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Rhee, Shin, Cha, Kim, Oh, Cho, Yu, Jang, Chung, and Lim: Pharmacokinetic Characteristics of Cefcapene Pivoxil Hydrochloride after Single Oral Administration in Healthy Korean Subjects
Original Article

J Korean Soc Clin Pharmacol Ther 2013;21(2):104-112.

Published online: 11 January 2013

DOI: https://doi.org/10.12793/jkscpt.2013.21.2.104

Pharmacokinetic Characteristics of Cefcapene Pivoxil Hydrochloride after Single Oral Administration in Healthy Korean Subjects

Su-jin Rhee1, Kwang-Hee Shin2, Yu-Jung Cha1, Jung-Ryul Kim3, Dal-Seok Oh4, Joo-Youn Cho1, Kyung-Sang Yu1, In-Jin Jang1, Jae-Yong Chung1, Kyoung Soo Lim1

1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, South Korea

2Kyungpook National University College of Pharmacy, Daegu, South Korea

3Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Seoul, South Korea

4Korea Institute of Oriental Medicine, Daejeon, South Korea

E-mail: kslim96@snu.ac.kr

Received 8 July 201312 November 2013       Accepted 15 November 2013

Copyright © 2013 Korean Society for Clinical Pharmacology and Therapeutics

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background:

Cefcapene pivoxil hydrochloride (CFPN-PI) is an oral ester cephalosporin antibiotic with a broad spectrum. In this study, we investigated the pharmacokinetics (PK) and tolerability of CFPN-PI following single oral administration in healthy Korean subjects.

Methods:

An open label, dose escalation, parallel group study was conducted in 18 healthy male volunteers. A single dose of CFPN-PI was administered to 6 subjects in each treatment group of 100, 150 and 200 mg. Serial blood and urine samples were collected up to 12 h and 24 h after dosing, respectively. Plasma and urine concentrations of cefcapene were measured by HPLC-UV. PK parameters were estimated using non-compartmental analysis. For the safety evaluation, adverse event monitoring, clinical laboratory tests and physical examination were performed throughout the study.

Results:

Median values of time to peak plasma concentration were observed around 1.5 to 2.0 h. Maximum plasma concentrations (Cmax) were 1.04 ± 0.22, 1.24 ± 0.46 and 1.56 ± 0.43 mg/L (mean ± SD), and area under the plasma concentration time curve (AUCinf) were 2.94 ± 0.46, 3.97 ± 1.28 and 4.70 ± 1.19 h*mg/L in 100, 150 and 200 mg dose groups, respectively. The differences of dose normalized Cmax and AUCinf among three groups were not statistically significant. The fractions of drug excreted in urine unchanged were 31.5 % - 42.9 %. There were no serious adverse events or clinically significant abnormalities related to CFPN-PI.

Conclusion:

CFPN-PI was well tolerated with single oral administration and showed a linear PK property within 100 - 200 mg in healthy Korean male subjects.

Keywords: Cefcapene pivoxil hydrochloride, Pharmacokinetics, Tolerability, Korean, Healthy subjects

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Figure 1.
Mean plasma concentration time profiles of cefcapene after single oral administration of 100, 150 and 200 mg (left: linear scale, right: log-linear scale). Error bars mean standard error. * 100 mg. †150 and 200 mg. Mean concentrations on 12 hours after dose include only plasma concentrations above lower limit of quantification.
jkscpt-21-104f1.tif
Figure 2.
Comparison of dose-normalized pharmacokinetic parameters among the dosing groups (100, 150 and 200 mg). The boxes represent 50 % of the values, and the horizontal lines correspond to the median(—) and the mean(—) (left: dose normalized Cmax, right: dose normalized AUCinf).
jkscpt-21-104f2.tif
Table 1.
Demographic data of subjects
Demography Treatment group
 Total (n=18) P-value*
100 mg (n=6) 150 mg (n=6) 200 mg (n=6)
Age (years) 23.5 ± 2.6 28.0 ± 7.1 23.2 ± 1.7 24.9 ± 4.8 0.094
Height (cm) 172.8 ± 5.6 180.4 ± 5.6 170.7 ± 5.0 174.6 ± 4.7 0.030
Weight (kg) 68.1 ± 5.7 76.5 ± 9.8 65.2 ± 8.5 70.0 ± 9.1 0.071

Data are presented as mean ± standard deviation. *Kruskal-Wallis test.

Table 2.
Pharmacokinetic parameters of cefcapene after single oral administration
Pharmacokinetic parameter Treatment group
 P-value*
100 mg (n=6) 150 mg (n=6) 200 mg (n=6)
  Tmax (h) 1.50 [1.00 - 4.00] 2.00 [1.50 - 3.00] 1.75 [1.00 - 3.00] 0.509
 Cmax (mg/L) 1.04 ± 0.22 (21.44) 1.24 ± 0.46 (36.63) 1.56 ± 0.43 (27.72) 0.073
AUCinf (h*mg/L) 2.94 ± 0.46 (15.67) 3.97 ± 1.28 (32.29) 4.70 ± 1.19 (25.37) 0.025
 AUCextra (%) 2.07 [1.42 - 5.48] 3.10 [1.35 - 4.49] 2.29 [1.14 - 4.49] 0.203
  t1/2 (h) 1.03 ± 0.21 (20.72) 1.31 ± 0.27 (20.71) 1.96 ± 0.96 (49.18) 0.091
 CL/F (L/h) 34.7 ± 5.4 (15.54) 40.8 ± 11.4 (27.96) 45.0 ± 12.1 (26.81) 0.250
  fe*F (%) 31.5 ± 8.7 (27.66) 39.7 ± 6.9 (17.28) 42.9 ± 15.8 (36.80) 0.220
  CLr (L/h) 11.0 ± 2.7 (24.31) 16.3 ± 3.7 (22.72) 18.2 ± 3.3 (17.85) 0.008

Data are presented as mean ± standard deviation (coefficient of variation, %) except for Tmax and AUCextra, for which median [minimum-maximum] are shown. Tmax: time of maximum observed plasma concentration. Cmax: maximum observed plasma concentration. AUCinf : area under the plasma concentration versus time curve from dosing to time infinity. AUCextra: percent of AUCinf extrapolated. t1/2: terminal elimination half life. CL/F: apparent clearance. fe*F: fraction of the non-intravenously administered drug excreted into the urine. CLr: renal clearance of the drug from plasma. * Kruskal-Wallis Test.

Table 3.
Comparison of dose normalized Cmax and AUCinf among three dosing groups
Pharmacokinetic parameter Treatment group
 P-value*
100 mg (n=6) 150 mg (n=6) 200 mg (n=6)
Cmax/Dose (mg/L/mg)
 0.0104 ± 0.0022 (21.44)
 0.0083 ± 0.0030 (36.63)
 0.0078 ± 0.0022 (27.72)
 0.109
AUCinf/Dose (h*mg/L/mg) 0.0294 ± 0.0046 (15.67) 0.0265 ± 0.0086 (32.29) 0.0235 ± 0.0060 (25.37) 0.250

Data are presented as mean ± standard deviation (coefficient of variation, %). Cmax: maximum observed plasma concentration. AUCinf: area under the plasma concentration versus time curve from dosing to time infinity. *Kruskal-Wallis test.

Table 4.
Linear regression and power model for dose proportionality assessment of cefcapene
Dependent variable
Cmax AUCinf
Simple linear regression*
  Intercept of regression line 0.494 1.237
   (95 % CI) (-0.216 - 1.205) (-0.695 - 3.169)
  Slope of regression line 0.005 0.018
   (95 % CI) (0.001 - 0.010) (0.005 - 0.030)
Power model†
  Intercept of regression line -2.576 -1.927
   (95 % CI) (-5.075 - -0.760) (-4.041 - 0.188)
  Slope of regression line 0.558 0.651
   (95 % CI) (0.056 - 1.060) (0.226 - 1.076)

Cmax: maximum observed plasma concentration. AUGinf: area under the plasma concentration versus time curve from dosing to time infinity. CI: confidence interval. *Y = α + β × (Dose), †In(Y) = α + β × In (Dose), Y: dependent variable.

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