Comparison of plasma pharmacokinetics and bioequivalence of ceftiofur sodium in cattle after a single intramuscular or subcutaneous injection

Ceftiofur sodium, a broad-spectrum cephalosporin, is active against gram-positive and gram-negative pathogens of veterinary importance. This study was designed to compare the bioequivalence of the sodium salt in cattle after a single intramuscular (i.m.) or subcutaneous dose (s.c.) of 2.2 mg ceftiofur equivalents/kg body weight. The criteria used to evaluate bioequivalence were (1) the area under the curve from time of injection to the limit of quantitation (LOQ) of the assay (AUC0-LOQ), and (2) time concentrations remained above 0.2 microg/mL (t>0.2). Twelve crossbred beef cattle were enrolled in a three-period, two-treatment crossover trial, with a minimum 2-week washout period between doses of 2.2 mg ceftiofur equivalents/kg. Blood samples were collected serially for up to 72 h post-injection. Plasma samples were then analyzed using a validated assay that measures ceftiofur, and all desfuroylceftiofur-related metabolites, by high-performance liquid chromatography (HPLC) as the stable derivative, desfuroylceftiofur acetamide. A maximum plasma concentration (Cmax) of 13.9+/-3.55 microg/mL was observed from 0. 67-2.0 h after i.m. administration, whereas a Cmax of 13.6+/-3.85 microg/mL was observed from 0.67-3.0 h after s.c. administration. The AUC0-LOQ was 108+/-35.0 microg. h/mL after i.m. dosing, compared with 105+/-29.8 microg. h/mL after s.c. dosing. The pre-established criterion for equivalence of the AUC0-LOQ for the i.m. and s.c. routes of administration was satisfied. The t>0.2 was 49.2+/-8.55 h after i.m. administration, compared with 47.0+/-9.40 h after s.c. administration. The pre-established criterion for equivalence of the t>0.2 for i.m. and s.c. administration was satisfied. The equivalence of AUC0-LOQ and t>0.2 for i.m. and s.c. administration of 2.2 mg ceftiofur equivalents (CE)/kg doses of ceftiofur sodium suggest similar therapeutic efficacy and systemic safety for the two routes of administration.     

头孢噻呋钠在猪体内的药代动力学和生物利用度研究

用微生物杯蝶法测定血清药物浓度,6头实验猪按5 mg/kg单剂量静注、肌注头孢噻呋钠(Ceftiofur Sodium),对其药代动力学和生物利用度进行了研究.试验菌为蜡样芽孢杆菌1.1687,结果平均回收率为96.52%,血清最低检测浓度为0.15 μg/ml,日内日间变异系数为2.5%～4.9%,血清浓度在0.3～0.8 μg/ml范围内呈良好线性关系(r=0.9884).药时数据经Mcpkp药代动力学计算机程序处理,猪静注、肌注头孢噻呋钠体内药物运转都符合二室开放模型,其中静注的药代动力学参数为T1/2α=2.22 h,T1/2β=14.64 h, K12=0.09/h, K21=0.078/h, Kel=0.20/h, V1=0.34 l/kg, VB =1.38 l/kg, CLB=0.07 l/kg/h,AUC=76.56 mg/l*h; 肌注药代动力学参数为Tmax=0.69 h,Cmax=12.09 μg/ml,T1/2ka=0.19 h,T1/2β=15.18 h,Kel=0.23/h,K12=0.14/h,K21=0.08/h;生物利用度为AUCi.m/AUCi.v=87.97%.     

Impact of an experimental PRRSV and Streptococcus suis coinfection on the pharmacokinetics of ceftiofur hydrochloride after intramuscular injection in pigs

This study determined the impact of porcine reproductive and respiratory syndrome virus (PRRSV) and Streptococcus suis coinfection on the pharmacokinetic (PK) profile of ceftiofur hydrochloride in pigs after intramuscular (i.m.) injection. Eighteen clinically normal crossbred gilts were assigned by weight into a challenge group (10 pigs) and control group (eight pigs). Pigs in both groups received a single i.m. injection of ceftiofur hydrochloride (Excenel RTU Sterile Suspension; Zoetis) at a 5 mg/kg BW dose. Serial blood samples were collected to characterize the plasma concentration curve. After a 10 days drug washout period, the challenge group was inoculated with 2 mL of PRRSV isolate VR‐2385 (10^5.75 50% tissue culture infective doses per mL) intranasally and 8 days later inoculated S. suis. When clinical disease was evident, the second PK assessment began in both challenge and control groups. Coinfected pigs demonstrated lower values of AUC and C_MAX, but higher values of Cl/F and Vz/F indicating drug kinetics were altered by infection. The data from this study have implications on ceftiofur treatment regimens in diseased pigs.     

肌肉注射盐酸头孢噻呋混悬注射液对猪安全性试验

头孢噻呋(ceftiofur)是第一个畜禽专用的第3代头孢菌素类抗生素,具有抗菌谱广、抗菌活性强、对胃酸和β-内酰胺酶较稳定、过敏反应少、毒性小、在动物体内残留低的特点[1].国内外已批准的制剂有注射用头孢噻呋钠和盐酸头孢噻呋注射液,用于肉牛、奶牛、马、羊、猪呼吸道病和1日龄鸡细菌性感染的防治[2].     

Pharmacokinetics of ceftiofur and metabolites after single intravenous and intramuscular administration and multiple intramuscular administrations of ceftiofur sodium to sheep

Twenty-four sheep (38.0–54.1 kg body wt) were allocated into four treatment groups and dosed with ceftiofur sodium at 1.1 mg ceftiofur free acid equivalents (CFAE)/kg or 2.2 CFAE/kg using a complete two-route (intravenous, i.v.; intramuscular, i.m.), two-period crossover design, with a two-week washout between injections. After another two-week washout period, 12 sheep were selected and dosed with ceftiofur sodium i.m. for five consecutive days at either 1.1 or 2.2 mg CFAE/kg. After all injections, blood samples were obtained serially for determination of serum concentrations of ceftiofur and metabolites. The terminal phase half-lives derived from the last 3–5 concentration-time points were 350 and 292 min (harmonic means) after i.v. doses of 1.1 and 2.2 mg/kg, respectively, and 389 and 459 min after i.m. doses of 1.1 and 2.2 mg/kg, respectively. The i.m. bioavailability of ceftiofur sodium in sheep was 100%, and the area under the curve from time 0 to the limit of quantitation ( AUC _0–LOQ) was dose-proportional from 1.1–2.2 mg CFAE/kg body wt in sheep. After 5 daily i.m. doses of ceftiofur sodium at either 1.1 or 2.2 mg CFAE/kg there was minimal accumulation of drug in serum as assessed by the observed maximum serum concentration ( C _max), and serum concentrations were dose-proportional after the multiple dosing regimen.     

Pharmacokinetics of ceftiofur and metabolites after single intravenous and intramuscular administration and multiple intramuscular administrations of ceftiofur sodium to dairy goats

Twelve (12) lactating dairy goats (46–71 kg body wt at study initiation) were divided into four treatment groups and dosed with ceftiofur sodium at 1.1 mg ceftiofur free acid equivalents (CFAE)/kg or 2.2 CFAE/kg using a complete two route (intravenous, i.v.; intramuscular, i.m.), two-period crossover design, with a 2-week washout between injections. After another 2-week washout period, the goats were dosed with ceftiofur sodium i.m. for 5 consecutive days at either 1.1 or 2.2 mg CFAE/kg. The goats from the 2.2 mg/kg multiple dose group were dried off and the i.v. kinetic study repeated. After all injections, blood samples were obtained serially for determination of combined serum concentrations of ceftiofur and metabolites. After intravenous doses of 1.1 and 2.2 mg/kg, the harmonic means of the terminal phase half-lives were 171.8 and 233 min, respectively, for lactating does. The harmonic mean of the terminal phase half-life after an i.v. dose of 2.2 mg/kg in non-lactating does was 254 min. The AUC _0–∞ was significantly less and the clearance significantly greater during lactation. After i.m. doses of 1.1 and 2.2 mg/kg, the harmonic mean terminal phase half-lives were 163 and 156 min, respectively. The i.m. bioavailability of ceftiofur sodium in goats was 100%, and the AUC _0–∞ was dose-proportional from 1.1–2.2 mg CFAE/kg body weight. After five daily i.m. doses of ceftiofur sodium at either 1.1 or 2.2 mg CFAE, there was minimal accumulation of drug in serum as assessed by C _max, and serum concentrations were dose-proportional after the multiple dosing regimen.     

Population pharmacokinetics of ceftazidime after a single intramuscular injection in wild turtles

Ceftazidime, a third‐generation cephalosporin, is important for treating opportunistic bacterial infections in turtles. Antibacterial dosage regimens are not well established for wild turtles and are often extrapolated from other reptiles or mammals. This investigation used a population pharmacokinetic approach to study ceftazidime in wild turtles presented for rehabilitation. Ceftazidime was administered to 24 wild turtles presented to the Turtle Rescue Team at North Carolina State University. A sparse blood sampling protocol was used to collect samples from 0 to 120 hr with three samples per individual after injection. Plasma samples were analyzed by high‐pressure liquid chromatography (HPLC). A nonlinear mixed‐effects model (NLME) was fitted to the data to determine typical values for population parameters. We identified a long half‐life (T½) of approximately 35 hr and volume of distribution (V_SS) of 0.26 L/kg. We concluded that this long T½ will allow for a dose of 20 mg/kg injected IM to maintain concentrations above the MIC of most wild‐type bacteria for 5 days. Because of long intervals between injections, stability of stored formulations was measured and showed that 90% strength was maintained for 120 hr when stored in the refrigerator and for 25 days when stored in the freezer.     

Pharmacodynamics and pharmacokinetics of flumequine in pigs after single intravenous and intramuscular administration

The pharmacokinetics and intramuscular (IM) bioavailability of flumequine (15 mgkg(-1)) were investigated in healthy pigs and the findings related to published minimal inhibitory concentrations (MICs) for susceptible bacteria of animal origin, and to experimentally determined MICs for susceptible strains of porcine origin. We found MICs for Escherichia coli, Salmonella spp., Pasteurella spp. and Bordetella spp. in the range 0.5 to >64 microg mL(-1) isolated from infected pigs in the Forli area of Italy; only the Pasteurella multocida strains were sensitive (MIC(90)=0.5 microg mL(-1)). After intravenous (IV) injection, flumequine was slowly distributed and eliminated (t(1/2lambda(1))1.40+/-0.16 h and t(1/2lambda(2))6.35+/-1.69 h). The distribution volume at steady state (V(dss)) was 752.59+/-84.03 mL kg(-1) and clearance (Cl(B)) was 237.19+/-17.88 mL kg(-1)h(-1). After IM administration, peak serum concentration (4.99+/-0.92 microg mL(-1)) was reached between the 2nd and the 3rd hour. The results on MIC of isolated bacteria, although only indicative, suggest that the efficacy of flumequine on Gram-negative bacteria may be impaired by the emergence of less sensitive or resistant strains.     

Pharmacokinetics of ceftiofur sodium in cats following a single intravenous and subcutaneous injection

Ceftiofur, a third‐generation cephalosporin antibiotic, is being extensively used by pet doctors in China. In the current study, the detection method was developed for ceftiofur and its metabolites, desfuroylceftiofur (DCE) and desfuroylceftiofur conjugates (DCEC), in feline plasma. Then, the pharmacokinetics studies were performed following one single intravenous and subcutaneous injection of ceftiofur sodium in cats both at 5 mg/kg body weight (BW) (calculated as pure ceftiofur). Ceftiofur, DCE, and DCEC were extracted from plasma samples, then derivatized and further quantified by high‐performance liquid chromatography. The concentrations versus time data were subjected to noncompartmental analysis to obtain the pharmacokinetics parameters. The terminal half‐life (t_1/2λz) was calculated as 11.29 ± 1.09 and 10.69 ± 1.31 hr following intravenous and subcutaneous injections, respectively. After intravenous treatment, the total body clearance (Cl) and volume of distribution at steady‐state (V_SS) were determined as 14.14 ± 1.09 ml hr^‐1 kg^‐1 and 241.71 ± 22.40 ml/kg, respectively. After subcutaneous injection, the peak concentration (C_max; 14.99 ± 2.29 μg/ml) was observed at 4.17 ± 0.41 hr, and the absorption half‐life (t_1/2ka) and absolute bioavailability (F) were calculated as 2.83 ± 0.46 hr and 82.95%±9.59%, respectively. The pharmacokinetic profiles of ceftiofur sodium and its related metabolites demonstrated their relatively slow, however, good absorption after subcutaneous administration, poor distribution, and slow elimination in cats. Based on the time of drug concentration above the minimum inhibitory concentration (MIC) (T>MIC) calculated in the current study, an intravenous or subcutaneous dose at 5 mg/kg BW of ceftiofur sodium once daily is predicted to be effective for treating feline bacteria with a MIC value of ≤4.0 μg/ml.     

Comparative plasma pharmacokinetics of ceftiofur sodium and ceftiofur crystalline‐free acid in neonatal calves

The objective of this study was to compare the plasma pharmacokinetic profile of ceftiofur crystalline‐free acid (CCFA) and ceftiofur sodium in neonatal calves between 4 and 6 days of age. In one group (n = 7), a single dose of CCFA was administered subcutaneously (SQ) at the base of the ear at a dose of 6.6 mg/kg of body weight. In a second group (n = 7), a single dose of ceftiofur sodium was administered SQ in the neck at a dose of 2.2 mg/kg of body weight. Concentrations of desfuroylceftiofur acetamide (DCA) in plasma were determined by HPLC. Median time to maximum DCA concentration was 12 h (range 12–48 h) for CCFA and 1 h (range 1–2 h) for ceftiofur sodium. Median maximum plasma DCA concentration was significantly higher for calves given ceftiofur sodium (5.62 μg/mL; range 4.10–6.91 μg/mL) than for calves given CCFA (3.23 μg/mL; range 2.15–4.13 μg/mL). AUC_0‐∞ and Vd/F were significantly greater for calves given CCFA than for calves given ceftiofur sodium. The median terminal half‐life of DCA in plasma was significantly longer for calves given CCFA (60.6 h; range 43.5–83.4 h) than for calves given ceftiofur sodium (18.1 h; range 16.7–39.7 h). Cl/F was not significantly different between groups. The duration of time median plasma DCA concentrations remained above 2.0 μg/mL was significantly longer in calves that received CCFA (84.6 h; range 48–103 h) as compared to calves that received ceftiofur sodium (21.7 h; range 12.6–33.6 h). Based on the results of this study, CCFA administered SQ at a dose of 6.6 mg/kg in neonatal calves provided plasma concentrations above the therapeutic target of 2 μg/mL for at least 3 days following a single dose. It is important to note that the use of ceftiofur‐containing products is restricted by the FDA and the use of CCFA in veal calves is strictly prohibited.     

Comparison of bioavailability of two chloramphenicol preparations in dogs after intramuscular injection.

Aqueous chloramphenicol glycinate was compared with propylene glycol solution of chloramphenicol after equivalent intramuscular doses (22 mg/kg) were given to 10 normal, healthy dogs in a crossover study. Duration and magnitude of plasma concentrations of chloramphenicol were significantly longer and higher with the glycinate than with the propylene glycol solution.     

Pharmacokinetics of ceftiofur sodium in Peekapoo dogs following a single intravenous and subcutaneous injection

The present study aimed to determine the pharmacokinetic profiles of ceftiofur (as measured by ceftiofur and its active metabolites concentrations) in a small-size dog breed, Peekapoo, following a single intravenous or subcutaneous injection of ceftiofur sodium. The study population comprised of five clinically healthy Peekapoo dogs with an average body weight (BW) of 3.4 kg. Each dog received either intravenous or subcutaneous injection, both at 5 mg/kg BW (calculated as pure ceftiofur). Plasma samples were collected at different time points after the administration. Ceftiofur and its active metabolites were extracted from plasma samples, derivatized, and further quantified by high-performance liquid chromatography. The concentrations versus time data were subjected to noncompartmental analysis to obtain the pharmacokinetic parameters. The terminal half-life (t_1/2λz) was calculated as 7.40 ± 0.79 and 7.91 ± 1.53 hr following intravenous and subcutaneous injections, respectively. After intravenous treatment, the total body clearance (Cl) and volume of distribution at steady-state (V_SS) were determined as 39.91 ± 4.04 ml hr⁻¹ kg⁻¹ and 345.71 ± 28.66 ml/kg, respectively. After subcutaneous injection, the peak concentration (C_max; 10.50 ± 0.22 μg/ml) was observed at 3.2 ± 1.1 hr, and the absorption half-life (t_1/2ka) and absolute bioavailability (F) were calculated as 0.74 ± 0.23 hr and 91.70%±7.34%, respectively. The pharmacokinetic profiles of ceftiofur and its related metabolites demonstrated their quick and excellent absorption after subcutaneous administration, in addition to poor distribution and slow elimination in Peekapoo dogs. Based on the time of concentration above minimum inhibitory concentration (T > MIC) values calculated here, an intravenous or subcutaneous dose at 5 mg/kg of ceftiofur sodium once every 12 hr is predicted to be effective for treating canine bacteria with a MIC value of ≤4.0 μg/ml.     

头孢噻呋注射液在猪体内的药动学和相对生物利用度

研究并比较了头孢噻呋注射液和速解灵注射液在猪体内药物代谢动力学特征和相对生物利用度。20头健康猪,随机均分为2组,进行单次给药剂量(5mg/kg)肌注头孢噻呋注射液(洛阳惠中)和速解灵注射液(美国辉瑞),前腔静脉采血,高效液相色谱法检测猪血浆中头孢噻呋的浓度。采用药动学软件WinNonlin 5.2.1的非房室模型分析方法,计算出药物的动力学参数。猪肌注头孢噻呋注射液和速解灵注射液后的药动学参数分别为:达峰时间(Tmax):(2.63±0.74)、(3.38±1.92)h;峰质量浓度(Cmax):(14.06±2.21)、(9.48±1.84)mg/L;消除半衰期(t1/2β):(17.65±2.07)、(17.70±2.43)h;平均滞留时间(MRT):(23.21±2.68)、(22.11±2.50)h;药时曲线下面积(AUClast):(240.81±47.73)、(182.51±36.12)μg·h·mL-1。参数Cmax、AUClast统计差异极显著(P<0.01),头孢噻呋注射液较速解灵注射液吸收迅速、完全,达峰时间短,峰浓度显著升高;参数Tmax、t1/2β、MRT统计差异不显著(P>0.05),头孢噻呋注射液的相对生物利用度为132%,高于速解灵注射液。结果表明头孢噻呋注射液肌注后吸收迅速、完全,达峰时间短,峰浓度高,生物利用度高。     

Preparation of a newly formulated long‐acting ceftiofur hydrochloride suspension and evaluation of its pharmacokinetics in pigs

Tang, S., Xiao, J., Guo, G., He, J., Hao, Z., Xiao, X. Preparation of a newly formulated long‐acting ceftiofur hydrochloride suspension and evaluation of its pharmacokinetics in pigs. J. vet. Pharmacol. Therap. 33 , 238–245. A new long‐acting ceftiofur hydrochloride preparation was formulated and its physical properties, stability, and pharmacokinetics were investigated in this study. The prepared ceftiofur hydrochloride suspension demonstrated a milk white consistency, was easy to re‐disperse and was stable in light, heat and humidity stability tests. Its other physical properties such as flowability, syringeability, settling volume ratio, particle size and distribution were perfectly consistent with the standard of Ministry of Agriculture of the People’s Republic of China. After intramuscular administration of a single dose in swine (5 mg/kg B.W.), the drug concentration‐time data in plasma were well fitted using the two‐compartment open model. Compared with the ceftiofur hydrochloride preparation (EXCENEL^®) from Pfizer, the peak concentration (C_max) in plasma was decreased by 2.34 times (P < 0.001), the half‐life of elimination phase (T_1/2β) was 1.65 times longer (P < 0.001), and the therapeutic level of ceftiofur above the lowest effective plasma concentration of 0.2 μg/mL (T > 0.2) was prolonged from 87.20 h to 135.36 h (P < 0.001). The ceftiofur hydrochloride suspension prepared in this study provides therapeutically effective plasma concentrations for a longer duration, which make it more effective and more convenient to use in the treatment of respiratory diseases that require the maintenance of therapeutic plasma concentrations over a long duration.     

Preparation and pharmacokinetics of ceftiofur sodium liposomes in cows

Liu, S., Guo, D., Guo, Y., Zhou, W. Preparation and pharmacokinetics of ceftiofur sodium liposomes in cows. J. vet. Pharmacol. Therap. 34 , 35–41. The objective of this study was to prepare ceftiofur sodium liposomes and assess their physical properties, stability, antibacterial effects, and pharmacokinetics. These liposomes appeared as a milky, light yellow suspension with encapsulation efficiency at 57.2 ± 1.17%, and there were no significant changes in all estimated indexes at 4 °C for 90 days. The minimum inhibitory concentrations of liposomes were all 1/4th that of ceftiofur sodium against Streptococcus suis, Staphylococcus aureus, Escherichia coli, and Salmonella enteritidis. Six healthy, adult cows in two treatment groups were dosed intravenously with ceftiofur sodium liposomes and ceftiofur sodium, serial blood samples collected, and plasma concentrations determined by high performance liquid chromatography. Intravenous plasma concentration profiles of liposomes best fit a two‐compartment model and the elimination half‐life was 2.11 times that of ceftiofur sodium. Thus, this liposome preparation provided therapeutically effective plasma concentrations for a longer duration than with the drug alone, making it more effective and convenient for use in treating bovine mastitis that requires long duration maintenance of therapeutic plasma concentrations.     

Pharmacokinetics of amikacin in pony foals after a single intramuscular injection

Six healthy pony foals, from 2 to 11 days of age, were given a single IM injection of amikacin sulfate (250 mg/ml) at a dosage rate of 7 mg/kg of body weight. Serum amikacin concentrations were measured serially over a 24-hour period. The mean peak serum concentration was 14.7 micrograms/ml at 0.5 hour. The elimination rate constant for amikacin was 0.24/hour, the elimination half-life was 3.0 hours, and the apparent volume of distribution was 0.58 L/kg.