were detected in negative electrospray
ionization mode. Multiple reaction monitoring (MRM) was used to monitor
precursor to product ion transition of \emph{m/z} 644.1-528.1 for
cefoperazone, \emph{m/z} 231.9-140.1 for sulbactam, and
\emph{m/z}521.9-127.0 for IS. Ion spray voltage was at 4500 V and
capillary temperature was at 550. Declustering potential (DP) was at 30
V for cefoperazone and IS, 12 V for sulbactam. The collision energy (CE)
was optimized at 15 eV for cefoperazone, 17 eV for sulbactam, and 30 eV
for IS, respectively. Dwell time was set at 100 ms for all the analytes.

The calibration curves ranged from 10 to 500 \selectlanguage{greek}μ\selectlanguage{english}g
mL\textsuperscript{-1}for cefoperazone and 2 to 100 \selectlanguage{greek}μ\selectlanguage{english}g
mL\textsuperscript{-1} for sulbactam, respectively. The accuracy and
precision of QC samples were within \selectlanguage{ngerman}±10\%.

\textbf{Pharmacokinetic calculations}

Specific pharmacokinetic parameters were used to evaluate the effect of
TPE on CFP/SUL including the amount of drug eliminated during TPE
(Q\textsubscript{PE}); the fraction eliminated by TPE (\emph{fe} \%);
Apparent volume of distribution (Vd); Area under the plasma level versus
time curve (AUC); Elimination rate constant (Kel); Half-life
(T\textsubscript{1/2}) and Drug clearance (CL).

Q\textsubscript{PE} was calculated as total volume of efluent port
(V\textsubscript{ep})×concentration of CFP or SUL concentration from
effluent port (C\textsubscript{ep}); In the equation:
Q\textsubscript{PE}= V\textsubscript{ep}×C\textsubscript{ep}{[}12{]}.

\emph{fe} \% can be calculated as Q\textsubscript{PE}/TBS × 100\%. Total
Body Stores (TBS)=Vd×concentration before plasma exchange {[}13{]}.

Kel=(ln C\textsubscript{a}-ln
C\textsubscript{b})/(T\textsubscript{b}-T\textsubscript{a}).
T\textsubscript{b}-T\textsubscript{a,} duration of two blood collection
time points, ln C\textsubscript{a} and ln C\textsubscript{b,} natural
log of plasma drug concentrations at the corresponding time points
T\textsubscript{a} and T\textsubscript{b}. Kel\textsubscript{Total}=(ln
C\textsubscript{1}-ln
C\textsubscript{3})/(T\textsubscript{3}-T\textsubscript{1}). ln
C\textsubscript{1}, natural log of plasma concentration at start of TPE.
ln C\textsubscript{3}, natural log of plasma concentration at the end of
TPE; Kel\textsubscript{Patient}=(ln C\textsubscript{1}-ln
C\textsubscript{3})/(T\textsubscript{3}-T\textsubscript{1}) on session
II {[}4{]}; Definitions, the Elimination rate constant during TPE
(Kel\textsubscript{Total}) represents the contribution of durg removed
due to TPE and patient; The contribution of durg eliminated due to
patient is Kel\textsubscript{patient}. T\textsubscript{1/2} can be
calculated as 0.693/Kel {[}4{]}.

Drug clearance while off TPE (CL\textsubscript{patient}) was calculated
for the values of Kel\textsubscript{Patient}×Vd {[}13, 14{]}. The Drug
clearance due to TPE (CL\textsubscript{PE}) was calculated using the
equation:
CL\textsubscript{PE}=Q\textsubscript{PE}/AUC\textsubscript{PE}.
AUC\textsubscript{PE}, the AUC during TPE {[}12, 13{]}. Total drug
clearance (CL\textsubscript{Total}) =
CL\textsubscript{PE}+CL\textsubscript{patient}; The proportion of
\%CL\textsubscript{PE} was determined by
CL\textsubscript{PE}/CL\textsubscript{Total}×100\%. Creatinine clearance
(Ccr) was calculated using the Cockroft-Gault equation {[}15{]}.

Data were analyzed using the SPSS statistic version 22 (IBM; New York,
NY, United). The Paired-samples t-test was used to compare the
pharmacokinetics of the day with and without TPE. Calculated values of
\textless{}0.05 were considered to be statistically significant.
The~correlation~between plasma drug concentration before TPE and
Q\textsubscript{PE} were analyzed by Pearson's correlation coefficient.

\textbf{Results}

Four critically ill TTP patients with confirmed or suspected infections
receiving~cefoperazone/sulbactam~monotherapy were enrolled. The
median~age~was~55 years. \textbf{Table 1} lists the demographic clinical
features in these patients. Of the 4~patients, mean (±SD) serum albumin
concentration was 34.75±1.64g L\textsuperscript{-1}, mean total
bilirubin (TBIL) was 49.2±13.53 \selectlanguage{greek}μ\selectlanguage{english}mol L\textsuperscript{-1} and mean
creatinine clearance (Ccr) was 55.5\selectlanguage{ngerman}±12.36 \selectlanguage{greek}μ\selectlanguage{english}mol L\textsuperscript{-1}.
Patient 2 and 3 had a Ccr of 36 and 54 ml min\textsuperscript{-1},
respectively. The Ccr of patient 1 and 4 were above 60 mL
min\textsuperscript{-1}. Three~patients~recovered and one patient died
of sepsis. Mean duration and plasma~volume~exchanged per session were
96\selectlanguage{ngerman}±10 min (85\selectlanguage{english}~112 min) and 1970+-36 mL (1910\selectlanguage{english}~2000 ml), respectively.

The Q\textsubscript{PE} of CFP was 395+-147 mg (268\selectlanguage{english}~645 mg) and \emph{fe}
\% was 11.38+-3.18\% (8.43\textasciitilde{}16.75 \%). For SUL, the
Q\textsubscript{PE} was 35+-11 mg (20\textasciitilde{}51 mg) and\emph{fe}
\% was 2.74+-1.13 \% (1.35\textasciitilde{}4.28 \%)\textbf{(Table 2)} .
Noteworthy, a positive~correlation was found between the amount of drug
removed and plasma drug concentration of CFP and SUL before TPE, but
there were no statistically significances (r= -0.895, p=0.056 for CFP,
and r= -0.821, p=0.179 for SUL) \textbf{(Figure 2).}

Kel\textsubscript{Total} and Kel\textsubscript{patient} were described
in \textbf{Table 2} , respectively. For CFP, Kel\textsubscript{Total}
and Kel\textsubscript{patient} were 0.4+-0.14 and 0.26+-0.13
h\textsuperscript{-1}, which correspond to T\textsubscript{1/2} of
3.73+-1.27 and 3.24+-1.57 h; estimated Kel\textsubscript{Total} and
Kel\textsubscript{patient} for SUL were 0.65+-0.15 and 0.46+-0.2
h\textsuperscript{-1}, which correspond to T\textsubscript{1/2} of
1.71+-0.26 and 1.72+-0.26 h, respectively. \textbf{(Figure 1).}The average
Kel\textsubscript{Total} for CFP and SUL were estimated to be 0.5-fold
higher than that for Kel\textsubscript{patient}. However,
no~significant~differences~were found in T\textsubscript{1/2a} for CFP
and SUL between the two sessions (P=0.974 and P=0.967). The fraction of
CFP and SUL eliminated due to TPE (\%CL\textsubscript{PE}) were
27.71+-10.8\% and 6.16+-2.16\%, respectively.

Pharmacokinetics of CFP and SUL were also compared on both sessions
\textbf{(Table 3).}AUC\textsubscript{0-8} of CFP on session I and
session II were 1532.8+-768.95 and 1411.4+-789.43 mgxh
L\textsuperscript{-1}, respectively (p=0.855). AUC\textsubscript{0-8} of
SUL on session I and session II were 110.47+-36.22 and 115.12+-39.81mgxh
L\textsuperscript{-1}, respectively (p=0.887) \textbf{(Table 3)} . There
were little differences in pharmacokinetic parameters
(AUC\textsubscript{0-8}, Vd, and t\textsubscript{1/2}) between session I
and session II. We noticed that the maximal peak concentration of
session I was higher than that of session II, it was thought to be the
cause of the pharmacokinetic instability. We did not observe a
redistribution phenomenon occurred at two hours after the TPE procedure

\textbf{(Figure 1).}

\textbf{Discussion}

To our knowledge, this is the first research to investigate the effect
of TPE on CFP and SUL pharmacokinetics in critically ill TTP patients.
The TPE specific properties and pharmacokinetic characteristics of the
drug are two key~factors determining drug elimination during TPE. The
time between the drug infusion and TPE initiation are two factors that
affect the amount of drug extracted from TPE. Researches~have shown that
the closer the time between drug infusion and TPE initiation, the
greater the amount of drug removed by TPE {[}10{]}. In our presented
four cases, TPE was initiated 10 min after intravenous infusion, at
which point the majority of drugs would be~primarily present in the
intravascular space, and could therefore be removed by TPE {[}4,16{]}.
Besides, volume of exchange is another significant TPE specific
parameter driving the amounts of drug be removed by TPE. The
treatment~target~for a~plasma~exchange~procedure should be 1 to 1.5 PV,
equivalent to a removal of approximately 63\% and 78\% of plasma
contents respectively {[}17{]}. An increase in volume of exchange can
increase a greater amount of drug extracted. In this study, the average
volume of exchange is approximately 1970+-36.74 mL, corresponding to
nearly one PV.

The pharmacokinetic properties of Vd and Pb are considered to be the
most dominant~factors determining whether a drug is susceptible to
removal by TPE. Low Pb and high Vd always correlate with drug's
distribution in tissues and cells and therefore are unsusceptible to
removal by TPE. In contrast, drug with small Vd (\selectlanguage{english}<0.2 L
kg\textsuperscript{-1}) and high Pb (\selectlanguage{english}>80\%) are more easier to be
removed during TPE due to the greater distribution of the drug in the
vascular space {[}12,17{]}. In our study, we found that approximately
2000 mL exchange yielded a higher Kel\textsubscript{Total} than the
Kel\textsubscript{patient} without TPE , suggesting that TPE lead to
increases in the rate of CFP and SUL elimination. Q\textsubscript{PE}and
\emph{fe} \% seems to be the most reliable parameters for the
determination of the amount of drug removed via TPE. The fraction
eliminated by TPE (\emph{fe} \%) was significant for CFP as 11.38+-3.18\%
(range 8.43\textasciitilde{}16.75\%). SUL is eliminated by TPE with only
2.74+-1.13\% (range 1.35\textasciitilde{}4.28\%) from effluent port of
depleted plasma. The \emph{fe} \% of CFP is over 4-fold higher than that
of SUL. The calculated smaller Vd (0.14+-0.03 L kg\textsuperscript{-1}for
CFP vs. 0.48+-0.15 L kg\textsuperscript{-1} for SUL) and higher Pb
(70-93\% for CFP vs. 38\% for SUL, obtained from non-critically ill
patients) may contribute to the remarkable increased fraction eliminated
by TPE. In addition, it was suggested that a 30\% increase in
\%CL\textsubscript{PE} could be considered a clinically significant
effect {[}13{]}. \%CL\textsubscript{PE} of CFP and SUL were about 27\%
and 6\%, respectively. It is suggest that CFP is more likely to be
removed than SUL during TPE. However, CFP and SUL removal by TPE may not
be clinically significant.

There were only slight differences in parameters between session I and
session II in those four patients\textbf{(Table 3)} .~Unexpectedly,
AUC\textsubscript{0-8} and Vd of CFP on session I were slightly
increased than those on session II, contrary to our expectations. There
are many aspects needed to be~considered. First, it seems that TPE did
not alter the pharmacokinetic behavior of CFP and SUL significantly.
Then, the relatively elevated peak concentration at session I might due
to pharmacokinetic instability might increase the
AUC\textsubscript{0-8}. Finally, the number of patients included in our
trial is limited and two of four critically ill patients with severe
infection or septic shock received aggressive fluid resuscitation.
Overhydrating status may lead to pharmacokinetics changes, such as AUC
and Vd {[}18{]}.

Additionally, TTP is considered as a life-threatening critical illness
and often associated with severe complications such as hypoalbuminemia
and multiple organ dysfunction (MOF). Hypoalbuminemia might cause
decreased drugs binding resulting in less distribution of drugs in the
vascular space, in favor of tissue distribution, especially for CFP with
a larger Pb {[}19{]}. Besides, positive~correlation was observed between
Q\textsubscript{PE} and plasma drug concentration before TPE, however it
failed to reach statistical significance. SUL is mainly excreted by
kidney (84\%) while most of CFP is excreted via bile. Organ dysfunction
is an important factor leading to elevated plasma drug concentration. In
our cohort, the largest amount of CFP removed (645 mg) was noted in the
patient with impaired~bile~excretion (TBIL 71.9 \selectlanguage{greek}µ\selectlanguage{english}mol
L\textsuperscript{-1}, DBIL 31.5 \selectlanguage{greek}µ\selectlanguage{english}mol L\textsuperscript{-1}). Similarly,
the largest amount of SUL (51 mg) removed in the patient with impaired
renal~function (Ccr 36 mL min\textsuperscript{-1}, serum creatinine 156
\selectlanguage{greek}μ\selectlanguage{english}mol L\textsuperscript{-1}). It is suggested that elevated plasma drug
concentration and extended half-life due to organ dysfunction allow more
drug removal by TPE. It is more remarkable when drug distribution
half-life (T\textsubscript{1/2a}) is longer than 2 hours of the TPE
procedure duration {[}20{]}. In our cohort, T\textsubscript{1/2a}~of CFP
and SUL~showed a prolongation compared with previous parameters in
noncritically ill patients (\textasciitilde{}1.7 h for CFP and
\textasciitilde{}1 h for SUL). T\textsubscript{1/2a} of CFP is longer
than 2 hours,~which is one of the reasons why its \emph{fe} \% is higher
than that of SUL.

The pharmacokinetics of CFP/SUL vary widely among critically ill
patients. Therefore, it would be worthwhile to carry out further studies
to confirm these results.

\textbf{Conclusion}

In general, we firstly describe the pharmacokinetics of CFP and SUL in
critically ill TTP patients undergoing TPE. Results confirmed that Vd
and Pb are the two dominant~factors determining drug elimination by TPE.
CFP is more likely to be removed than SUL during TPE due to its a small
Vd and high Pb. However, the amount of CFP and SUL removed by TPE may
not be clinically significant, and dosages should not be adjusted in
critically ill TTP patients undergoing TPE.

\textbf{Acknowledgment}

We thank Dr.Xin Hai, Drs. Chunlu Gao and Drs. Meihua Guo (Departmentof
Pharmacy, the First Affiliated Hospital, Harbin Medical University) for
providing some indispensable instruments, and Drs. ShengjinFan and
HongyuXie (Department of Hemato-oncological ICU, the First Affiliated
Hospital, Harbin Medical University) for the collection of samples.

\textbf{Funding}

No funding sources

\textbf{Competing interests}

None declared.

\textbf{Compliance with ethical standards}

Ethics approval was obtained from the ethics committee of the
participant hospital, and the study was conducted in adherence to the
Declaration of Helsinki. Informed consent was obtained from all
individual participants included in the study.

\textbf{Conflict of interest}

The authors declare no conflict of interest.

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\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/figure-1CPZ/figure-1CPZ}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/figure-1SUL/figure-1SUL}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/figure-2CPZ/figure-2CPZ}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/figure-2SUL/figure-2SUL}

\end{center}
\end{figure}

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\textbf{Hosted file}

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