J vet Pharmacol Therap. 2019;42:647–653. wileyonlinelibrary.com/journal/jvp © 2019 John Wiley & Sons Ltd
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6471 | INTRODUCTION
Cefquinome (CFQ) is a fourth- generation cephalosporin devel-oped exclusively for use in animals (CVMP, 2003). It has high an-timicrobial activity against a broad spectrum of gram- negative and gram- positive bacteria in connection with the introduction of a aminothiazolyl methoxyimino moiety into the acyl side chain, which make CFQ resistant to inactivation by chromosomally and plasmid- encoded β- lactamases (CVMP, 2003; Durckheimer, Adam, Fischer, & Kirrstetter, 1988; Limbert et al., 1991). It has been approved for treatment of respiratory tract diseases in cattle, pigs and horses,
acute mastitis and foot rot in cattle, calf and foal septicemia and metritis- mastitis- agalactia syndrome in sows (CVMP 1995, 1999, 2003). Its efficacy has been demonstrated against many infectious diseases of domestic animals (Lang, Rose, Thomas, & Zschiesche, 2002; Shpigel et al., 1997; Thomas et al., 2004; Widmer, Kummer, Wehrli Eser, & Fürst, 2009). Due to its broad antibacterial spectrum and excellent efficacy, CFQ has the potential to become a valuable antibiotic in the treatment of infectious diseases in sheep. The suc-cessful therapeutic use of CFQ, time- dependent antibiotic, requires knowledge of its pharmacokinetics and pharmacodynamics (PK/ PD) (Ahmad et al., 2015; Gu et al., 2015; Guo et al., 2015; Thomas, Received: 17 December 2018
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Accepted: 7 January 2019DOI: 10.1111/jvp.12750
P H A R M A C O K I N E T I C R E P O R T
Pharmacokinetics of cefquinome after single and repeated
subcutaneous administrations in sheep
Orhan Corum
1| Duygu Durna Corum
1| Ayse Er
2| Kamil Uney
21Department of Pharmacology and
Toxicology, Faculty of Veterinary Medicine, University of Kastamonu, Kastamonu, Turkey
2Department of Pharmacology and
Toxicology, Faculty of Veterinary Medicine, University of Selcuk, Konya, Turkey
Correspondence
Kamil Uney, Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Selcuk, Konya, Turkey.
Email: kuney@selcuk.edu.tr Funding information
The Coordination Unit of Scientific Research Projects, University of Selcuk, Turkey, Grant/Award Number: 15401151
Abstract
The purpose of this study was to determine the pharmacokinetics of cefquinome (CFQ) following single and repeated subcutaneous (SC) administrations in sheep. Six clinically healthy, 1.5 ± 0.2 years sheep were used for the study. In pharmacokinetic study, the crossover design in three periods was performed. The withdrawal interval between the study periods was 15 days. In first period, CFQ (Cobactan, 2.5%) was administered by an intravenous (IV) bolus (3 sheep) and SC (3 sheep) injections at 2.5 mg/kg dose. In second period, the treatment administration was repeated via the opposite administration route. In third period, CFQ was administrated subcutane-ously to each sheep (n = 6) at a dose of 2.5 mg/kg q. 24 hr for 5 days. Plasma concen-trations of CFQ were measured using the HPLC- UV method. Pharmacokinetic parameters were calculated using non- compartmental methods. The elimination half- life and mean residence time of CFQ after the single SC administration were longer than IV administration (p < 0.05). Bioavailability (F%) of CFQ following the sin-gle SC administration was 123.51 ± 11.54%. The area under the curve (AUC0-∞) and peak concentration following repeated doses (last dose) were higher than those ob-served after the first dose (p < 0.05). CFQ accumulated after repeated SC doses. CFQ can be given via SC at a dose of 2.5 mg/kg every 24 hr for the treatment of infections caused by susceptible pathogens, which minimum inhibitory concentration is ≤1.0 μg/ ml in sheep.
K E Y W O R D S
Thomas, & Wilhelm, 2006; Wang, Shan, Ding, Liang, & Zeng, 2014; Zhang et al., 2014). For this purpose, the useful pharmacokinetic/ pharmacodynamic (PK/PD) parameter, which calculated using the apparent volume of distribution and elimination half- life and the minimum inhibitory concentration (MIC), is the percentage of time interval (%T > MIC) that plasma concentration remains above MIC (Turnidge, 1998).
Cefquinome following intramuscular administration in sheep has shown the favorable pharmacokinetic properties such as high bioavailability and long elimination half- life (El- Hewaity, Abd El Latif, Soliman, & Aboubakr, 2014; Tohamy, 2011; Uney, Altan, & Elmas, 2011). This makes it suitable for wider dosing intervals in sheep for the labeled micro- organisms. However, no study on the pharmacoki-netics of CFQ following single and repeated subcutaneous injections (SC), which is a more convenient route of administration in sheep, has been reported. The objectives of this study were as follows: (a) to determine the PKs and bioavailability of CFQ after a single in-travenous (IV) and subcutaneous (SC) administration of 2.5 mg/kg; (b) to evaluate the pharmacokinetic behavior and accumulation of CFQ after repeated SC administrations of 2.5 mg/kg every 24 hr for 5 days and (c) to perform a PK/PD analysis using MIC values reported in previous studies and the pharmacokinetic parameters obtained from this study.
2 | MATERIALS AND METHODS
2.1 | Animals
The study was carried out on six clinically healthy Merinos sheep, which were ages of 1.5 ± 0.2 years and weighed 48 ± 2.8 (mean ± SD) and which received no medication for the at least 2 months prior to commencement of this study. Alfalfa hay and water were provided ad libitum. Animals were kept in a 40 m2 pen with a 4 m feeding trough
and received a standard feed ration. Animals were monitored for drug reactions by physical examinations during the experimental pe-riod and for 5 days after the completion of the study. Protocols and procedures were approved by The Ethics Committee of the Faculty of Veterinary Medicine (University of Selcuk, Konya, Turkey).
2.2 | Experimental design
The study was performed in three periods according to a two- way crossover design with a 15- day washout period between treatments. In the first period, CFQ (Cobactan, 2.5%, Intervet) was administered through IV (n = 3) and SC (n = 3) at the dose of 2.5 mg/kg. In the sec-ond period, animals received at the same dose of CFQ with opposite route following the washout period. Blood samples (approximate 3 ml) were collected into tubes containing lithium heparin from the controlateral jugular vein through a catheter prior to drug adminis-tration and at 5, 10, 15, 20, 25, 30, and 45 min and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, and 24 hr after drug administration.
In the third period, CFQ was administered subcutaneously at the dose of 2.5 mg/kg every 24 hr for 5 days. Each animal received a
total of 5 injections at a given dose level. Blood samples following the first (1) and last (5) drug injections were collected with the route and at the time defined in the first and second periods. On treatment days 2, 3, and 4, blood samples were taken by jugular venipuncture at 5 min and 1, 8, and 24 hr following the drug injection. The single and repeated SC injections were administered under the skin of the back at a single location in the thoraco-lumbar region lateral of the mid-line. The blood samples were centrifuged at 4,000 g for 10 min, separated immediately and frozen at −70°C until assayed.
2.3 | Analytical procedure
Plasma concentrations of CFQ were determined by method as de-scribed by Uney et al. (2011) using HPLC with ultraviolet detector (Shimadzu, Tokyo, Japan). Briefly, plasma samples were precipitated by adding 400 μl of methanol in 200 μl of sample followed by vor-tex for 10 s and centrifugation at 4,000 g for 10 min. The superna-tant of 300 μl was diluted with 150 μl of water, transferred to HPLC autosampler vials, and 50 μl of this solution was automatically in-jected into the HPLC system. Chromatographic separation was per-formed by using Gemini™ C18 column (250 mm × 4.6 mm i.d., 5 μm, Phenomenex, Torrance, CA, USA) and a linear gradient of acetoni-trile in water with a constant 0.1% trifluoroacetic acid at a flow rate of 0.9 ml/min. CFQ was detected using UV- VIS detector (SPD- 10A), which set at 268 nm.
Cefquinome sulfate powder, which supplied by Provet® (Turkey),
was dissolved in HPLC- grade water to obtain a concentration of 1 mg/ml. This solution was used to prepare standards of 0.02- 20 μg/ ml in HPLC- grade water or drug- free sheep plasma. The calibration curves were obtained by unweighted linear regression of CFQ peak areas versus known concentrations. The calibration curves ranged from 0.02 to 20 μg/ml was linear with correlation coefficient more than 0.9998. The limit of detection was 0.01 μg/ml based on a signal- to- noise ratio of 3:1. The limit of quantification was 0.02 μg/ml with acceptable accuracy and precision (<15% for each criterion). For the determination of recovery, intra- day and inter- day precision, and ac-curacy, three concentrations were included (0.1, 1, and 10 μg/ml). The extraction recovery at three concentrations was >87%. The precision and accuracy were expressed as the coefficient of variation and bias, respectively. The intra- day and inter- day assay coefficients of varia-tions were <7%. The intra- day and inter- day assay bias was ±4.3%.
2.4 | Pharmacokinetic calculations
Pharmacokinetic parameters for each sheep were analyzed by the non-compartmental method (Gibaldi & Perrier, 1982) using a com-mercially available software program (WinNonlin 6.1.0.173, Pharsight Corporation, Scientific Consulting Inc., North Carolina, USA). The area under the curve (AUC) was calculated by the linear/log method. The elimination rate constant (ʎz) was estimated from the terminal slope of the plasma concentration versus time curve. Systemic clearance (ClS) for IV administration was calculated as dose/AUC. The elimination half-life (t1/2ʎz) was calculated by the equation: t1/2ʎz = 0.693/ʎz. From
IV data, the distribution volume at steady state (VSS) was estimated as Cl × MRT and the apparent volume of distribution (Vdarea) in the termi-nal phase was estimated as Vdarea = Dose/(AUC × ʎz). Mean absorption time (MAT) was calculated as MAT = MRTSC – MRTIV. Bioavailability (F) was calculated using the following formula by determining AUC values after single SC and IV administration of CFQ.
The peak concentration (Cmax) and the time to reach Cmax (Tmax)
were determined by direct observation (observation values) on the plasma concentration–time curve of each animal following single and repeated (doses 1 and 5) SC administration. The minimum concen-tration (Cmin) was defined as the plasma concentration of drug
mea-sured at 24 hr following SC administration of CFQ.
The accumulation ratio (R) of CFQ in plasma was calculated using following formula (Colburn, 1983); 1. R1 = AUC(0-24)ss/AUC(0-24)1, where AUC(0-24)ss and AUC(0-24)1 are the AUCs calculated for the first
(day 1) and steady- state (day 5) doses, respectively. 2. R2 = C(min)
ss/C(min)1, where C(min)ss is the plasma concentration of drug at 24 hr
following the administration of the steady- state dose, C(min)1 is the plasma concentration of drug immediately before the second dose.
2.5 | Pharmacodynamic calculations
The percentage of dosing interval (%T > MIC) that plasma concen-tration of drug remains above MIC was calculated using pharmacoki-netic parameters and MIC values (Turnidge, 1998).
% T > MIC; The percentage of dosing interval that plasma con-centration of drug remains above MIC, MIC; minimum inhibitor
concentration (mg/L), ln; natural logarithm, D; planned dose (mg/kg),
Vdarea; apparent volume of distribution (L/kg), t1/2λz; elimination half-
life (h), DI; dose interval (h).
2.6 | Statistical analysis
All values were expressed as mean ± SD. Statistical differences be-tween the common variables determined following the single IV and SC administrations were analyzed using the Paired t test. The same test was also used to determine differences between the pa-rameters determined for doses 1 and 5 in repeated SC administra-tions. The harmonic mean was calculated for t1/2λz and MRT, which analyzed by Wilcoxon’s Rank Sum test. The statistical program (SPSS 22.0, IBM Corp, Armonk, NY) was used for data analysis. A value of p < 0.05 was considered statistically significant.
3 | RESULTS
No adverse effects were observed in any sheep after CFQ ad-ministration. The plasma concentrations and pharmacokinetic parameters following single IV and SC administrations of CFQ at the dose of 2.5 mg/kg in sheep were presented in Figure 1 and Table 1, respectively. CFQ following the single SC administration displayed significantly longer t1/2ʎz and MRT and higher AUC0-∞ than those in IV administration (p < 0.05). The mean bioavailability of CFQ following SC administration was 123.51%.
Figure 2 shows the mean concentrations of CFQ in plasma fol-lowing SC administration on day 1 and day 5. Table 2 presents the corresponding pharmacokinetic parameters. There were determined increases in values of the MRT, AUC0-∞, and Cmax in steady state (p < 0.05, Table 2). The level of drug accumulation on day 5 after the SC administration of repeated doses amounted to 1.31 ± 0.06 for R1 and 1.36 ± 0.06 for R2. The two methods showed partially the accumulation of CFQ after the SC administration at every 24 hr during 5 days. F(%) =AUCSC AUCIV× 100 %T > MIC = ln ( D Vdarea× MIC ) × (t 1∕2𝜆Z ln (2) ) ×( 100 DI ) F I G U R E 1 Semilogarithmic plot of
cefquinome concentrations versus time following single- dose intravenous (IV) and subcutaneous (SC) administrations at the dose of 2.5 mg/kg in sheep (mean ± SD,
To calculate % T > MIC values, plasma concentrations and phar-macokinetic parameters obtained following single IV and SC admin-istrations of CFQ were compared with the MIC values of 0.125–2 μg/ ml for CFQ against susceptible bacteria (Table 3). The calculation of % T > MIC for IV and SC administrations based on 10 and 24 hr inter-vals, respectively. CFQ for bacteria with MIC values of ≤0.125 μg/ml and ≤1 μg/ml after IV administration maintained mean T > MIC val-ues of 88% and 43%, respectively. Following SC administration, CFQ for bacteria with MIC values of ≤1 μg/ml and ≤2 μg/ml maintained mean T > MIC values of 90% and 59%, respectively.
4 | DISCUSSION
The present study did not reveal any clinical evidence of adverse drug reactions as systemic and in the injection site such as pain,
TA B L E 1 Mean (±SD) pharmacokinetic parameters for
cefquinome in plasma after single intravenous (IV) and subcutaneous (SC) administrations at the dose of 2.5 mg/kg in sheep (n = 6) Parameter IV SC t1/2ʎz (h) HM 1.49 ± 0.06 7.69 ± 0.56* AUC0-∞ (hr × μg/ml) 16.05 ± 0.37 20.85 ± 1.58* MRT (h) HM 1.79 ± 0.08 6.92 ± 0.34* MAT (h) 5.14 ± 0.31 ClS (L/hr/kg) 0.16 ± 0.00 - Vdarea (L/kg) 0.33 ± 0.01 - VSS (L/kg) 0.28 ± 0.01 - Tmax (h) - 1.75 ± 0.27 Cmax (μg/ml) - 3.65 ± 0.27 F% - 123.51 ± 11.54
AUC0–∞, area under the plasma concentration–time curve from zero (0)
hours to infinity (∞); ClS, systemic clearance; Cmax, peak concentration; F,
bioavailability; HM, Harmonic mean.; MAT, mean absorption time; MRT, mean residence time; t1/2λz, terminal elimination half- life; Tmax, time to
reach peak concentration; Vdarea, apparent volume of distribution; VSS,
volume of distribution at steady state.
*Significantly different from IV administration (p < 0.05).
F I G U R E 2 Semilogarithmic plot of
cefquinome plasma concentrations versus time following repeated subcutaneous administrations at the dose of 2.5 mg/ kg every 24 hr for 5 days in sheep (mean ± SD, n = 6)
TA B L E 2 Mean (±SD) pharmacokinetic parameters for
cefquinome in plasma after repeated subcutaneous administrations at the dose of 2.5 mg/kg every 24 hr for 5 days in sheep (n = 6)
Parameter 1 day 5 day
t1/2ʎz (h) HM 7.46 ± 0.37 7.39 ± 0.38
AUC0-∞ (hr × μg/ml) 21.14 ± 1.16 28.78 ± 1.05*
MRT (h) HM 6.73 ± 0.24 7.64 ± 0.16*
Tmax (h) 1.67 ± 0.26 1.67 ± 0.26
Cmax (μg/ml) 3.83 ± 0.19 4.16 ± 0.11*
AUC0–∞: area under the plasma concentration–time curve from zero (0)
hours to infinity (∞); Cmax: peak concentration, HM: Harmonic mean.;
MRT: mean residence time; t1/2λz: terminal elimination half- life; Tmax: time
to reach peak concentration.
*Significantly different from 1 day (p < 0.05).
TA B L E 3 Calculated %T > MIC values of cefquinome based on
the combined analysis of plasma pharmacokinetic parameters estimated following single intravenous (IV) and subcutaneous (SC) administrations of cefquinome at the dose of 2.5 mg/kg in sheep
MIC (μg/ml) IV (10 hourly dosing interval) SC (24 hourly dosing interval) 0.125 88 183 0.25 73 152 0.50 58 121 1.00 43 90 2.00 28 59
lameness, and redness following single and repeated SC admin-istrations of CFQ. These results are consistent with the results of repeated IM injections in the sheep (El- Hewaity et al., 2014; Rana, Sadariya, & Thaker, 2015).
In our study, the mean t1/2λz, ClS, and VSS of CFQ after IV dos-ing were 1.49 h, 0.16 L/h/kg, and 0.28 L/kg, respectively. These data showed that CFQ following IV administration is rapidly elimi-nated and limited distribution similar to those previously reported in sheep (Uney et al., 2011). The limited distribution of CFQ might be related to the fact that it is an organic acid with a pKa value of 2.51 or 2.91 and shows the low fat solubility and protein binding activity (CVMP, 1995). VSS and Vdarea are the volume in steady- state and pseudo- equilibrium conditions, respectively. For all drugs, VSS is smaller than Vdarea, but these values for a drug are generally close to each other (Toutain & Bousquet- Mélou, 2004a). In this study, VSS is 83% of Vdarea and this difference is likely to indicate a small fraction of CFQ eliminated before reaching the pseudo equilibrium.
After SC administration of CFQ, Cmax (3.65 ± 0.27 μg/ml) was attained at 1.75 ± 0.27 hr post- administration. The MAT (5.14 ± 0.31 hr) of CFQ was longer than MRTIV (1.79 ± 0.08 hr). These data indicated that CFQ was slowly absorbed, showing the influence of the absorption rate in the disposition of the drug. A lon-ger MAT than MRTIV suggests flip- flop kinetics (Toutain & Bousquet- Mélou, 2004b). Also, the longer t1/2ʎz of CFQ after SC administration (7.69 ± 0.56 hr) than IV administration (1.49 ± 0.06 hr) indicated the flip- flop situation exhibiting absorption rate- limited elimination. The longer t1/2ʎz of CFQ after IM administration than IV administration has been reported in piglets (IV; 1.85 hr, IM; 4.36 hr, Li et al., 2008), pigs (IV; 2.32 hr, IM; 4.92 hr, Lu, Yang, Li, & Jiang, 2007) and sheep (IV; 0.78 hr, IM; 1.88 hr, Uney et al., 2011). Following single SC ad-ministration, the mean bioavailability of CFQ was 123.51%, which was higher than that previously reported following IM administra-tion in the sheep (89.31%, Uney et al., 2011). The bioavailability of a drug following IV administration is assumed to be 100%. The bio-availability of extravascular administration is ≤100% compared with IV administration (Toutain & Bousquet- Mélou, 2004b). In this study, flip- flop kinetics seen in SC administration of CFQ might be one rea-son for the F of >100%.
Repeated drug administration may lead to an increase in blood levels of drug until a drug reaches a steady state (Van Rossum, 1968). In the present study, when the pharmacokinetic data of 1 and 5 doses in repeated SC administration were compared, in steady state, AUC0-∞ and Cmax of CFQ were significantly increased and MRT was prolonged. The accumulation ratio of R1 and R2 for CFQ was 1.31 and 1.36, respectively. These data indicate that CFQ accumulates gradually in the body following SC administration at every 24 hr during 5 days. Also, CFQ has accumulated in the body following IM administration at 24 hr intervals during 3 days in sheep (El- Hewaity et al., 2014) and in goats (El- Hewaity et al., 2014; Hamed, Mahmoud, & Altohamy, 2016).
The MICs of CFQ for bacteria isolated from sheep have not yet been established. Escherichia coli, Klebsiella pneumoniae, Mannheimia
haemolytica, Pasteurella multocida, Streptococcus pneumonia, and Staphylococcus aureus are the most common micro- organisms
iso-lated from sheep with pneumonia and sub- clinical abscess (Bell, 2008; Musa, Babiker, Eltom, Rodwan, & El Sanousi, 2012). The in
vitro efficacy of CFQ for these pathogens has been reported by
var-ious workers (Batzias, 2009; Chin, Gu, Fang, & Neu, 1992; Ehinger, Schmidt, & Kietzmann, 2006; FDA, 2006; Limbert et al., 1991; Luhofer et al., 2004; Meyns, Croubels, Verheyen, Sustronck, & Maes, 2006; Murphy, Erwin, & Jones, 1994; Thomas et al., 2006). In this study, the hypothetical MIC values (0.125- 2 μg/ml), which based on MIC90 values of 0.016- 1 μg/ml reported for susceptible pathogens above and the susceptibility breakpoint of 2 μg/ml rec-ommended by the AVID (Working Group for Veterinary Medicines and Diagnosis of Infections) in Germany (AVID, 1999), were used to calculate %T > MIC. Studies recommend T > MIC values of 40%– 70% for CFQ (Gu et al., 2015; Guo et al., 2015; Qiu et al., 2016; Shan, Liang, Wang, Li, & Zeng, 2014; Wang et al., 2014). In this study, % T > MIC values for two administration routes were calculated using
Vdarea determined following IV administration of CFQ. The 2.5 mg/
kg IV dose of CFQ at 10 hr intervals provided mean T > MIC values of 88% and 43%, respectively, with MIC values of ≤0.125 μg/ml and ≤1 μg/ml for bacteria. After SC administration of 2.5 mg/kg dose at 24 hr intervals, CFQ with MIC values of ≤1 μg/ml and ≤2 μg/ml for bacteria maintained mean T > MIC values of 90% and 59%, respec-tively. However, T > MIC of >80% (Toutain, del Castillo, & Bousquet- Melou, 2002) or T > 4 × MIC of 100% (Roberts et al., 2010; Smiet, Haritova, Heil, Fink- Gremmels, & Wijnberg, 2012; Zhang et al., 2014) have been recommended in critically ill patients and patients with compromised immune responses. In this study, T > MIC of >80% for bacteria, with MIC values of ≤0.125, and ≤1 μg/ml was provided by IV administration at 10 hr intervals and SC administration at 24 hr in-tervals, respectively. The T > 4 × MIC value of ≥100% is maintained by SC administration of CFQ at 24 hr intervals for bacteria, with MIC value of ≤0.125 μg/ml.
In conclusion, CFQ showed long t1/2ʎz and high bioavailability after SC administration in sheep. It accumulated in the body fol-lowing repeated SC administrations. CFQ folfol-lowing SC administra-tion provided a higher value of %T > MIC than that the IV route. CFQ might be recommended the use in repeated doses once daily to provide effective plasma concentrations in the treatment of in-fections caused by the susceptible bacteria with the MIC value of ≤1.0 μg/ml in sheep. However, in vitro and in vivo antibacterial ef-fects should be demonstrated for bacterial infections prior to use in sheep.
ACKNOWLEDGMENTS
This study was supported by The Coordination Unit of Scientific Research Projects, University of Selcuk, Turkey (project No. 15401151). The abstract form of study was presented as oral pres-entation to 2nd International Congress on Advances in Veterinary Sciences & Technics (ICAVST), October 4 - 8, 2017, Skopje, Macedonia.
CONFLIC T OF INTEREST
The authors declare no conflicts of interest.
AUTHORS’ CONTRIBUTION
All authors have read and approved the final manuscript. KU and OC contributed to conception, design, analysis, and acquisition, drafted the manuscript, critically revised the manuscript and gave final ap-proval. DDC contributed to analysis. AE contributed to conception and design.
ORCID
Orhan Corum https://orcid.org/0000-0003-3168-2510
Duygu Durna Corum https://orcid.org/0000-0003-1567-991X
Kamil Uney https://orcid.org/0000-0002-8674-4873
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How to cite this article: Corum O, Corum DD, Er A, Uney K.
Pharmacokinetics of cefquinome after single and repeated subcutaneous administrations in sheep. J vet Pharmacol
