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357（ 53 ）Population pharmacokinetic analysis of cefditoren
pivoxil in pediatric patients with infection
KAYOKO MATSUMOTO, NOBUO SATO,
NAYU MITOMI and SHIGEKI SHIBASAKI
Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd.
(Received for publication October 2, 2013)

Population pharmacokinetic analysis was conducted on cefditoren pivoxil(CDTR-PI, Brand name: MEIACT, Meiji Seika Pharma Co., Ltd.), a third generation
oral antibiotic, using plasma concentrations of cefditoren (CDTR, total number ofsampling points: 578) obtained from pediatric patients (153 subjects, dose: 5.62±
1.62 mg/kg) after CDTR-PI administration as well as demographic data of those
VXEMHFWV 1210(0 9HU 9, /(9(/   ZDV XVHG DV VRIWZDUH 7KH ¿UVWRUGHU
conditional estimation (FOCE) method without interaction was employed as
DOJRULWKP $ RQHFRPSDUWPHQW PRGHO ZLWK ¿UVWRUGHU DEVRUSWLRQ ZDV XVHG DV D
pharmacokinetic model. As the result of analysis, the following population
pharmacokinetic parameters were obtained for CDTR.
Population mean parameters: ka (hr−1)＝0.527, CL/F (L/hr/kg)＝−0.474×Scr＋0.82, Vd/F (L/kg)＝0.77, Tlag (hr)＝0.282×(1＋0.435×NAT) (NAT: 0＝
Japan, 1＝USA, interindividual variability: Ȧ (ka)＝17.23%, Ȧ (CL/F)＝33.02%,
Ȧ (Vd/F)＝86.66%, intraindividual residual variability: ı＝0.428 ȝg/mL.
%D\HVHVWLPDWLRQZDVFDUULHGRXWIRUHDFKVXEMHFWXVLQJWKH¿QDOPRGHOWRFDOFXODWH
secondary parameters such as Cmax, Tmax, AUC, and t1/2. Cmax and AUC increased
VLJQL¿FDQWO\ ZLWK GRVH +RZHYHU 7max was approximately 2 hours and t1/2 was
DSSUR[LPDWHO\ KRXU DW DQ\ GRVH OHYHO VKRZLQJ QR VLJQL¿FDQW GRVHGHSHQGHQWFKDQJHV:KHQ &'753, ZDV DGPLQLVWHUHG RUDOO\ WR D FKLOG D VLJQL¿FDQW LQFUHDVHZDV QRWHG LQ SODVPD &'75 FRQFHQWUDWLRQV VXJJHVWLQJ KLJK HI¿FDF\ ,Q DGGLWLRQ
pharmacokinetics of CDTR were simulated in patients with renal impairment using
WKH¿QDOPRGHO$VDUHVXOWDGHOD\LQ7max and increases in AUC, Cmax, and t1/2 were
presumed with increased Scr, and the degrees of such increases were also
quantitatively estimated.
As mentioned above, the population pharmacokinetic parameters of CDTR wereobtained, which is sure contribute to simulation of its plasma concentrations in
SDWLHQWVZLWKYDULRXVEDFNJURXQGVDQGWRVSHFXODWLRQRILWVHI¿FDF\DQGVDIHW\358（ 54 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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Introduction
Cefditoren pivoxil (CDTR-PI) is a third generation cephalosporin antibiotic synthesized by
Meiji Seika Pharma Co., Ltd1). It is an oral pro-drug whose gastrointestinal absorption has beenenhanced by introducing a pivaloyloxymethyl ester at the C4-carboxylic acid of cefditoren(CDTR) that has a broad spectrum and strong antibacterial activity against aerobic and anaerobic
Gram-positive bacteria as well as Gram-negative bacteria2,3). After oral administration, this compound is absorbed from the gastrointestinal tract and its ester bond is immediately hydrolyzed byan esterase in the enteric canal walls. It is distributed in plasma and tissues as CDTR, an antibacterial active form1,4〜7). In Japan, CDTR-PI received manufacturing approval in tablet form for
adults and granule form for children in April 1, 1994. The dosing regimen for a child is oral administration of 3 mg/kg after meal per dose, 3 times daily (t.i.d.). This compound has been widely
XVHG IRU YDULRXV W\SHV RI SHGLDWULF LQIHFWLRXV GLVHDVHV DQG LWV HI¿FDF\ DQG VDIHW\ KDYH DOUHDG\been established. As of March 2012, this compound has been approved and marketed for pediatric indication in Korea, Thailand and Turkey, and the same dosing regimen as in Japan is employed in these countries. In recent years, however, a lot of drug-resistant strains has been foundagainst existing oral antibiotics in Streptococcus pneumoniae (S. pneumoniae) and HaemophilusLQÀXHQ]DH (+ LQÀXHQ]DH), the major pathogens for acute otitis media, acute rhinosinusitis, andpneumonia. These diseases become refractory and protracted, which pose a big challenge to antibacterial therapy. To overcome this challenge, a high dose treatment with CDTR-PI has been proPRWHGIRU&'75WRH[HUWVXI¿FLHQWHI¿FDF\$IWHUFOLQLFDOWULDOVLQFKLOGUHQWRFRQ¿UPWKHHI¿cacy, safety, and plasma CDTR concentrations in CDTR-PI administration at 6 mg/kg, t.i.d.,dosage up to 6 mg/kg, t.i.d. was approved in Japan in 2012.
On the basis of above-mentioned background, thorough investigation of the pharmacokinetic
information of this compound in pediatric patients is considered to be useful for speculating theHI¿FDF\DQGVDIHW\LQSDWLHQWVZLWKGLIIHUHQWGHPRJUDSKLFGDWDDQGGRVLQJUHJLPHQ2QWKHRWKHU
hand, only a few reports are available resulting from clinical pharmacology studies on the pharmacokinetics of this compound in pediatric patients. Therefore, population pharmacokinetic anal\VLVKDVVLJQL¿FDQWLPSRUWDQFH,QWKLVVWXG\SRSXODWLRQSKDUPDFRNLQHWLFDQDO\VLVZDVFRQGXFWHG
on CDTR-PI using plasma CDTR concentrations (153 subjects, 578 sampling points) and the demographic data of pediatric patients enrolled in clinical trials that were conducted in Japan andthe USA. For oral administration of CDTR-PI to pediatric patients, population mean parametersof CDTR, interindividual variability, and intraindividual residual variability, were obtained which
contributs to simulating its plasma concentrations in patients with various types of backgrounds
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359（ 55 ）Materials and Methods
Pharmacokinetic sampling
Plasma CDTR concentrations (total sampling points: 578) obtained from 153 subjects (age:28 days 〜11 years and 10 months) in 3 clinical trials that were conducted in Japan between 1991
and 20118〜10) and 1 clinical trial in the USA between 2000 and 2001, and demographic data of
those subjects were used for analysis (Table 1). These trials were all performed according to thedeclaration of Helsinki, and CDTR-PI administration and blood sampling were conducted after
respective attending doctors received parental consent for all subjects. CDTR-PI was administered at doses of 3 mg/kg〜6 mg/kg (Japan) or 3 mg/kg〜9 mg/kg (USA). Plasma CDTR concentrations were measured with Bioassay method where Escherichia coli NIHJ JC-2 was used as atest bacterial strain (quantitation limit: 25 ng/mL, accuracy of determination C.V.: 6〜9%11)),
HPLC method (quantitation limit: 250 ng/mL, accuracy of determination C.V.: 3〜6%12〜14)), or
LC-MS/MS method (quantitation limit: 20 ng/mL, accuracy of determination C.V.: 3.3〜16.7%).
The plasma concentrations of CDTR and demographic data of the patients used for analysis werecollected retrospectively from medical records and clinical study reports.
Table 1. Sources of plasma cefditoren concentration data collected in adult clinical trials

Software and algorithms
For standard pharmacokinetic analysis, Phenix Winnonlin (ver. 6.1) was used. For population pharmacokinetic analysis, the non-linear mixed effects modeling program, NONMEM (Ver.
VI, LEVEL 2.0, PREDPP Ver. V LEVEL 2.0) and Wings for NONMEM (Ver. 6) were used. The¿UVWRUGHUFRQGLWLRQDOHVWLPDWLRQ )2&( PHWKRGZLWKRXWLQWHUDFWLRQZDVHPSOR\HGDVDOJRULWKP
Digital Visual Fortran (Version 11.1, Intel Corporation) was used as compiler. Wings for NONMEM (Ver. 6) was used for model validation by bootstrap method, and Microsoft Excel 2003
0LFURVRIW&RUSRUDWLRQ ZDVXVHGIRUSUHSDUDWLRQRIWDEOHVDQG¿JXUHVDVZHOODVFDOFXODWLRQRI
statistical parameters. The computer used for analysis was NEC MC-7 (CPU, Celeron 1.8 GHz;
memory, 960 MB; OS, Windows XP Professional).

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Population pharmacokinetic analysis
Population pharmacokinetic analysis was conducted using NONMEM to estimate the population pharmacokinetic parameters (population mean parameters, interindividual variability, andintraindividual residual variability).
$RQHFRPSDUWPHQWPRGHOZLWK¿UVWRUGHUDEVRUSWLRQZDVXVHGIRUSKDUPDFRNLQHWLFPRGHOing (equation shown below). Pharmacokinetic parameters included in the model were absorption
rate constant (ka), total clearance adjusted by bioavailability (CL/F), volume of distribution adjusted by bioavailability (Vd/F), and lag time (Tlag). As dose was determined per body weight(mg/kg), the parameters CL/F and Vd/F were assumed to be proportional to body weight.
C(t)＝ka*Dose/(Vd/F)/(ka − kel)* {EXP ( − kel*(t − Tlag)) − EXP( − ka*(t − Tlag))}
C(t): plasma CDTR concentration (ȝg/mL) at t-hour after CDTR-PI administration
Dose: single dosage (mg/kg)
ka: absorption rate constant (hr − 1)
F: bioavailability
Vd/F: volume of distribution adjusted by F (L/kg)
kel (＝(CL/F) / (Vd/F)): elimination rate constant (hr − 1)
CL/F: total clearance adjusted by F (L/hr/kg)
Tlag: lag time for absorption (hr)The exponential error model was used for determination of interindividual variability inpharmacokinetic parameters, and the proportional error model was used for determination of intraindividual residual variability.
Interindividual variability: Pi＝P×Exp (Și)
Intraindividual residual variability: Cpij＝Cpij＋İij
Pi: individual pharmacokinetic parameter
P: population mean of pharmacokinetic parameter
Cpij: individual plasma concentration
Cpij: estimated plasma concentration
Și: error of interindividual variability in pharmacokinetic parameter (the normally
distributed interindividual random effect of mean 0 and variance Ȧ2)İij: error of intraindividual residual variability in plasma concentrations (the normally
distributed intraindividual random effect of mean 0 and variance ı2)Firstly, population pharmacokinetic analysis was conducted using the basic model without
any covariates. Bayesian method was used to estimate pharmacokinetic parameters for each sub-

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361（ 57 ）ject, and then individual pharmacokinetic parameters and the demographic data of subjects (covariates) were plotted to investigate for any correlations between the parameters.
Covariate analysis
7KH LQÀXHQFH RI HDFK VXEMHFW FRYDULDWH RQ WKH SKDUPDFRNLQHWLF SDUDPHWHUV ZDV DQDO\]HGThe following steps were taken to establish a full model.
Step 1: Demographic data (age, weight: WT, serum creatinine: Scr) were sequentially related
to the pharmacokinetic parameters in the basic model (ka, CL/F, Vd/F, T lag) to build additive
PRGHOV $ OLNHOLKRRG UDWLR WHVW ZDV FRQGXFWHG WR DVVHVV WKH VLJQL¿FDQFH RI GHFUHDVH LQ 2%-¨2EMHFWLYHIXQFWLRQYDOXH2%- LQWKLVPRGHOFRPSDUHGWRWKDWLQWKHEDVLFPRGHO
7KHFULWHULDIRUMXGJLQJWKHVLJQL¿FDQFHRI¨2%-ZDVVHWWREHDVLJQL¿FDQFHOHYHORIRU
lower in accordance with X2GLVWULEXWLRQ7KHPRGHOZLWKWKHODUJHVW¨2%-ZDVVHOHFWHGDPRQJVLJQL¿FDQWPRGHOVThis procedure was repeated until no more covariates could be included.
Step 2: Using the model selected in Step 1 by incorporating the demographic data, the effectof the gender and the location where the clinical trial was conducted (Japan or the USA) was examined with the likelihood ratio test to build a full model.
1H[WDUHGXFHGPRGHOZDVEXLOWE\HOLPLQDWLQJ¿[HGHIIHFWSDUDPHWHUV 7+(7$ RQHE\RQH
IURPWKHIXOOPRGHODQGE\FRQGXFWLQJDOLNHOLKRRGUDWLRWHVWRQWKHVLJQL¿FDQFHRILQFUHDVHLQ¨2%-LQWKLVPRGHOFRPSDUHGWRWKDWLQWKHIXOOPRGHO$OOLQVLJQL¿FDQW7+(7$VZHUHUHPRYHG
IURPWKHIXOOPRGHOIRURSWLPL]DWLRQWRWKH¿QDOPRGHO
7KHSRSXODWLRQSKDUPDFRNLQHWLFSDUDPHWHUVZHUHHVWLPDWHGXVLQJWKH¿QDOPRGHOHVWDEOLVKHG
in the above.
Model evaluation
7KHYDOLGLW\RIWKH¿QDOPRGHOZDVHYDOXDWHGRQWKHEDVLVRIWKHYDOLGLW\RIJRRGQHVVRI¿W
plots shown below:— Correlation between predicted concentrations based on population mean parameters(Cpred_mean) and observed concentrations in plasma (Cobs)— Correlation between predicted concentrations based on Bayes estimates (Cpred_indiv) andobserved concentrations in plasma (Cobs)— Distribution of predicted concentrations based on population mean parameters (Cpred_mean)and conditional weighted residuals (CWRES)%RRWVWDSYDOLGDWLRQZDVXVHGWRHYDOXDWHWKHYDOLGLW\DQGUREXVWQHVVRIWKH¿QDOPRGHO7ZR
hundred data sets were reconstructed by resampling from the original dataset. Successful estimaWLRQZDVGH¿QHGDVWKHQRUPDOFRPSOHWLRQRIERWKHVWLPDWLRQDQGFRYDULDQFHVWHSVRI1210(0)RU HDFK SDUDPHWHU HVWLPDWH ZKHQ FDOFXODWLRQ ZDV ¿QDOL]HG ZLWKRXW HUURU WKH PHDQ VWDQGDUG

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error (SE), minimum value (Min), median value (Median), maximum value (Max), and 95% twoVLGHGFRQ¿GHQFHLQWHUYDO &, LQSHUFHQWDJHZHUHFDOFXODWHGWRH[DPLQHWKHLUVLPLODULW\WRWKHSDUDPHWHUHVWLPDWHVLQWKH¿QDOPRGHOCalculation of secondary parameters by the Bayesian method
For all patients subjected to analysis, individual secondary parameters based on the Bayesian
PHWKRGZHUHHVWLPDWHGLQWKH¿QDOPRGHO
Tmax＝Tlag＋LN(ka/kel)/(ka − kel)
Cmax＝ka*Dose/(Vd/F)/(ka−kel)*{EXP( − kel*(Tmax − Tlag)) − EXP( − ka*(Tmax − Tlag))}
AUC0 −∞＝Dose/(CL/F)
t1/2＝0.693/kel
TukeyʼVWHVWZDVFDUULHGRXWWRGHWHUPLQHZKHWKHUWKHUHZDVDVLJQL¿FDQWGLIIHUHQFHLQWKHVHFondary parameters for each dose group (3, 5, 6, 7, 9 mg/kg).
Simulation of pharmacokinetic parameters in case of impaired renal function
For pediatric patients with impaired renal function with elevated Scr, the pharmacokinetic
parameters of CDTR-PI, and the plasma concentrations were simulated. The dose was set to be
3 mg/kg. Following the guideline for chronic renal diseases15), Scr was calculated on the basis of
Schwartzʼs conversion formula (shown below) for mild renal impairment (GFR＝70 mL/
min/1.73 m3) or moderate renal impairment (GFR＝40 mL/min/1.73 m3).
GFR＝k×HT (cm)/Scr (mg/dL) . . .18)*)5HVWLPDWHGJORPHUXODU¿OWUDWLRQUDWHLQDFKLOG P/PLQP3)
NFRHI¿FLHQW 〜12 years old＝0.55)
HT: height (cm)
Scr: serum creatinine concentration (mg/dL)
2.5 and 6 years old boys with national average heights16,17) were hypothesized for the simulation.
The following 4 conditions (I〜IV ) were used for simulation and the results were comparedto population mean values:
I. 2.5 years old, male, height 90 cm, mild renal impairment, Scr 0.7 mg/dL
II. 6 years old, male, height 116.5 cm, mild renal impairment, Scr 0.9 mg/dL
III. 2.5 years old, male, height 90 cm, moderate renal impairment, Scr 1.2 mg/dL
IV. 6 years old, male, height 116.5 cm, moderate renal impairment, Scr 1.6 mg/dL

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363（ 59 ）Results
Demographic data
The demographic data of the patients used for analysis are shown in Table 2, and the relationship among them are shown in Fig. 1. The data for analysis included gender, age (years),
body weight (WT; kg), serum creatinine concentration (Scr; mg/dL) before the start of administration, and the country where a clinical trial was conducted (Japan or the USA). As for clinical
trials conducted in Japan, the subjects were all Japanese. On the other hand, as for clinical trial
conducted in the USA, the subjects included Blacks, Caucasians, and Hispanics. The total number of subjects enrolled were 153, among which 108 subjects were from studies conducted inJapan (all administered with the tablet form) and 45 subjects from the study conducted in the
USA (all administered with the suspension). When categorized by gender, there were 85 boys and68 girls. The average dose was 5.62±1.62 mg/kg (mean±S.D.), and the minimum, median andmaximum doses were 2.91, 6.00, and 9.18 mg/kg, respectively. WT and Scr tended to increase
ZLWK DJH 7KHUH ZDV QR GH¿QLWH UHODWLRQVKLSV EHWZHHQ JHQGHU DQG SDWLHQWVʼ demographic data
(Fig. 1).

Table 2. Summary of patients used in the analysis

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Fig. 1. Relationships in patient demographic data

Plasma concentrations of CDTR and pharmacokinetic model
The plasma concentrations of CDTR measured in all the clinical trials are shown in Fig. 2.
From the results, it was found that CDTR was eliminated mono-exponentially from the plasma.
,Q DGGLWLRQ WKH FRQFHQWUDWLRQWLPH SUR¿OHV RI SODVPD FRQFHQWUDWLRQV RULJLQDWLQJ IURP VXEMHFWVwith at least 4 blood samples were individually analyzed by subject using a one-compartment
PRGHOZLWK¿UVWRUGHUDEVRUSWLRQZLWKDQGZLWKRXWODJWLPH$VDUHVXOWWKH$,& $NDLNHʼs inforPDWLRQFULWHULD REWDLQHGLQWKHPRGHOZLWKODJWLPHZDVVLJQL¿FDQWO\ORZHUWKDQWKDWLQWKHPRGHOZLWKRXWODJWLPH GDWDQRWVKRZQ 7KHUHIRUHDRQHFRPSDUWPHQWPRGHOZLWK¿UVWRUGHUDEVRUStion and lag time was used for population analysis of CDTR-PI. The number of samples obtained
from one subject in all the clinical trials is shown in Table 3. The most frequently obtained sample size was 8 points per subject; however, sparse data with only 1 point per subject were also included in the analysis.
Population pharmacokinetic analysis
Population mean parameters obtained in the basic model were as follows: ka(hr−1)＝0.810,
CL/F (L/hr/kg)＝0.639, Vd/F(L/kg)＝1.190, Tlag(hr)＝0.373, interindividual variability： Ȧ(ka)＝82.2%, Ȧ(CL/F)＝39.4%, Ȧ(Vd/F)＝28.7%, intraindividual residual variability： ı＝0.439 ȝg/
mL. Interindividual variability for Tlag was not estimated.

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365（ 61 ）Fig. 2. Plasma concentrations of cefditoren after oral administration of cefditoren pivoxil inpediatric patients (153 subjects, 578 points)
Dose: 5.62±1.62 mg/kg (Mean±S.D., 2.91~9.18 mg/kg)
A: Vertical axis: linear, B: Vertical axis: logarithm

Table 3. Sample size of population used in the analysis$FFRUGLQJWRJRRGQHVVRI¿WSORWVREWDLQHGLQWKHEDVLFPRGHOREVHUYHGSODVPDFRQFHQWUDtions coincided relatively well with individual estimates calculated from population mean parameters (data not shown). When Bayesian estimates for pharmacokinetic parameters (ka, CL/F, Vd/F) and demographic data (Age, WT, Scr, Gender) were plotted, a negative correlation was noted
EHWZHHQ%D\HVLDQHVWLPDWHRI&/)DQG6FU )LJ$ 7KHUHZDVQRGH¿QLWHJHQGHUGLIIHUHQFH
in the demographic data (Fig. 3-B)。
The development process of the full model is shown in Table 4.
Step 1: Likelihood ratio test were repeated by sequentially including the patientsʼ demographic data as covariates with reference to the results of the basic model. The following model
was constructed:ka (hr − 1)＝θ1
CL/F (L/hr/kg)＝θ2×Scr＋θ5
Vd/F (L/kg)＝θ3
Tlag (hr)＝θ4

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Fig. 3. Relationship between patient demographic data (A: Age, WT and Scr, B: Gender) and
un-normalized apparent pharmacokinetic parameters (ka, CL/F and Vd/F) of
cefditoren estimated by Bayesian method using the basic model
B: IQR; interquartile range, Dotted line; median, solid line; average, Box＝25 and 75th percentile.

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367（ 63 ）7DEOH  3URFHGXUHIRUPRGLI\LQJ¿[HGHIIHFWPRGHOVTable 5. Population pharmacokinetic parameters of cefditoren pivoxil in pediatric patients

Step 2: When the effect of the country where the clinical trial was conducted (NAT) was examined for each parameter in the above-mentioned model, Tlag was mostly affected (p<0.001,
degree of freedom (df)＝1, likelihood ratio test). Since there was no gender difference in the patientsʼ demographic data, gender difference was not examined (Fig. 3-B).
Based on the above-mentioned results, a full model was constructed (Table 4).
Finally a reduced model was developed on the basis of the full model, and ΔOBJ was deterPLQHGDJDLQVWWKHIXOOPRGHO$VDUHVXOW7+(7$VLQWKHIXOOPRGHOZHUHDOOVLJQL¿FDQWDQGWKH
IXOOPRGHOZDVLGHQWLFDOWRWKH¿QDOPRGHO 7DEOH 

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Fig. 4. *RRGQHVVRI¿WSORWVIRUWKH¿QDOSRSXODWLRQSKDUPDFRNLQHWLFPRGHOIRUFHIGLWRUHQSLYR[LOA: The population predicted concentrations versus the observed concentrations.
B: The individual predicted concentrations versus the observed concentrations.
C: The population predicted concentrations versus the conditional weighted residual.

Model evaluation*RRGQHVVRI¿WSORWVREWDLQHGLQWKH¿QDOPRGHODUHVKRZQLQ)LJ
Observed plasma concentrations coincided well with the individual estimates calculated
from Bayesian estimates, and the individual estimates calculated from the population mean parameters and CWRES were almost equally distributed in the upper and lower sides with the distribution centered around zero. The results of model validation using bootstrap method are shown
LQ7DEOH1LQHW\¿YHSHUFHQWDJHRIFDOFXODWLRQV RXWRIUXQV FRPSOHWHGVXFFHVVIXOO\Mean value or median value of each parameter calculated by the bootstrap method was similar to
WKHSDUDPHWHUHVWLPDWHVIURPWKH¿QDOPRGHO ¿QDOHVWLPDWHV 7KH¿QDOHVWLPDWHVIRUDOOWKHSDUDPHWHUV ZHUH ZLWKLQ WKH UDQJH RI WKH  FRQ¿GHQFH LQWHUYDOV REWDLQHG IURP WKH ERRWVWUDS
method. Accordingly, the population pharmacokinetic parameters shown in Table 5 were judged
to be appropriate.

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369（ 65 ）Table 6. Model validation of population pharmacokinetic parameters of cefditoren pivoxil inpediatric patients (Bootstrap method)

Calculation of secondary parameters%D\HVHVWLPDWLRQZDVFDUULHGRXWIRUHDFKVXEMHFWXVLQJWKH¿QDOPRGHOWRFDOFXODWHVHFRQGary parameters such as Cmax, Tmax, AUC, and t1/2 (Table 7). The subjects were grouped by dosage.
CmaxZDVVLJQL¿FDQWO\GLIIHUHQWEHWZHHQWKHPJNJJURXSDQGHDFKRIWKHJURXSVRIPJNJDQG
higher, as well as the 9 mg/kg group and each of the other dose groups (Tukey-Kramer method,
p<0.05 or p<0.001). In addition, AUC showed similar results as in the case of Cmax. Tmax was approximately 2 hours at any dose level, and t1/2 was approximately 1 hour at any dose level.

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Table 7. Secondary parameters of cefditoren pivoxil calculated by Bayesian method using the¿QDOPRGHOLQSHGLDWULFSDWLHQWVFig. 5. The simulated plasma concentrations of cefditoren after administration of cefditoren
pivoxil (3 mg/kg) for different degrees of renal function
A: single administration, B: repeated administration (3 times daily)
Scr: 0.38 mg/dL : population mean
Scr: 0.7 mg/dL＝2.5 years old, male, HT90 cm16), GFR: 70 mL/min/1.73 cm3( Pediatric CKD stage 2、Mild renal failure)
Scr: 0.9 mg/dL＝6 years old, male, HT117 cm17), GFR: 70 mL/min/1.73 cm3( Pediatric CKD stage 2、Mild renal failure)
Scr: 1.2 mg/dL＝2.5 years old, male, HT90 cm16), GFR: 40 mL/min/1.73 cm3( Pediatric CKD stage 2、Moderate renal failure)
Scr: 1.6 mg/dL＝6 years old, male, HT117 cm17), GFR: 40 mL/min/1.73 cm3( Pediatric CKD stage 2、Moderate renal failure)

Simulation of pharmacokinetic parameters for different degrees of renal function
The simulated of plasma concentrations under each condition are shown in Fig. 5. CL/F decreased with increasing Scr, (Fig. 6). Under the condition IV, CL/F (0.062 L/hr/kg) decreased toDec. 2013

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371（ 67 ）Fig. 6. Relationship between Scr and pharmacokinetic parameters (CL/F, AUC, Cmax, Tmax, t1/2)
of cefditoren
Dose: 3 mg/kg single administration

1/10 compared to the population mean value (CL/F: 0.64 L/hr/kg). On the other hand, pharmacokinetic parameters and secondary parameters increased with increasing Scr (Fig. 6).

Discussion
CDTR-PI gained manufacturing approval in a tablet form for adults and granule form forchildren in April 1, 1994 in Japan. Package insert describes the dosing regimen as “In general,
cefditoren pivoxil is administered orally to pediatric patients of 3 mg (potency)/kg per dose after
meals, t.i.d. The dose level shall be adjusted in accordance with age and symptoms.” It has been
ZLGHO\ XVHG IRU YDULRXV W\SHV RI SHGLDWULF LQIHFWLRXV GLVHDVHV DQG LWV HI¿FDF\ DQG VDIHW\ KDYH
been established.
In recent years, however, we have found a lot of drug-resistant strains against existing oral
antibiotics in S. pneumoniae and +LQÀXHQ]DH, the major pathogens for acute otitis media, acuterhinosinusitis, and pneumonia. These diseases become refractory and protracted, which pose a
big challenge to antibacterial therapy. CDTR possesses strong antimicrobial activity among existing oral antimicrobials against both of S. pneumoniae resistant to penicillin and macrolides, and+ LQÀXHQ]DH resistant to ampicillin. Accordingly, a high dose of CDTR-PI or amoxicillin(AMPC) is been recommended under the “Guideline for treatment of pediatric acute otitis media,
2009”19) to treat severe acute otitis media, and moderate acute otitis media that is not improved by
AMPC at regular dose, and under the “Guideline for treatment of acute rhinosinusitis, 2010”20) totreat severe acute rhinosinusitis, and mild or moderate acute rhinosinusitis that is not improved by372（ 68 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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AMPC at regular dose. In addition, the “Guideline for treatment of pediatric respiratory tract infections, 2011”21) also recommends treatment with CDTR-PI at a high dose for pneumonia forwhich involvement of drug-resistant pathogen is suspected.
Based on the above-mentioned background, clinical trials in pediatric patients with bacterial
SQHXPRQLDDFXWHRWLWLVPHGLDRUDFXWHUKLQRVLQXVLWLVZHUHSHUIRUPHGWRGHWHUPLQHWKHHI¿FDF\safety, and plasma CDTR pharmacokinetics of the administration of CDTR-PI at a high dose. As
DUHVXOWKLJKHI¿FDF\DQGVDIHW\ZHUHFRQ¿UPHG10), and the high dosage of CDTR-PI was grantedwith manufacturing approval in 2012. Accordingly, the current recommended dosing regimen of
CDTR-PI is of 6 mg (potency)/kg per dose, t.i.d. to treat pediatric patients with bacterial pneumonia, acute otitis media, or acute rhinosinusitis, for which drug-resistant bacterial involvement ishighly suspected.
Under these situations, pharmacokinetic information of this compound in pediatric patients
LVFUXFLDOO\LPSRUWDQWWRGHWHUPLQHLWVHI¿FDF\DQGVDIHW\,QWKLVVWXG\DRQHFRPSDUWPHQWPRGHOZLWK ¿UVWRUGHU DEVRUSWLRQ DQG ODJ WLPH ZDV IRXQG WR EH DSSURSULDWH DV WKH SKDUPDFRNLQHWLF
model for population analysis of CDTR-PI. Namely, it is necessary to estimate parameters suchas ka, CL/F, Vd/F, and Tlag. Moreover, the sampling size such as the total number of sampling
points and the number of sampling points per patient is reportedly important for precise estimation of pharmacokinetic parameters of a drug by population analysis22〜25). Several reports mentioned that a small number of sampling points per patient would lead to a decrease in precision ofka and Tlag, raise the chance of shrinkage of interindividual variability (ETA) or individual
weighted residual (IWRES) to 0, and degrade the reliability of empirical Bayes estimates26,27). In
the present study, we obtained data from abundant number of subjects and blood sampling points
for analysis; however, the number of sampling points per patient was not enough because of thepatients being children (Table 3). Owing to this big sample size as a whole, it was possible to estimate 4 population pharmacokinetic parameters. However, despite improvement in the model
precise estimation of ETA for Tlag was not possible because of the small number of sampling
points per patient. Thus, we used a model without interindividual variability, for the population
pharmacokinetic analysis.
Through above-mentioned improvements, population pharmacokinetic analysis on CDTR-PI
was carried out in pediatric patients, and a model where CL/F was affected by Scr was obtained,
and CL/F was found to decrease along with increasing Scr. Such results were considered appropriate, since CDTR is a drug excreted renally28). In addition, Tlag was affected by the differencein countries where the clinical trials were conducted. Fine granules were used in Japan, and suspensions in the USA; which is thought to contribute to the current results. Lag time was longer in
WKH 86$ VXVSHQVLRQV  WKDQ LQ -DSDQ ¿QH JUDQXOHV  EXW WKH GLIIHUHQFH ZDV PLQLPDO VXFK DV
0.12 hour.
%D\HVHVWLPDWLRQZDVFDUULHGRXWIRUHDFKVXEMHFWXVLQJWKH¿QDOPRGHOWRFDOFXODWHVHFRQG-

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373（ 69 ）ary parameters such as Cmax, Tmax, AUC, and t1/2 (Table 7). AUC and CmaxLQFUHDVHGVLJQL¿FDQWO\with increase in dose. Thus, in the oral administration of CDTR-PI to pediatric patients, plasma&'75FRQFHQWUDWLRQVLVH[SHFWHGWRLQFUHDVHVLJQL¿FDQWO\DORQJZLWKLQFUHDVHGGRVHVVXJJHVWLQJKLJKHI¿FDF\Based on the fact that CL/F is affected by Scr, pharmacokinetic parameters were calculated
in the oral administration of CDTR-PI at 3 mg/kg to pediatric patients with impaired renal function, and plasma concentrations of CDTR were simulated. CL/F was shown to decrease proportionally with increasing Scr, and CL/F decreased to 1/10 compared to the population mean incondition IV (Fig. 6-A). Accordingly under the condition IV, the blood concentration was relatively high after repeated administration 3 times daily, and Cmax was 6〜7 ȝg/mL at the steadystate (Fig. 5). This Cmax was, however, within the blood concentration level for which tolerability
ZDVFRQ¿UPHGLQWKHFOLQLFDOWULDOFRQGXFWHGLQWKH86$ 〜9 mg/kg). In addition, secondary parameters such as AUC, Cmax, Tmax, and t1/2 all increased with increasing Scr. Particularly AUC andt1/2LQFUHDVHGZLWKLQFUHDVLQJ6FUVLJQL¿FDQWO\ )LJ%( The relationship between renal functions and pharmacokinetics of this drug has been reSRUWHGLQFOLQLFDOWULDOVLQDGXOWVZKLFKFRQ¿UPHGWKHHOHYDWLRQRISODVPDFRQFHQWUDWLRQVDQGSURlongation of half-life along with impairment in renal functions29,30). Accordingly, it has beenstated that greatest care should be taken to the administration of this drug to adult patients with
impaired renal function. In the present study, the elevation of plasma concentrations and prolongation of the half-life were also suggested in pediatric patients with impaired renal function as in
the case of adult cases. Even in condition IV having the longest half-life, the blood concentration
reached steady state 2 days after the start of repeated administration (3 times daily).
Finally, pediatric population pharmacokinetic parameters allow us to simulate pharmacokinetics for various patient demographic data administered with various dosing regimens, which
ZLOOOHDGWRGHWHUPLQDWLRQRIHI¿FDF\RUVDIHW\RIWKLVGUXJ

Conclusion
Population pharmacokinetic parameters were obtained using plasma CDTR concentrations
for oral administration of CDTR-PI after meals to pediatric patients. This analysis has revealed
that Scr affects the CL/F of CDTR and the location where the clinical trial was conducted (NAT)
affects Tlag.
Therefore oral administration of CDTR-PI to a pediatric patient with impaired renal function
was suggested to show a delay in Tmax, increases in AUC and Cmax, and prolongation of t1/2 withincreasing Scr.
As mentioned above, population mean parameters of CDTR, interindividual variability, andintraindividual residual variability when CDTR-PI was orally administered to pediatric patients374（ 70 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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were obtained, which is sure contribute to simulation of its plasma concentrations in patients withYDULRXVEDFNJURXQGVDQGWRVSHFXODWLRQRILWVHI¿FDF\DQGVDIHW\&RQÀLFWRILQWHUHVW
7KHDXWKRUVGHFODUHQRFRQÀLFWRILQWHUHVWReferences
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