Aug. 2013

THE JAPANESE JOURNAL OF ANTIBIOTICS

66―4

189（ 1 ）Population pharmacokinetics of tazobactam/
piperacillin in Japanese patients with
community-acquired pneumonia
YUKIHIRO HAMADA1,*, SAKI TAKAHASHI2,**, TAKESHI HIRAYAMA1,2,
KEISUKE SUNAKAWA3 and MASAKAZU KUROYAMA1,2
12Department of Pharmacy, Kitasato University East Hospital
Pharmacy Practice and Science II (Kitasato University East Hospital),
School of Pharmacy, Kitasato University
3
Infectious Disease Science, Kitasato University
Kitasato Institute for Life Sciences(Received for publication July 1, 2013)

The population pharmacokinetics on tazobactam/piperacillin (TAZ/PIPC; 1 : 8, 4.5 g×3) was analyzed in Japanese patients with community-acquired pneumonia using the
Nonlinear Mixed Effect Model version VI. Analysis by the one-compartment modelyielded the following results for PIPC: total clearance (CL)＝8.22＋(Ccr−71.4)×0.0561 (L/hr), distribution volume (Vd)＝13.7 (L). The pharmacokinetic parameters
for TAZ were: CL＝8.67＋(Ccr−71.4)×0.0682 (L/hr), Vd＝14.4 (L). Of thepharmacokinetic parameters of PIPC, CL included Ccr as a variation factor, whereas
the Vd included no variation factor. Because PIPC is excreted into the urine in the
XQFKDQJHGIRUPLWVSKDUPDFRNLQHWLFIDFWRUVVHHPWRUHÀHFWWKHUHQDOIXQFWLRQVWDWXVIn this study of patients with community-acquired pneumonia, the mean Vd per
body weight was 0.26 L/kg, and the results suggested an increase of the Vd inpatients with community-acquired pneumonia as compared with the value in healthy
adults.

Introduction
Tazobactam/piperacillin (TAZ/PIPC) is a preparation of a penicillin family antimicrobial
agent combined with a ȕ-lactamase inhibitor and has been shown to have a broad antimicrobial
spectrum. The 1 : 8 TAZ/PIPC combination has been approved in more than 90 countries in the*Currently; Department of Infection Control and Prevention, Aichi Medical University Hospital**Currently; Department of Pharmacy, Kitasato University Hospital190（ 2 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

66―4

Aug. 2013

world, including the USA and Europe, and has been extensively used in the treatment of severe or
intractable infections. In Japan, a 1 : 4 TAZ/PIPC combination was initially marketed, the doselevel of PIPC in this combination was lower than that in foreign countries, and the use of this formulation was restricted to a narrower spectrum of indications. In 2008, a 1 : 8 TAZ/PIPC combination, identical to the formulation approved overseas, was also approved in Japan, making it
possible to administer PIPC at higher dose levels and expanding the available scope of antimicrobial agents for the treatment of intractable infections.
5HFHQWO\ GLVFXVVLRQV KDYH EHHQ KHOG DERXW WKH LPSRUWDQFH RI HI¿FDF\VDIHW\ RSWLPL]DWLRQ
from the viewpoint of ensuring proper use of antimicrobial agents, as well as about the importance of designing administration of antimicrobial agents based on the pharmacokinetic and pharmacodynamic (i.e.3.3'WKHRU\ SUR¿OHVRIWKHGUXJVWRVXSSUHVVWKHGHYHORSPHQWRIUHVLVWDQW
strains of microorganisms. The antimicrobial activities of penicillins are time-dependent, and thetime above the minimum inhibitory concentration (TAM) has been shown to serve as a usefulpharmacokinetic-pharmacodynamic (PK-PD) parameter for appropriate use of the penicillins. It
has been suggested that penicillins exert cytostatic activity when the TAM is over 30% and maximal cytocidal activity when the TAM is over 50%1). Thus, it is essential to take into account theTAM when considering treatment with the penicillins. Exploration and elucidation of the pharmacokinetics of TAZ/PIPC may be expected to allow optimum methods of treatment with this combination to be devised based on the PK-PD parameters. Under such circumstances, the present
study was carried out to investigate the pharmacokinetics of TAZ/PIPC in Japanese patients with
community-acquired pneumonia by analysis of the population pharmacokinetics.

Materials and Methods
Population
Referring to the data yielded by the clinical pharmacological study of patients with community-acquired pneumonia carried out by WATANABE et al.2), we performed a population pharmacokinetic analysis in 53 patients, involving 157 points of blood sampling for PIPC and 146 for TAZ.
TAZ/PIPC was administered three times a day (4.5 g×3) for all patient. It was carried out in accordance with the Ethical Guidelines on Epidemiological Studies (Ministry of Education, Culture, Sports, Science and Technology, and Ministry of Health, Labour and Welfare of Japan) andthe Law on Protection of Individual Information, as well as the Ethical Guidelines for Clinicalstudies of our hospital.
Pharmacokinetic model building
The analysis of the population pharmacokinetics was conducted using the Nonlinear Mixed
Effect Model (NONMEM), version VI. The computer was used under the following settings:

Aug. 2013

THE JAPANESE JOURNAL OF ANTIBIOTICS

66―4

191（ 3 ）CPU, Intel® Core™ i3 2.13 GHz; memory, 4.00 GB; OS, Windows®7 (Microsoft corporation).
NONMEM was compiled with Digital Visual Fortran® 5.0A (Digital Equipment Corporation).
Algorithm for analysis$QDO\VLV XVLQJ 1210(09, LV EDVHG RQ  DOJRULWKPV ¿UVW RUGHU )2  ¿UVW RUGHU FRQGLtional estimation (FOCE), and FOCE-interaction (FOCE-I). To determine then optimum algorithm for our analysis, we carried out analysis with the linear 1-compartment model, assuming an
exponential error of total clearance (CL) for inter-individual variation and relative error for intraindividual variation, and compared the results on predictability obtained using the algorithms,
using the scale of predicted error for the population.
Pharmacokinetic models
The predictability of the pharmacokinetic models was analyzed on the linear 1-compartment
model (NONMEM sub-routine ADVAN1 TRANS2) not including covariates, and the 2-compartment model (ADVAN3 TRANS4). The 1-compartment model was adopted for both PIPC and
TAZ, with the CL and distribution volume (Vd) serving as the PK parameters. Predictability wasevaluated based on a general assessment of the Akaike Information Criteria (AIC)3–5), root meansquare error (RMSE).
Error models
Inter-individual variations were evaluated through analysis of objective function (OBJ),
RMSE, to determine the exponential errors and absolute errors. Exponential errors were used forevaluation of the inter-individual variation of CL. No error model was assumed for determining
WKHLQWHULQGLYLGXDOYDULDWLRQRI9G,QWHULQGLYLGXDOYDULDWLRQZDVGH¿QHGDV&/i＝CL×exp (Și),
where CL denotes a population parameter, CLi denotes an individualʼs parameter, Ș is 0 on average, and Ȧ2 denotes variance.
For evaluation of intra-individual variation, the relative error model was selected on the basisof the results of evaluation of the predictability of the three models, i.e., relative error model, absolute error model and absolute-exponential mixed error model. Intra-individual variation was de¿QHGDV&S＝F×(1＋İ), where Cp denotes the observed blood drug level, F indicates the blood
drug level predicted from the compartment model, İ averages 0, and ı2 denotes variance.
Factors affecting the pharmacokinetics
Covariates were incorporated one by one into the basic model originally free of covariates,
WRHYDOXDWHWKHLQÀXHQFHRIWKHVHFRYDULDWHVRQWKHSKDUPDFRNLQHWLFV2IWKHYDULDEOHVDJHERG\weight, gender, aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum creatiQLQH 6FU DQGFUHDWLQLQHFOHDUDQFH &FU ZHUHLQFRUSRUDWHGLQWRWKHPRGHO7KHVWDWLVWLFDOVLJQL¿-

192（ 4 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

66―4

Aug. 2013cance of the contribution of the covariates was judged on the basis of the likelihood ratio testcomparing the variable in OBJ obtained from the NONMEM (−2 log likelihood difference;¨2%- ZLWKWKHȤ2 YDOXH%HFDXVH¨2%-FDQEHDSSUR[LPDWHGZLWKWKHȤ2 distribution, a 3.84 or
JUHDWHUFKDQJHRIWKH¨2%-DVVRFLDWHGZLWKDQLQFUHDVHRIșE\ZDVUHJDUGHGDVVLJQL¿FDQW S＜
 7KHQDOOFRYDULDWHVIRXQGWREHVLJQL¿FDQWZHUHLQFRUSRUDWHGLQWRWKHPRGHOWRREWDLQD
full model. From this model, covariates were then eliminated one by one. A covariate whose
UHPRYDOUHVXOWHGLQDRUJUHDWHULQFUHDVHRIWKH¨2%-ZDVUHJDUGHGDVVLJQL¿FDQW S＜0.01).
7KHFRYDULDWHVWKXVUDWHGDVLQVLJQL¿FDQWZHUHHOLPLQDWHGIURPWKHPRGHORQHE\RQHEHJLQQLQJZLWKWKHFRYDULDWHZKRVHHOLPLQDWLRQFDXVHGWKHVPDOOHVWFKDQJHRIWKH¨2%-,QWKLVZD\D¿QDOPRGHO LQFRUSRUDWLQJ RQO\ VLJQL¿FDQW FRYDULDWHV ZDV FRQVWUXFWHG 6HOHFWLRQ RI FRYDULDWHV ZDVEDVHGRQDJHQHUDODVVHVVPHQWFRYHULQJQRWRQO\WKHVLJQL¿FDQFHRIHDFK¿[HGHIIHFWEXWDOVR
the accuracy of parameter estimation and the applicability.
Validity of the basic model
The validity of the basic model was evaluated in accordance with the European Medicines
Evaluation Agency Guidelines through analysis of predictability, diagnosis of residuals, and assessment of the regularity of residuals on the GOF plots6).
(1) Plasma drug level (Cp) vs. population predicted drug level (PRED)(2) CP vs. individually predicted drug level (IPRED)(3) Time after drug administration vs. weighted residual (weighted residual [WRES] or conditional weighted residual [CWRES])(4) Population predicted drug level vs. weighted residual(5) Population predicted drug level vs. absolute weighted residual
When the algorithm FO was used, WRES was adopted as the weighted residual. When thealgorithm FOCE or FOCE-I was used, CWRES was adopted as the weighted residual7).
Validation of the thus-developed population pharmacokinetic model
Bootstrap re-sampling is used for evaluation of the stability and robustness of the population
pharmacokinetic model. Bootstrap re-sampling was carried out 200 times to compare the parameWHUVRIWKH¿QDOPRGHOZLWKWKHDYHUDJHSDUDPHWHUYDOXHVHVWLPDWHGZLWKWKHERRWVWUDS

Results
Patients
Table 1 shows the blood sampling points for PIPC and TAZ and the variables of the 53 patients. Table 2 shows the PearsonʼV SURGXFWPRPHQW FRUUHODWLRQ FRHI¿FLHQW U  DPRQJ WKH YDULables. The study involved adults (age over 16) ranging in age from 21 to 90 years. There were 39

Aug. 2013

THE JAPANESE JOURNAL OF ANTIBIOTICS

66―4

193（ 5 ）Table 1. Patientsʼ demographic dataa.

Table 2. Relationships with the patientsʼ demographic dataa,b.

males and 14 females, with body weights ranging from 38 to 112.6 kg. Creatinine clearance, ascalculated using the Cockcroft-Gault equation8), ranged from 31.7 to 349.4 mL/min. Correlation
was noted between the age and Ccr (r＝−0.678), between the body weight and Ccr (r＝0.597),

194（ 6 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

66―4

Aug. 2013

and between the Scr and Ccr (r＝−0.513). The number of blood sampling points from 53
patients was 157 for PIPC and 146 for TAZ.
Population pharmacokinetic parameters(1) PIPC
When the NONMEM sub-routine ADVAN1 TRANS2 1-compartment model was comparedwith the ADVAN3 TRANS4 2-compartment model, without incorporation of any covariate, the
SUHGLFWDELOLW\GLGQRWGLIIHUVLJQL¿FDQWO\EHWZHHQWKHWZRPRGHOV)RUWKLVUHDVRQWKHFRPSDUWment model was adopted. The AIC was calculated to be 1086.654 for the 1-compartment modeland 1063.06 for the 2-compartment model. When the blood drug level was plotted against time, alinear course of the blood drug level was obtained (Fig. 1). RMSE (root mean square error) did
QRW GLIIHU VLJQL¿FDQWO\ EHWZHHQ WKH FRPSDUWPHQW PRGHO ȝg/mL) and the 2-compartment
model (47.8 ȝg/mL). So, the 1-compartment model was adopted. The population predicted error
assessment scale scores, calculated from the results of analysis with each algorithm, were as follows: FO (mean error (ME)＝−0.43 ȝg/mL, mean absolute error (MAE)＝34.06 ȝg/mL, RMSE
＝51.15 ȝg/mL), FOCE (ME＝9.9 ȝg/mL, MAE＝29.14 ȝg/mL, RMSE＝49.2 ȝg/mL), FOCE-I(ME＝6.8 ȝg/mL, MAE＝29.41 ȝg/mL, RMSE＝48.7 ȝg/mL). Thus, the obtained predictability
was slightly better with algorithm FOCE-I. For inter-individual variation of the CL, the exponential error model was assumed. No improvement of the predictability of the inter-individual variations of Vd was noted even when the exponential error model was assumed. For this reason, theerror model was not assumed for inter-individual variation of the Vd. For intra-individual variation, the relative error model was assumed. Comparison of the relative error model, absolute error
model and absolute-relative mixed error model revealed that a greater OBJ was obtained with theabsolute error model than with the other two models. OBJ did not differ between the relative
Fig. 1. Plot of observed concentration of PIPC vs. timeAug. 2013

THE JAPANESE JOURNAL OF ANTIBIOTICS

66―4

195（ 7 ）error model and the mixed error model, and no improvement was obtained with the mixed error
model. For these reasons, the relative error model was adopted.
Table 3 shows the results of analysis with the covariate models, incorporating each variable.
−ORJOLNHOLKRRGGLIIHUHQFHGHFUHDVHGVLJQL¿FDQWO\IROORZLQJLQFRUSRUDWLRQRIDJHERG\ZHLJKWScr or Ccr. Because these factors were correlated with each other, the Ccr causing the greatest decrease of the OBJ was incorporated into the full model. As only one variation factor was involved, no backward selection was performed. When a full model incorporating all of these facWRUV ZDV SUHSDUHG DQG EDFNJURXQG VHOHFWLRQ ZDV SHUIRUPHG WKH 2%- VKRZHG QR VLJQL¿FDQW
increase following removal of age, body weight or Scr from the model, eventually resulting in thesame model following removal of any of these factors. Vd was not analyzed because the inter-inGLYLGXDOYDULDWLRQZDVYHU\VPDOODQGZDVVFDUFHO\LQÀXHQFHGE\WKHYDULDWLRQIDFWRUV
(2) TAZ
Like for the case of PIPC, the values of the parameters estimated using the FO algorithm differed markedly from those estimated using the FOCE or FOCE-I algorithm. The population7DEOH  +\SRWKHVLVWHVWLQJIRU¿[HGHIIHFWVRQWKH3,3&SKDUPDFRNLQHWLFVa,b.

196（ 8 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

66―4

Aug. 2013

predicted error assessment scale scores, calculated from the results of analysis with the FOCE
and FOCE-I algorithms, were as follows: FOCE (ME＝1.36 ȝg/mL, MAE＝3.41 ȝg/mL, RMSE＝5.48 ȝg/mL), FOCE-I (ME＝1.00 ȝg/mL, MAE＝3.38 ȝg/mL, RMSE＝5.36 ȝg/mL). Thus, thepredictability was slightly better with FOCE-I. For this reason, FOCE-I was used for the comparison between the 1-compartment analysis and 2-compartment analysis.
The obtained AIC was smaller by more than 100 with the 1-compartment model (455.222)
than with the 2-compartment model (560.421). The predictability of each model was checkedwith DV-PRED plots, and the 1-compartment model was adopted. The inter-individual variationsin the distribution volume were very small, like for the case of PIPC. For this reason, the expoQHQWLDOHUURUPRGHOZDVQRWXVHGDQGWKH¿[HGHIIHFWPRGHOZDVQRWHYDOXDWHGHLWKHU7KHLQWUD
individual variation was similar to the results for PIPC. For this reason, the relative error was assumed for TAZ. With the basic model, the OBJ was 447.222 and the intra-individual variation
was 31.8%. The estimated parameter value was 9.03 L/hr for CL and 14.6 L for Vd. Table 4 shows
the results of analysis with the models incorporating each variable as a covariate. A tendency similar to that seen for PIPC was observed. The OBJ decreased following incorporation of each of
7DEOH  +\SRWKHVLVWHVWLQJIRU¿[HGHIIHFWVRQWKH7$=SKDUPDFRNLQHWLFVa,b.

Aug. 2013

THE JAPANESE JOURNAL OF ANTIBIOTICS

66―4

197（ 9 ）age, body weight, Scr and Ccr. Finally, a model incorporating only Ccr was adopted.
PK model performance(1) PIPC)LJVKRZVWKHJRRGQHVVRI¿WSORWIRU3,3&
The Cp-PRED regression analysis revealed a relationship of R2＝0.8382 (Fig. 2(A)). The
Cp-IPRED regression analysis disclosed a relationship of R2＝0.8531 (Fig. 2(B)). The distribution of CWRES plotted against PRED was almost homogeneous around the line CWRES＝0(Fig. 2(C)). The distribution of CWRES relative to time was not biased (Fig. 2(D)). The successrate in bootstrap re-sampling was 99.5% (success in 199/200 points). The population pharmacoNLQHWLFSDUDPHWHUVIRUWKHGDWDVHWZHUHDSSUR[LPDWHO\LGHQWLFDOWRWKRVHIRUWKH¿QDOPRGHO 7DEOH
5).
(2) TAZ)LJLOOXVWUDWHVWKHJRRGQHVVRI¿WSORWIRU7$=
The Cp-PRED regression analysis revealed a relationship of R2＝0.8268 (Fig. 3(A)). CpIPRED regression analysis disclosed a relationship of R2＝0.8749 (Fig. 3(B)). The distribution of
CWRES plotted against PRED was almost homogeneous around the line CWRES＝0 (Fig. 3(C)).
The distribution of CWRES relative to time was not biased (Fig. 3(D)). The success rate in bootstrap re-sampling was 99.5% (success at 199/200 points). The population pharmacokinetic paUDPHWHUVIRUWKHGDWDVHWZHUHDSSUR[LPDWHO\LGHQWLFDOWRWKRVHIRUWKH¿QDOPRGHO 7DEOH 
Final-model PK parameter
The calculation for PIPC yielded the following results: CL＝8.22＋(Ccr−71.4)×0.0561(L/hr), Vd＝13.7 (L); intra-individual variation, 33.9%. The OBJ decreased from 1078.654 to
1037.401 (p＜0.001), while no change was revealed by analysis of intra-individual variation.
The calculation for TAZ yielded the following results: CL＝8.67＋(Ccr−71.4)×0.0682 (L/hr), Vd＝14.4 (L); intra-individual variation, 31.5%. The OBJ decreased from 447.222 to402.838 (p＜0.001), and the intra-individual variation changed from 31.8% to 31.5%.

Discussion
In regard to the pharmacokinetics of PIPC, some investigators have previously reported that
QRQOLQHDUSKDUPDFRNLQHWLFSUR¿OHVDUHQRWHGIROORZLQJDGPLQLVWUDWLRQRIWKLVGUXJDWH[WUHPHO\high dose levels9). In the present study, the drug was administered using the dosing method and
GRVH OHYHO VSHFL¿HG LQ WKH SDFNDJH LQVHUW DQG WKH SKDUPDFRNLQHWLF SDUDPHWHUV PHDVXUHG ZHUH
linear. Therefore, we assumed linearity in the present study. Although a report of analysis using a198（ 10 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

66―4

Aug. 2013)LJ  *RRGQHVVRI¿WIRUWKH3,3&¿QDOPRGHO FRPSDUWPHQWPRGHO (A) Relationship between the observed PIPC plasma concentrations and the predicted values on the population mean parameters35(' GHWHUPLQHGXVLQJWKH¿QDOPRGHO% 5HODWLRQVKLSEHWZHHQWKHREVHUYHG3,3&SODVPDFRQFHQWUDWLRQVDQGWKHSUHGLFWHGYDOXHVDIWHULQGLYLGXDO%D\HVLDQ¿WWLQJ
,35(' GHWHUPLQHGXVLQJWKH¿QDOPRGHO(C) Conditional weight residual (CWRES) between the observed PIPC plasma concentrations and the predicted values based on
WKHSRSXODWLRQPHDQSDUDPHWHUV 35(' XVLQJWKH¿QDOPRGHOvs. predicted values based on the population mean parameters.
(D) Conditional weight residual (CWRES) between the observed PIPC plasma concentrations and the predicted values based on
WKHSRSXODWLRQPHDQSDUDPHWHUV 35(' XVLQJWKH¿QDOPRGHOvs. time after PIPC administration.

Aug. 2013

THE JAPANESE JOURNAL OF ANTIBIOTICS

66―4

199（ 11 ）Table 5. Final estimates for population pharmacokinetics parameters of PIPC in communityacquired pneumonia and bootstrap validation.

2-compartment model has been published10), there11) was no marked difference between the Įphase half-life and ȕ phase half-life according to this report, and the Į phase was also short. We
therefore considered that analysis using the 1-compartment model would not be inferior in terms
of predictability, as compared to analysis using the 2-compartment model.
,QWKHSUHVHQWVWXG\WKHLQÀXHQFHRIDJHJHQGHUSK\VLTXHDQGKHSDWLFIXQFWLRQRQWKHSKDUPDFRNLQHWLFSDUDPHWHUVZDVHYDOXDWHG2IWKH3.SDUDPHWHUVIRU3,3&&FUZDVLGHQWL¿HGDVD
YDULDWLRQ IDFWRU IRU &/ ZKLOH QR YDULDWLRQ IDFWRUV ZHUH LGHQWL¿HG IRU9G %HFDXVH 3,3& LV H[creted into the urine in the unchanged form at a percentage of 46.0-52.9%12), its PK factors seem
WRUHÀHFWWKHUHQDOIXQFWLRQVWDWXV$67DQG$/7ZHUHDOVRDQDO\]HGEXWQHLWKHUZDVLGHQWL¿HGDV
a variation factor. The active metabolite of PIPC is desethyl piperacillin (DEt-PIPC), and no inactive metabolite is known. It has been estimated that CYP2C8, CYP2A6 and CYP2C9*1 are involved in the conversion of PIPC to DE-tPIPC, and that 5% of the PIPC administered is converted into this form, as judged from the plasma drug level and percent urinary excretion10). ThereZDVRQHSRLQWEODQNYDOXHDSDWLHQWFDOFXODWHG&FUVLJQL¿FDQWO\KLJKYDOXHRIP/PLQE\&RFNFURIW*DXOW +RZHYHU LW GLG QRW LQÀXHQFH 33. UHJDUGOHVV RI LQSXW RI WKH YDOXH RU EODQN
value. Metabolism in the liver affected the disappearance of PIPC little, and neither AST nor ALT
was incorporated into the model equation. PIPC level in bile was high, and this drug is transferred well into bile. It has been reported that administration of PIPC to patients with jaundice resulted in lower bile PIPC levels13), suggesting that disorders of the biliary tract can affect the200（ 12 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

66―4

Aug. 2013)LJ  *RRGQHVVRI¿WIRUWKH7$=¿QDOPRGHO FRPSDUWPHQWPRGHO (A) Relationship between the observed TAZ plasma concentrations and the predicted values on the population mean parameters35(' GHWHUPLQHGXVLQJWKH¿QDOPRGHO%  5HODWLRQVKLS EHWZHHQ WKH REVHUYHG7$= SODVPD FRQFHQWUDWLRQV DQG WKH SUHGLFWHG YDOXHV DIWHU LQGLYLGXDO %D\HVLDQ ¿WWLQJ
,35(' GHWHUPLQHGXVLQJWKH¿QDOPRGHO(C) Conditional weight residual (CWRES) between the observed TAZ plasma concentrations and the predicted values based on
WKHSRSXODWLRQPHDQSDUDPHWHUV 35(' XVLQJWKH¿QDOPRGHOvs. predicted values based on the population mean parameters.
(D) Conditional weight residual (CWRES) between the observed TAZ plasma concentrations and the predicted values based on
WKHSRSXODWLRQPHDQSDUDPHWHUV 35(' XVLQJWKH¿QDOPRGHOvs. time after TAZ administration.

Aug. 2013

THE JAPANESE JOURNAL OF ANTIBIOTICS

66―4201（ 13 ）Table 6. Final estimates for population pharmacokinetics parameters of TAZ in communityacquired pneumonia and bootstrap validation.

pharmacokinetics of this drug.
Because inter-individual variation in Vd was small, no model of inter-individual variation
was adopted in this study. This is probably because the variation in physique was smaller among
the patients studied, except for the case of one patient who weighed 112 kg. The data on the Vd
LQGLFDWHWKDWWKLVGUXJLVORFDWHGLQH[WUDFHOOXODUÀXLGDQGPD\EHDIIHFWHGE\WKHSK\VLTXHRILQdividual patients. However, since the inter-individual variation was small in the present study,
analysis of variation factors was not possible. Increase in the Vd of several drugs has been reported in infected patients14). In the present study of patients with community-acquired pneumonia, the mean Vd per body weight was calculated to be 0.26 L/kg. If this result is combined withthe report that the Vd per body weight was 0.21 L/kg in healthy adults13), it seems likely that the
Vd of PIPC can increase in infected patients.
TAZ showed a tendency similar to that of PIPC in terms of the error models and PK parameters. For the same reason as that for PIPC, the 1-compartment model was adopted for TAZ. Considering that TAZ is excreted into the urine in the unchanged form at 63.5-71.2% of the adminisWHUHGGRVHZHPD\VD\WKDWWKLVPRGHOUHÀHFWLQJWKHUHQDOIXQFWLRQZDVYDOLGIRUWKLVGUXJDVIRU
the case of PIPC. TAZ is degraded in the kidneys into inactive metabolites, and the liver is not involved in the metabolism or excretion of this drug. For this reason, neither AST nor ALT served
DVDYDULDWLRQIDFWRU9GVHHPVWREHFRQ¿QHGWRWKHH[WUDFHOOXODUÀXLGEXWWKHLQWHULQGLYLGXDOYDULDWLRQZDVVPDOODQGQRYDULDWLRQIDFWRUZDVLGHQWL¿HGIRUVLPLODUUHDVRQVWRWKRVHIRU3,3&202（ 14 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

66―4

Aug. 2013

The Vd of TAZ per unit body weight in healthy individuals has been reported to be 0.21 L/kg13).
7KXVOLNH3,3&7$=VHHPVWRVKRZDQLQFUHDVHRI9GLQLQIHFWHGSDWLHQWV:KHQWKH¿QDOPRGHOwas evaluated, homogeneous distribution along y＝[ZDVQRWHGZLWKDKLJKFRHI¿FLHQWRIUHJUHVsion between the predicted plasma drug level and the PRED, and the bias in the residual was also
relatively small in the evaluation of CWRES. Furthermore, in the evaluation by the bootstrap
PHWKRGWKHVXFFHVVUDWHZDVKLJKDQGWKHPHDQFRQYHUJHQFHUDWHZDVFORVHWRWKDWRIWKH¿QDO
model, thus endorsing the internal validity of the population pharmacokinetic parameters measured in this study. We will be analyzed PK-PD modeling based on this PPK in Japanese.
&RQÀLFWRILQWHUHVW
7KLVVWXG\ZDVFDUULHGRXWZLWKRXWDQ\¿QDQFLDOVXSSRUWIURPDQ\SDUW\:HKDYHQRFRQÀLFWof interests to declare.
Acknowledgments
We appreciate allowing to submit this paper that we received original data of this researchfrom prof. A. WATANABE (Tohoku University).
The authors are indebted to Mr. HIDEFUMI KASAI and Mr. JUN TANAKA (BELLSYSTEM24,
Inc.) for their advice on NONMEM analysis. The authors would also like to express their gratitude to Mr. TATSUYA UJI (Taiho Pharmaceutical Co., Ltd.).

References
1) DRUSANO, G. L.: Prevention of resistance: a goal for dose selection for antimicrobial agents. Clin.
Infect. Dis. 36: S42〜50, 2003
2) WATANABE, A.; N. AOKI, Y. NIKI, et al.: Clinical pharmacological study of tazobactam/piperacillin
in patients with community-acquired pneumonia [Japanese]. Jpn. J. Chemoth. 58: 11〜28, 2010
3) AKAIKE+$QHZORRNDWWKHVWDWLVWLFDOPRGHOLGHQWL¿FDWLRQ,(((7UDQV$XWRPDW&RQWURO
716〜723, 1974
4) YAMAOKA, K.: Development of evaluation methods and computer softwares for pharmacokinetic
analysis. Xenobiotic Metabolism & Disposi. 16: 92〜103, 2001
5) YAMAOKA, K.; T. NAKAGAWA & T. UNO: Application of Akaikeʼs information criterion (AIC) in theevaluation of linear pharmacokinetic equations. J. Pharmacokinet. Biopharm. 6: 165〜175, 1978
6) GAGE, R. & D. A. STOPHER: A rapid HPLC assay for voriconazole in human plasma. J. Pharm.
Biomed. Anal. 17: 1449〜1453, 1998
7) HOOKER, A. C.; C. E. STAATZ & M. O. KARLSSON: Conditional weighted residuals (CWRES): a
model diagnostic for the FOCE method. Pharm. Res. 24: 2187〜2197, 20078) COCKCROFT, D. W. & M. H. GAULT: Prediction of creatinine clearance from serum creatinine.
Nephron 16: 31〜41, 1976
9) VINKS, A. A.; J. G. DEN HOLLANDER, S. E. OVERBEEK, et al.: Population pharmacokinetic analysis ofnonlinear behavior of piperacillin during intermittent or continuous infusion in patients with cys-

Aug. 2013

THE JAPANESE JOURNAL OF ANTIBIOTICS

66―4

203（ 15 ）WLF¿EURVLV$QWLPLFURE$JHQWV&KHPRWKHU〜547, 2003
10) PATEL, N.; M. H. SCHEETZ, G. L. DRUSANO, et al. ,GHQWL¿FDWLRQ RI RSWLPDO UHQDO GRVDJH DGMXVWments for traditional and extended-infusion piperacillin-tazobactam dosing regimens in hospitalized patients. Antimicrob. Agents Chemother. 54: 460〜465, 201011) ROBERTS, J. A.; C. M. KIRKPATRICK, M. S. ROBERTS, et al.: First-dose and steady-state population
pharmacokinetics and pharmacodynamics of piperacillin by continuous or intermittent dosing in
critically ill patients with sepsis. Int. J. Antimicrob. Agents 35: 156〜163, 201012) SHIBA, K.: Phase I study of tazobactam/piperacillin in healthy volunteers. Jpn. J. Chemoth. 58: 1〜
10, 2010
13) VAN DEN HANZEL, S. J.; X. H. DE VRIES, P. SPEELMAN, et al. %LOLDU\ H[FUHWLRQ RI FLSURÀR[DFLQ
and piperacillin in the obstructed biliary tract. Antimicrob. Agents Chemother. 40: 2658〜2660,
199614) TANIGAWARA, Y.; R. SATO, K. MORITA, et al.: Population pharmacokinetics of arbekacin in patients
infected with methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 50:
3754〜3762, 2006