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33（ 33 ）Prediction of clinical bacteriological efficacy of oral
antibiotics using a mechanism-based pharmacokineticpharmacodynamics modeling
KAYOKO MATSUMOTO, TOSHIE SUGANO, NOBUO SATO,
TAKASHI IDA and SHIGEKI SHIBASAKI
Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd.
(Received for publication December 2, 2013)

7KH REMHFWLYH RI WKLV VWXG\ ZDV WR SUHGLFW WKH FOLQLFDO EDFWHULRORJLFDO HI¿FDF\ RI
antibiotics and to examine the pharmacodynamics（PD）characteristics of antibiotics
against bacterial strains using a mechanism-based pharmacokineticpharmacodynamics （PK-PD） modeling developed on the basis of interaction
between drug concentrations and antibacterial activities.
Dynamic PD parameters（İ, Ȗ, EC50）and growth rate of organisms（Ȝ）were
obtained from in vitro WLPHNLOO SUR¿OH GDWD RI RUDO DQWLELRWLFV WHELSHQHP SLYR[LO（TBPM-PI）and cefditoren pivoxil（CDTR-PI）against Streptococcus pneumoniae
or +DHPRSKLOXVLQÀXHQ]DH PD characteristics of both drugs against 6SQHXPRQLDH
or + LQÀXHQ]DH were examined, which indicated TBPM was concentrationdependent as well as time-dependent, and CDTR was mainly time-dependent to
exhibit their bactericidal activities. Next, we simulated TBPM and CDTR
concentrations in plasma after oral administration according to the dosage regimen
RI HDFK GUXJ VSHFL¿HG LQ SDFNDJH LQVHUW XVLQJ SRSXODWLRQ SKDUPDFRNLQHWLF
parameters of both drugs in pediatric patients with infections. In addition, changes in
viable in vivo bacterial counts in humans were simulated using dynamic PD
parameters and mean plasma concentrations of each drug. As a result, simulated
SUR¿OHRIYLDEOHFRXQWVRI6SQHXPRQLDH and +LQÀXHQ]DH were well corresponding
WRWKHEDFWHULRORJLFDOHI¿FDF\UHVXOWVLQFOLQLFDOGRXEOHEOLQGHGFRPSDUDWLYHVWXG\RITBPM-PI and CDTR-PI in oral administration to pediatric patients with acute otitis
media.
As mentioned in the above, it was considered to be possible to clarify the PD
characteristics of TBPM and CDTR against each bacterial strain using themechanism-based PK-PD model developed on the basis of interaction between drugconcentrations and antibacterial activities, and to estimate the clinical bacteriological
HI¿FDF\RIWKRVHGUXJV

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Introduction
Pharmacokinetic-pharmacodynamics（PK-PD）approach plays an important role in establishing optimum dosing conditions for antibiotics and designing individualized dosage regimen.
Among PK-PD approaches of antibiotics, there is static MIC approach1）developed by using
MIC data and it is commonly used for research and development of antibiotics and appropriate
usage of those. In the static MIC approach, Cmax/MIC, AUC/MIC, and time above MIC were usedDV3.3'SDUDPHWHUV,WKDVDFRQFHSWWKDW3.3'SDUDPHWHUVWKDWDUHFRUUHODWHGWRWKHHI¿FDF\of an antibiotic differ depending on PD characteristics of the antibiotic, and there are targetYDOXHVIRU3.3'SDUDPHWHUVDWZKLFKWKHDQWLELRWLFPD\H[HUWLWVHI¿FDF\$ORWRIUHSRUWVKDYH
pointed out that static MIC approach would produce good correlations between the target values
DQG FOLQLFDO HI¿FDF\ DV D PHULW2〜4）. On the other hand, static MIC approach has the following
three problems: 1）A large scale of animal experiments is required to determine PD characteristics, which may raise a controversial issue in terms of animal welfare. 2）It is not possible to see
the interaction between the concentrations and bactericidal effects at the concentrations exceeding the MIC. 3）It is not possible to explain sub-MIC effect5）.
SATO, HWDO broke through the above-mentioned problems and reported the following concept
as mechanism-based PK-PD approach6）. That is to say, “Direct interaction between antibiotics
and bacterial strains is characterized by dynamic PD parameters（İ, Ȗ, EC50）and the growth rateof a microorganism（Ȝ）, and the time course of in vivoDQWLEDFWHULDOHI¿FDF\LVDOPRVWGHWHUPLQHG
by these PD parameters and the in vivoGUXJFRQFHQWUDWLRQSUR¿OH,QWKHSURFHVVIRUPHFKDQLVP
based PK-PD approach, in vitroWLPHNLOOSUR¿OHGDWDLVDQDO\]HGE\WKHPRGHODQG3'SDUDPHters that quantify the interaction between bactericidal effects and antibiotic concentrations are obtained. In addition, if PK information（plasma concentrations, etc.）has been combined with PD
parameters, it is possible to carry out in vivo PD estimation. SATO, HW DO set up the following
criteria to speculate PD characteristics from dynamic PD parameters.
1） if the İ/Ȝ is about 10 or greater, and Ȗ is about 1 or less, the pharmacodynamics should be“concentration-dependent”.
2） if the İ/Ȝ is within the range of 1 to 2, and Ȗ is about 5 or more, the pharmacodynamics
should be “time-dependent”.
3） if the İ/Ȝ is within the range of 1 to 4, and Ȗ is within the range of 1 to 12, the pharmacodynamics should be “time-dependent” or “both concentration- and time-dependent”.
The PD characterization of antibiotics against various strains of different microorganisms
FDQ EH SUHGLFWHG UHODWLYHO\ HDVLO\ E\ XWLOL]LQJ WKHVH FULWHULD 7KH\ UHSRUWHG WKDW WKHVH ¿QGLQJV
would make it possible to determine the kinds of causative pathogens to which the antibiotics
should be applicable, and to establish the optimum dosage regimens in clinical sites.
However, possibility of clinical application has not been discussed yet in a previous report6）,

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35（ 35 ）although the PD characteristics of various antibiotics were analyzed.
In this study, we therefore examined whether mechanism-based PK-PD approach would be
able to predict in vivo bacteriological effects using oral carbapenem antibiotic, tebipenem pivoxil（TBPM-PI, orapenem®, an active substance; TBPM, Meiji Seika Pharma Co., Ltd.）and oral
cephem antibiotic, cefditoren pivoxil（CDTR-PI, MEIACT®, an active substance; CDTR, Meiji
Seika Pharma Co., Ltd.）. The dosage regimen of CDTR-PI to pediatric patients is to be oral
administration at one time dose of 3 mg/kg after meal, 3 times daily. The maximum dose of 6 mg/kg,
3 times daily is applicable for treatment of pediatric bacterial pneumonia, acute otitis media, andacute rhinosinusitis, to which drug-resistant bacteria are largely involved.
We used Streptococcus pneumoniae and +DHPRSKLOXVLQÀXHQ]DH that have been frequently
isolated as causative pathogens for major indications of above-mentioned two drugs（pediatricrespiratory infections）7KHSUR¿OHRIin vivo bacterial counts, which was estimated by dynamic
PD parameters of each drug and population pharmacokinetic parameters in children, was compared with clinical trial results to discuss mechanism-based PK-PD approach. In addition, the PD
characteristics of both antibiotics were examined against 6SQHXPRQLDH and +LQÀXHQ]DH as follows.

Materials and Methods
Microorganisms
Clinical isolates, 6 SQHXPRQLDH; TH-1230, MSC-33（PRSP）and + LQÀXHQ]DH; MSC-238（BLNAS）, HI00542（BLNAR）were used in this study. Already determined and published values by broth microdilution method were used as MIC against each bacterial strain6,7）（Table 1）.
As for dynamic PD parameters of TBPM and CDTR against 6SQHXPRQLDH; TH-1230, MSC-33（PRSP）and +LQÀXHQ]DH; MSC-238（BLNAS）, already published data6）were used（Table 1）.

Table 1. MICs and dynamic PD parameters* of antibiotics against strains of S. pneumoniae
and +LQÀXHQ]DH*; TH-1230, MSC-33, MSC-238: reference 6）, HI00542: reference 7）36（ 36 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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Dynamic PD parameters of TBPM and CDTR against +LQÀXHQ]DH；HI00542（BLNAR）were
calculated as described in the “ PK-PD Model ” section on the basis of alreadyreported7）in vitroWLPHNLOOSUR¿OHGDWD
PK-PD modelFig. 1 explains the concept of mechanism-based PK-PD approach based on the interaction
between drug concentrations and antibacterial effects. The following formula（PRGL¿HG (maxmodel）ZDVXVHGIRUDQDO\]LQJWLPHNLOOSUR¿OHDQGVLPXODWLQJin vivo bacterial counts6,8,9）.
dN（t）/dt＝｛Ȝ−İ×CȖ（/ CȖ＋EC50）｝×N（t）

Eq 1

Fig. 1. Schematic illustration of the general concept of the mechanism-based PK-PD approacht（hr）: the time after addition of antibiotics
N（t）（CFU/mL）: the number of viable organisms at time t
C（μg/mL）: the concentration of antibiotics
λ（hr−1）: Growth rate constant of the organisms without exposure to antibiotics
ε（hr−1）: the maximum kill rate constantγ; Hill coefficientEC50（μg/mL）: the concentration of antibiotics at which 50% of the maximum effect is obtained

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37（ 37 ）Where,
t（hr）: the time after addition of antibiotics（CFU/mL）: the number of viable organisms at time t
N（t）
C（ȝg/mL）: the concentration of antibiotics
Ȝ（hr−1）: Growth rate constant of the organisms without exposure to antibiotics
İ（hr−1）: the maximum kill rate constantȖ+LOOFRHI¿FLHQW
EC50（ȝg/mL）: the concentration of antibiotics at which 50% of the maximum effect isobtained.
PD parameters that specify the interaction between antibiotics and bacterial strains are İ, Ȗ,
EC50.
In addition, Eq1 was integrated by time（t）to have Eq2 for simulating time-course changes
in bacterial counts（N）.
N（t）＝N（0）×exp［｛Ȝ−İ×CȖ（/ CȖ＋EC50）｝
×t］

Eq 2

The term｛Ȝ−İ×CȖ（/ CȖ＋EC50）｝on the right-hand side of Eq1 describes the net antibacterial activity（ĳ）of an antibiotic as a difference between the growth rate of organism and the kill
UDWHRIWKHDQWLELRWLF7KHDQWLEDFWHULDODFWLYLW\LVGH¿QHGDVIXQFWLRQRIDQWLELRWLFFRQFHQWUDWLRQV
in the following formula.
/ CȖ＋EC50）
ĳ＝Ȝ−İ×CȖ（Eq 3

A positive value of ĳ indicates bacterial growth, and a negative value indicates a decrease inbacterial counts. The smaller the ĳLVWKHVWURQJHUWKHEDFWHULFLGDOHI¿FDF\LV7KHĳ value when
WKHEDFWHULFLGDOHI¿FDF\KDVUHDFKHGPD[LPXPZDVGH¿QHGDVĳmax. The interaction between the
drug concentration and ĳ was displayed in a curve to examine the PD characteristics of antibiotics. The ĳmaxLVREWDLQHGZKHQ&YDOXHKDVVHWWREHLQ¿QLW\LQ(TDQGGHVFULEHGE\(T
ĳmax＝−（İ−Ȝ）

Eq 4,QRUGHUWRVSHFL¿FDOO\XQGHUVWDQGWKHUHODWLRQVKLSEHWZHHQĳmax and the rate of decrease in
the number of organisms, the time required to attain a 1 log reduction of the number of organisms（t1/10）was obtained by assuming N（t）＝N（0）/10 in Eq2（Eq5）.
t1/10＝−2.303/ĳmax

Eq 5

Stationary concentration（SC） LV GH¿QHG DV D GUXJ FRQFHQWUDWLRQ DW ZKLFK WKH JURZWK UDWH
equals the kill rate8）, as shown in the following formula. SC indicates the drug concentration
where there is no net change in the number of organisms in a time-course manner, that is, static
condition（dN/dt＝0）. The SC is obtained by introducing dN/dt＝0 into Eq1, as shown in the following formula.
SC＝｛ Ȝ/（İ−Ȝ）｝1/Ȗ×EC50

Eq 6

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7KHWLPHNLOOSUR¿OHGDWDRI7%30DQG&'75DJDLQVW6SQHXPRQLDH or +LQÀXHQ]DH wereanalyzed by Eq1 to obtain the growth rate（Ȝ）, İ, Ȗ and EC50. The SC was calculated by Eq6. In
addition, in vivo bacterial counts were simulated on the basis of those PD parameters and clinicalplasma concentrations of the drug. The number of viable microorganisms at the time of adminisWUDWLRQZDV¿[HGWREH×106（CFU/mL）. Phoenix WinNonlin（ver.6.1, Pharsight Corporation）
was used for PK and PK-PD analyses.
Population pharmacokinetic parameters
Population mean pharmacokinetic parameters proposed by SATO, HWDO were used for simulating plasma concentrations of TBPM in pediatric patients10）. The population pharmacokinetic
analysis was conducted using plasma concentrations of samples obtained from Japanese pediatric（Table 2）. Means of demopatients（217 subjects, 395 sampling points; dosage at 4〜6 mg/kg）
graphic data of the patients were used as covariates that affected population mean parameters.
Population mean pharmacokinetic parameters proposed by MATSUMOTO, HWDO were used for simulating plasma concentrations of CDTR in pediatric patients11）. The population pharmacokinetic
analysis was conducted on plasma concentrations of samples obtained from Japanese and Ameri（Table
can pediatric patients（153 subjects, 578 sampling points; dosage of 5.62±1.62 mg/kg）2）. Means of demographic data of the patients were used as covariates that affected population
mean parameters.
Clinical trial
Phase III study results in pediatric patients with acute otitis media12）were used as control forcomparison of in vivo bacterial counts estimated by mechanism-based PK-PD analysis（Table 3）.
This Phase III study was performed as double-blinded comparative study with the high dose of&'753, DV FRQWURO WR H[DPLQH WKH HI¿FDF\ DQG VDIHW\ RI 7%303, LQ WUHDWPHQW RI SHGLDWULF
acute otitis media. TBPM-PI was orally administered at one time dose of 4 mg/kg（3.5 mg/kg or
Table 2. Population mean pharmacokinetic parameters in pediatric patientsFeb. 2014

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39（ 39 ）7DEOH  %DFWHULRORJLFDOHI¿FDF\（eradication）after 3 days and 7 days administration

1）
After 7 days administration: end of treatment
Eradication（%）＝number of eradications/number of total × 100

higher, less than 5.0 mg/kg）twice daily for 7 days, and CDTR-PI was orally administered at thehigh dose（one time dose of 4.2 mg/kg or higher, less than 6.0 mg/kg）three times daily for 7
days.
6SQHXPRQLDH was detected as causative organism in 31 subjects of TBPM-PI administration group, and 33 subjects of CDTR-PI administration group. + LQÀXHQ]DH was detected as
causative organism in 33 subjects of TBPM-PI administration group, and 28 subjects of CDTR-PI
administration group. According to sensitivity distribution against all possible causative organisms in this clinical trial, MIC90 of TBPM and CDTR was both 0.5 ȝg/mL. In the TBPM-PI administration group 3 days after the start of administration, the eradication rate was 100%（27/27）
for 6SQHXPRQLDH and 96%（24/25）for +LQÀXHQ]DH. In the same group after the administration¿QDOL]HGWKHHUDGLFDWLRQUDWHZDV（31/31）for 6SQHXPRQLDH and 100%（69/69）for +LQÀXHQ]DH. In the CDTR-PI administration group 3 days after the start of administration, the eradication rate was 64%（21/33）for 6SQHXPRQLDH and 100%（27/27）for +LQÀXHQ]DH. In the sameJURXSDIWHUWKHDGPLQLVWUDWLRQ¿QDOL]HGWKHHUDGLFDWLRQUDWHZDV（30/31）for 6SQHXPRQLDH
and 100%（65/65）for +LQÀXHQ]DH.

Results
Dynamic PD parameters and PD characteristics
The interaction between the ĳ and drug concentrations（ĳ curve）is shown in Fig. 2 to examine the PD characteristics of TBPM and CDTR against each bacterial strain.
1） TBPMThe maximum bactericidal activity（ĳ max）was from −2 to −3, and t1/10 was about 1 hourbased on the ĳ curve for 6SQHXPRQLDH（PRSP: TH-1230, MSC-33）. Bactericidal effects werenoted to be enhanced along with increased drug concentrations, but the bactericidal effects would
be leveled off at around Cmax.

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Fig. 2. Interaction between concentrations of TBPM or CDTR and their antimicrobialactivities against S. pneumoniae and +LQÀXHQ]DH

A: TBPM-PI, B: CDTR-PI◆ : C▲ : SC, ■ :MIC, ● : EC50, ◆ : Cmax（TBPM-PI; 4 mg/kg, CDTR-PI; 3 mg/kg）,◆（TBPM-PI; 6 mg/kg, CDTR-PI; 6 mg/kg）
max

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41（ 41 ）On the other hand, the ĳ curve for +LQÀXHQ]DH（BLNAS:MSC-238）indicated that the maximum bactericidal activity（ĳmax: −1.3）for +LQÀXHQ]DH was smaller than that for 6SQHXPRQLDH.
The t1/10 was 1.7 hours. That is to say, the bactericidal activity of TBPM-PI was shown to be 6
pneumoniae（PRSP）＞+LQÀXHQ]DH（BLNAS）. Bactericidal effects were noted to be enhanced
along with increased drug concentrations, but to be leveled off at around Cmax. In addition, the ĳ
curve for BLNAR（HI00542）showed enhanced bactericidal activity along with increased drugconcentrations within the clinical plasma concentration range（dose: 6 mg/kg, Cmax: 4.5 ȝg/mL）.
The t1/10 was 0.7 hour.
2） CDTR
The ĳ curve for 6SQHXPRQLDH（PRSP: TH-1230）indicated that ĳ max value was about −1.5,
and t1/10 value was 1.5 hours. Along with increased drug concentrations, the bactericidal activity
became outstandingly noticeable at around MIC, and it would not be enhanced any more eventhough the concentration was increased.
On the other hand, the ĳ curves for 6 SQHXPRQLDH（PRSP: MSC-33）and + LQÀXHQ]DH（BLNAS: MSC-238）indicated that ĳmax values were about −1.5, and t1/10 was about 1.5 hours.
The bactericidal activity was shown to be enhanced along with increased drug concentrations.
The bactericidal activity against + LQÀXHQ]DH（BLNAS: MSC-238）was leveled off at around
Cmax.
Furthermore, in the ĳ curve for +LQÀXHQ]DH（BLNAR: HI00542）, enhancement of bactericidal activity was noted along with increased drug concentrations within the clinical plasma concentration range（dose: 6 mg/kg, Cmax: 2.5 ȝg/mL）. The t1/10 was 0.54 hour.
Simulation of plasma concentrations
Plasma concentrations were simulated in the following dosage regimens set up by using PPKparameters of TBPM-PI and CDTR-PI（Fig. 3）.
1） TBPM-PI, 4 mg/kg×2/day, 7 days repeated dose
2） TBPM-PI, 6 mg/kg×2/day, 7 days repeated dose3） CDTR-PI, 3 mg/kg×3/day, 7 days repeated dose4） CDTR-PI, 4 mg/kg×3/day, 7 days repeated dose5） CDTR-PI, 6 mg/kg×3/day, 7 days repeated dose
Cmax of TBPM was about 3 ȝg/mL at static condition after repeated dosing of TBPM-PI at
one time dose of 4 mg/kg twice daily, and it was 4.5 ȝg/mL at 6 mg/kg twice daily. On the other
hand, when CDTR-PI was administered at one time dose of 3 mg/kg three times daily, Cmax atstatic condition was about 1.25 ȝg/mL, and it was about 1.7 ȝg/mL at 4 mg/kg and about 2.5 ȝg/mL at 6 mg/kg.

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Fig. 3. Plasma concentration simulations of TBPM or CDTR after oral administration of
TBPM-PI or CDTR-PI in child using their population mean parameters

A: TBPM-PI; 2 times/day×7 days, B: CDTR-PI; 3 times/day×7 days

6LPXODWHGWLPHFRXUVHSUR¿OHVRIYLDEOHEDFWHULDOFRXQWVin vivo
7KHWLPHFRXUVHSUR¿OHRIin vivo bacterial counts was simulated for each bacterial strain by
LQWURGXFLQJ HVWLPDWHG SODVPD FRQFHQWUDWLRQ SUR¿OHV RI7%30 DQG &'75 LQWR (T7KH UHVXOWVare shown in Fig. 4.
1） TBPMTBPM-PI administration at 4 mg/kg and 6 mg/kg rapidly decreased in vivo bacterial countsof 6SQHXPRQLDH（PRSP: TH-1230, MSC-33）and +LQÀXHQ]DH（BLNAS: MSC-238）, and completely eradicated those within one day or so after the administration initiated. On the contrary, inthe case of +LQÀXHQ]DH（BLNAR: HI00542）, TBPM-PI administration at 4 mg/kg decreased invivo bacterial counts slowly, and some microorganisms were expected to be viable even 7 days
after the start of administration. TBPM-PI at 6 mg/kg, however, seemed to eradicate the microorganisms completely on 4 days after the start of administration.

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A: TBPM-PI; 2 times/day×7 days, B: CDTR-PI; 3 times/day×7days

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2） CDTR
CDTR-PI administration at 3 mg/kg decreased in vivo bacterial counts of 6 SQHXPRQLDH（PRSP: MSC-33）relatively slowly, and complete eradication was expected to be on 4 days after
the administration initiated. By increasing the dose level from 4 mg/kg to 6 mg/kg, one or 2 days
administration seemed to be enough for eradication of microorganisms. In the case of 6SQHXPRQLDH（PRSP: TH-1230）, CDTR-PI administration at 3 mg/kg did not decrease but increase in vivo bacterial counts. By increasing the dose level to 4 mg/kg or 6 mg/kg, the in vivo bacterial counts
turned to be decreasing. Complete eradication of microorganisms seemed to require CDTR-PI administration at 4 mg/kg for at least 4 days or the administration at 6 mg/kg for 1 day or longer. In
the case of +LQÀXHQ]DH（BLNAS: MSC-238, BLNAR: HI00542）, the in vivo bacterial counts
were decreased rapidly at any dose levels（3〜6 mg/kg）, and complete eradication of microorganisms was expected to be within one day after the start of administration.

Discussion,Q WKLV VWXG\ ZH H[DPLQHG WKH 3' VSHFL¿F FKDUDFWHULVWLFV RI7%30 DQG &'75 DJDLQVW 6
pneumoniae and +LQÀXHQ]DH major causative pathogens for pediatric respiratory infections, andestimated the in vivoEDFWHULDOFRXQWSUR¿OHVLQWKHDGPLQLVWUDWLRQXQGHUFOLQLFDOGRVDJHUHJLPHQ
using a mechanism-based PK-PD model.
PD characteristics
According to the criteria established by SATO HWDO and the ĳ curve（Fig. 2）, the PD characteristics of TBPM against 6 SQHXPRQLDH （PRSP: TH-1230, MSC-33） and + LQÀXHQ]DH（BLNAS: MSC-238, BLNAR: HI00542）as well as those of CDTR against 6 SQHXPRQLDH（PRSP: MSC-33）and + LQÀXHQ]DH（BLNAS: MSC-238, BLNAR: HI00542）were considered
to be concentration-dependent and also time-dependent. On the other hand, the PD characteristics
of CDTR against 6SQHXPRQLDH（PRSP: TH-1230）was assumed to be “time-dependent”, whichsuggested that antibiotics have different PD characteristics against different strains of the same
bacterial species.
Simulation of in vivo bacterial counts and clinical bacteriological effects
1） TBPMThe stationary concentrations（SC）of TBPM against 6 SQHXPRQLDH（PRSP: TH-1230,
MSC-33）and +LQÀXHQ]DH（BLNAS: MSC-238）were 0.03〜0.04 ȝg/mL, and the Cmax of clinical plasma concentrations（dose: 4 mg/kg; 3 ȝg/mL, dose: 6 mg/kg; 4.5 ȝg/mL）was about 100
times the SC（Fig. 2）. According to the SC and ĳmax value, TBPM-PI was expected to exert highHI¿FDF\ DJDLQVW 6 SQHXPRQLDH and + LQÀXHQ]DH（BLNAS）at clinical dosages. Simulation

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45（ 45 ）results of in vivo bacterial counts also projected a very rapid decrease of 6 SQHXPRQLDH（TH1230, MSC-33）and +LQÀXHQ]DH（MSC-238）after repeated oral administration of TBPM-PI at
4 mg/kg and 6 mg/kg, and complete eradication within one day after the start of administration（Fig. 4-A）. The bacteriological results in clinical trials（Table 3）supported this simulation inwhich the eradication rates of 6SQHXPRQLDH and +LQÀXHQ]DH were almost 100% 3 days after
the start of administration.
On the other hand, the SC of TBPM against + LQÀXHQ]DH （BLNAR: HI00542） was
0.075 ȝg/mL, and Cmax of clinical plasma concentrations（dose: 4 mg/kg; 3 ȝg/mL, dose: 6 mg/kg;
4.5 ȝg/mL）largely exceeded the SC. However, ȖZDVVLJQL¿FDQWO\VPDOODV(YHQWKRXJKWKH
concentration was raised within the range of clinical plasma concentrations, it did not reach toĳmax and the ĳ at around Cmax was about −1. The simulation results of in vivo bacterial counts
suggested the degree of decrease in the count of +LQÀXHQ]DH（BLNAR: HI00542）ZDVVLJQL¿cantly different depending on dose levels of 4 mg/kg and 6 mg/kg in repeated oral administration
RI7%303,7KDWLVWRVD\7%30H[HUWVLWVHI¿FDF\ “concentration-dependently” against +LQÀXHQ]DH（BLNAR: HI00542）, and higher dose level gives stronger bactericidal activity, which
supports the result of bacterial eradication by raising the dose level from 4 mg/kg to 6 mg/kg（Fig.
4-A）.
2） CDTRThe SCs of CDTR against 6SQHXPRQLDH（PRSP: TH-1230, MSC-33）were 0.9 and 0.5 ȝg/mL, and the Cmax of clinical plasma concentrations（dose: 6 mg/kg; 2.5 ȝg/mL）was 2.8 and 5
times the SCs, respectively. Simulation results of in vivo bacterial counts predicted complete
eradication of microorganisms within 1〜4 days after the start of administration of CDTR-PI at
4〜6 mg/kg（Fig. 4-B）. The bacteriological effect results of clinical trials（Table 3）supported theeradication ratio of 6SQHXPRQLDH at 96.8% on 7 days after the start of CDTR-PI administration.
On the other hand, the SCs of CDTR against + LQÀXHQ]DH （BLNAS: MSC-238 and
BLNAR: HI00542）were 0.015 and 0.005 ȝg/mL, and the Cmax of clinical plasma concentrations（dose: 6 mg/kg; 2.5 ȝg/mL）was 100 times the SC or higher. The SCs and ĳmax values suggested
WKDW&'753,H[HUWVLWVKLJKHI¿FDF\RQ+LQÀXHQ]DH（BLNAS and BLNAR）at clinical doses.
Simulation results of in vivo bacterial counts predicted a rapid decrease in in vivo counts of +LQÀXHQ]DH（BLNAS and BLNAR）at both doses of 4 mg/kg and 6 mg/kg, and complete eradicaWLRQRIPLFURRUJDQLVPVZLWKLQWKH¿UVWGD\RI&'753,DGPLQLVWUDWLRQ（Fig. 4-B）. The bacteriological effect results in clinical trials supported almost 100% eradication ratio of +LQÀXHQ]DH on
3 days after the start of CDTR-PI administration（Table 3）.
As mentioned in the above, the in vivo bacterial counts predicted on the basis of mechanismEDVHG3.3'DSSURDFKZHUHZHOOFRUUHVSRQGHQWWRWKHEDFWHULRORJLFDOHI¿FDF\UHVXOWVLQFOLQLFDO
trials.
The present study allowed us to profoundly investigate the PD characteristics of TBPM and46（ 46 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

67―1

Feb. 2014

CDTR against 6SQHXPRQLDH and +LQÀXHQ]DHDQGSUHGLFWWKHFOLQLFDOEDFWHULRORJLFDOHI¿FDF\of those. We recognized, however, the existence of resistant strains that are hardly eradicated at
the ordinary clinical doses in cases of TBPM against + LQÀXHQ]DH（BLNAR: HI00542）and
CDTR against 6SQHXPRQLDH（PRSP: TH-1230）. Owing to the analysis of PD characteristics, we
now understand increased one-time dosage of up to 6 mg/kg would be effective for both TBPMPI and CDTR-PI.
The present study revealed that the PD characteristics of an antibiotic differ depending on
bacterial species and strains. We would like to further deepen our discussions on other bacterial
species and strains as well. In addition, it is also considered to be very crucial to examine the
FOLQLFDOEDFWHULRORJLFDOHI¿FDF\XVLQJRWKHUDQWLELRWLFVIRUWKHSXUSRVHRIFRQ¿UPLQJDSSURSULDWHness of mechanism-based PK-PD approach.

Conclusion
In vitro bactericidal curve was analyzed using the mechanism-based PK-PD model, and the
PD characteristics of TBPM and CDTR against 6SQHXPRQLDH and +LQÀXHQ]DHZHUHFODUL¿HG
on the basis of dynamic PD parameters obtained. In addition, the simulation results of in vivo
bacterial counts after administration in the clinical dosage regimen were well correspondent to
WKH EDFWHULRORJLFDO HI¿FDF\ UHVXOWV LQ FOLQLFDO VHWWLQJV $FFRUGLQJO\ PHFKDQLVPEDVHG 3.3'
DSSURDFKZDVFRQVLGHUHGWREHEHQH¿FLDOWRSUHGLFWin vivoFOLQLFDOEDFWHULRORJLFDOHI¿FDF\&RQÀLFWRILQWHUHVW
7KHDXWKRUVGHFODUHQRFRQÀLFWRILQWHUHVWReferences
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