J. vet. Pharmacol. Therap. 39, 40--44. doi: 10.1111/jvp.12239.
Pharmacokinetics of cefuroxime after intravenous, intramuscular, and subcutaneous administration to dogs G. A. ALBARELLOS* L. MONTOYA* P. M. LORENZINI*
Albarellos, G. A., Montoya, L., Lorenzini, P. M., Passini, S. M., Lupi, M. P., Landoni, M. F. Pharmacokinetics of cefuroxime after intravenous, intramuscular, and subcutaneous administration to dogs. J. vet. Pharmacol. Therap. 39, 40–44.
S. M. PASSINI* M. P. LUPI* & M. F. LANDONI † *Catedra de Farmacologıa, Facultad de Ciencias Veterinarias, Universidad de Buenos Aires, Buenos Aires, Argentina; † Catedra de Farmacologıa, Facultad de Ciencias Veterinarias, Universidad Nacional de La Plata, Buenos Aires, Argentina
Cefuroxime pharmacokinetic profile was investigated in 6 Beagle dogs after single intravenous, intramuscular, and subcutaneous administration at a dosage of 20 mg/kg. Blood samples were withdrawn at predetermined times over a 12-h period. Cefuroxime plasma concentrations were determined by HPLC. Data were analyzed by compartmental analysis. Peak plasma concentration (Cmax), time-to-peak plasma concentration (Tmax), and bioavailability for the intramuscular and subcutaneous administration were (mean SD) 22.99 7.87 lg/mL, 0.43 0.20 h, and 79.70 14.43% and 15.37 3.07 lg/ mL, 0.99 0.10 h, and 77.22 21.41%, respectively. Elimination half-lives and mean residence time for the intravenous, intramuscular, and subcutaneous administration were 1.12 0.19 h and 1.49 0.21 h; 1.13 0.13 and 1.79 0.24 h; and 1.04 0.23 h and 2.21 0.23 h, respectively. Significant differences were found between routes for Ka, MAT, Cmax, Tmax, t½(a), and MRT. T > MIC = 50%, considering a MIC of 1 lg/mL, was 11 h for intravenous and intramuscular administration and 12 h for the subcutaneous route. When a MIC of 4 lg/mL is considered, T > MIC = 50% for intramuscular and subcutaneous administration was estimated in 8 h. (Paper received 15 December 2014; accepted for publication 22 April 2015) Gabriela A. Albarellos, Catedra de Farmacologıa, Facultad de Ciencias Veterinarias, Universidad de Buenos Aires, Chorroarın 280 (1427), Buenos Aires, Argentina. E-mail: [email protected]
INTRODUCTION Cefuroxime is a second-generation cephalosporin with a broader spectrum of activity. It is active against many grampositive (e.g., staphylococci and streptococci), gram-negative (Enterobacteriaceae), and some anaerobes bacteria (Prescott, 2013). Although there is no information on cefuroxime susceptibility of bacteria isolated from animals, reports from human medicine indicate that cefuroxime minimum inhibitory concentration (MIC) could be as low as 0.015 lg/mL (MIC90 for S. pyogenes) (Dohar et al., 2004). However, it is usually higher for other bacteria (MIC90 for staphylococci: 1 lg/mL and MIC90 for E. coli: 4 lg/mL) (von Eiff et al., 2005; Lerma et al., 2008). Susceptibility break point for human isolates is ≤0.5 lg/mL for Streptococcus pneumoniae and ≤8 lg/mL for Enterobacteriaceae (CLSI, 2014). Efficacy of cephalosporins is related to the time that plasma concentrations exceed the MIC, and a T > MIC of 40–60% of the dosing interval is the best efficacy predictor for assuring
40
therapeutic success (Craig, 1998; Turnidge, 1998; Toutain et al., 2002; McKellar et al., 2004). Cefuroxime pharmacokinetics has been studied in humans (Foord, 1976; Bundtzen et al., 1981), laboratory animals (Ryan et al., 1976; Ruiz-Carretero et al., 2000; Zhao et al., 2012a), goats (Abo El-Sooud et al., 2000; Prawez et al., 2001, 2004), buffalo calves (Chaudhary et al., 1999), calves (Soback et al., 1989), and dogs (Zhao et al., 2012b). After i.v. administration, cefuroxime is rapidly and widely distributed into the extravascular fluid, with a fast elimination by renal mechanisms (glomerular filtration and tubular secretion). It has a very short elimination half-life (1 h) (Soback et al., 1989; Abo El-Sooud et al., 2000; Ruiz-Carretero et al., 2000; Zhao et al., 2012b), and therefore, it requires frequent administrations. In human medicine, cefuroxime is used for the treatment of lower respiratory tract infections, urinary, and other soft tissue infections caused by susceptible bacteria. Cefuroxime could be a useful tool for the treatment of similar infections in companion animals’ medicine.
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Cefuroxime pharmacokinetics in dogs 41
Extravascular parenteral administration routes, such as intramuscular (i.m.) or subcutaneous (s.c.), have in small animal practice some advantages compared to intravascular routes. They are easier to administer, enabling ambulatory treatment and, for some antibiotics, could extend plasma concentrations allowing longer dosage intervals. To authors’ knowledge, there are no pharmacokinetic studies on cefuroxime after intramuscular or subcutaneous administration in dogs; therefore, the aim of this study was to describe cefuroxime pharmacokinetic after i.v., i.m., and s.c. administration in this species.
was separated by centrifugation (15 min at 3500 g) and stored at 20 °C until analysis. Blood sampling schedule was the same on the three phases of the study. Cefuroxime determination
Experimental animals were six adult Beagle dogs, 4 females, and 2 males, weighing 12.50 1.38 kg. All dogs were healthy as determined by clinical examination, complete blood and serum biochemical analysis and urinalysis. Animals were housed in the UBA Faculty of Veterinary Medicine facilities and allowed to acclimatize for 2 months before the experiment. Access to standard commercial dry food (Purina ProPlanâ, Nestle Argentina S.A., Buenos Aires, Argentina) and water was ad libitum. All animal procedures were approved by the Institutional Animal Care and Use Committee, School of Veterinary, University of Buenos Aires, Argentina.
Plasma cefuroxime concentrations were determined by HPLC according to the technique described by Al-Said et al. (2000). Briefly, 0.1 ml of 12.5% trichloroacetic acid was added to 0.4 ml of sample containing 20 lL of a 1000 lg/mL cephalexin solution (internal standard). The contents of the tube were mixed and then centrifuged at 3500 g for 10 min. A 50-lL aliquot was injected onto an HPLC system comprising an isocratic solvent delivery system (Thermo Scientific Dionex UltiMate, HPG-3200SD, Sunnyvale, CA, USA) and a variable UV/Vis detector (UV Visible MultiLength 151, Gilson Inc., WI, USA). The chromatograph consisted of a 125 9 4 mm, 5 lm LiChroCARTâ (Merck KGaA, Darmstadt, Germany) RP C18 column. The mobile phase was acetonitrile and 0.05 M potassium dihydrogen phosphate buffer (pH 4) (10:90). The flow rate was 2.0 mL/min and detection wavelength 280 nm. Cefuroxime standard curve was linear between 0.4 and 50 lg/mL, and the low limit of quantification (LLOQ) was 0.4 lg/mL. Intraday and interday LLOQ coefficient of variation were 1.6% and 2.3%, respectively.
Dosage forms
Pharmacokinetic analysis
An aqueous 10% cefuroxime sodium salt solution (Cefuroxâ 1.5 g; GlaxoSmithKline, Victoria, Buenos Aires, Argentina) was used. The formulation was prepared according to manufacturer’s instructions. Cefuroxime was administered i.v., i.m., and s.c. at a dosage of 20 mg/mL.
Individual cefuroxime plasma concentration vs. time curves was analyzed with a computer software (Phoenixâ WinNonlinâ 6.3, 2005–2012, Certara, L.P., Princeton, NJ, USA). Initial estimates were determined using the residual method (Gibaldi & Perrier, 1982) and refitted by nonlinear regression. The number of exponents needed for i.v., i.m., and s.c. administration data was determined by applying the Schwartz (Schwartz, 1978) and Akaike criterions (Yamaoka et al., 1978), and the residual distribution around the estimated concentrations. Most pharmacokinetic parameters were calculated using classic equations associated with compartmental analysis (distribution half-life, t½(d); elimination half-life, t½; absorption halflife, t½(a); microrate constants; intercepts; and rate constants) and noncompartmental methods (total body clearance, ClB; area under the curve from time 0 to time, AUC(0–t); area under the curve from time 0 to infinity, AUC(0-∞); mean residence time (MRT); mean absorption time (MAT); volume of distribution of the area during the elimination phase, Varea; volume of distribution at the steady-state, V(d(ss); maximum plasma concentration, Cmax; time of maximum plasma concentration, Tmax) (Gibaldi & Perrier, 1982). Cefuroxime bioavailability for extravascular administrations (F) was calculated by relating intramuscular and subcutaneous AUC to the intravenous one:
MATERIALS AND METHODS Experimental animals
Experimental design A three-period, three-treatment crossover design was used. As a result, each animal received cefuroxime i.v., i.m., and s.c. in a randomized sequence. For i.v. administration, cefuroxime was given via bolus (over a 2 min period) through a catheter placed in the left cephalic vein. For the i.m. route, the dose was administered in the dorsal lumbar muscles, and for the s.c. administration, the dose was injected under the lateral ribcage skin. A 2-week washout period elapsed between each phase. Blood sampling Samples (2.5 mL) were collected through a catheter placed in the right cephalic vein prior antibiotic administration and at 5, 10, 20, 30, 45 min and at 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 h. Samples were taken with heparinized syringes, placed into tubes, mixed, and kept on ice until plasma separation. Plasma
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42 G. A. Albarellos et al.
Fð%Þ ¼ ðAUCEV =AUCiv Þ 100;
Statistical analysis Pharmacokinetic parameters are expressed as mean standard deviation. Main estimated pharmacokinetic parameters were statistically compared for the different administration routes, applying an ANOVA test (AUC(0–t), AUC(0–∞), t½, MRT) or a t test (ka, t½(a), MAT, Tmax, Cmax, F) (GraphPad Prismâ, GraphPad Software, version 5.00, 2007, San Diego, CA, USA). Results were considered significant when P < 0.05.
IV IM SC
Plasma concentration ( g/mL)
where AUCEV and AUCiv are the areas under the concentration– time curves for the extravascular routes (i.m. or s.c.) and the i.v. administration, respectively.
100
10
MIC = 4 g/mL
MIC = 1 g/mL
1
0.1
PK/PD integration Time above the minimum inhibitory concentration (T > MIC) for the three studied administration routes was estimated by visual approximation from the plasma concentration vs. time curve. The MIC value applied was based on human reports (staphylococci MIC90 = 1 lg/mL; E. Coli MIC90 = 4 lg/mL) (von Eiff et al., 2005; Lerma et al., 2008).
RESULTS No adverse effects were recorded by physical examination in any of the dogs during or after cefuroxime administration. The applied blood sample withdrawal schedules after i.v., i.m., and s.c. cefuroxime administration allowed a proper description of the plasma concentrations vs. time curves as shown in Fig. 1. Estimated pharmacokinetic parameters are shown in Table 1. Cefuroxime plasma concentrations after intravascular and extravascular administrations were best fitted to a bicompartmental (i.v.) and a monocompartmental (with first-order input) model (i.m. and s.c.). After i.v. administration, cefuroxime showed a rapid distribution, reflected by the rate constant of the process (k1 10.73 8.25 h1) and its short half-life (T½(d) 0.10 0.06 h). However, the extent of distribution was moderate, with a volume of distribution (V(d(ss))) of 0.49 0.03 L/kg. After i.v. administration, cefuroxime was rapidly eliminated from the body as reflected by the high body clearance (ClB) (0.34 0.04 L/hkg), short elimination half-life (T½) (1.12 0.19 h), and short mean residence time (MRT) (1.49 0.21 h). Cefuroxime blood concentrations remained above the LLOQ for 4 h in only three dogs. Cefuroxime absorption was much slower after s.c. than after i.m. administration, and this was evident (P < 0.05) when parameters associated with this process (ka, T½(a), Tmax, and Cmax) were compared. However, extent of absorption was the same for both extravascular routes, with a bioavailability of
0
1
2
3
4
5
6
Time (h)
Fig. 1. Mean and SD cefuroxime plasma concentration–time profile after intravenous (i.v.) (■), intramuscular (i.m.) (▲), and subcutaneous (s.c.) (●) administration to dogs at a dosage of 20 mg/kg (n = 6).
79.70 14.43% and 77.22 21.41% for the i.m. and s.c. administration, respectively. Cefuroxime elimination after i.m. and s.c. administration was rather similar, with identical body clearance (0.34 0.04 L/hkg) and similar elimination half-life (1.13 0.13 h, i.m.; 1.04 0.23 h, s.c.). However, significant differences were found when MRT values were compared. As body clearances were identical for the three routes, observed MRT differences should be consequence of an absorption delay after extravascular administrations. Cefuroxime blood concentration was above 0.40 lg/mL (LLOQ) for 6 h after i.m. (5/6 dogs) and s.c. (6/6 dogs) administration. Cefuroxime plasma concentrations above the MIC are shown in Fig. 1. After i.m. and s.c. administration, T > MIC for more susceptible bacteria (MIC ≤1 lg/mL) was 5.5–6 h, while for less susceptible micro-organisms (MIC ≤ 4 lg/mL), this time was 3.5–4 h.
DISCUSSION Cefuroxime could be a good option to treat susceptible bacteria causing infections in dogs. However, the lack of pharmacokinetic information makes impossible the design of a rational administration schedule. The results obtained on this study would be useful to optimize cefuroxime parenteral use in dogs. Observed cefuroxime pharmacokinetic profile after i.v. administration was the expected for a beta-lactam and similar to that reported for dogs, goats, calves, and buffalo calves (Soback et al., 1989; Chaudhary et al., 1999; Abo El-Sooud
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Cefuroxime pharmacokinetics in dogs 43 Table 1. Mean (SD) pharmacokinetic parameters of cefuroxime after intravenous, intramuscular, and subcutaneous administration to dogs at a dosage of 20 mg/kg
Pharmacokinetic Parameter C1 (lg/mL) C2 (lg/mL) Cp(0) (lg/mL) k1 (h1) k2 (h1) AUC(0–t) (lgh/mL) AUC(0–∞) (lgh/mL) K12 (h1) K21 (h1) K12/k21 T½(d) (h) Varea (L/kg) V(d(ss)) (L/kg) ka (h1) T½(a) (h) MAT (h) Tmax (h) Cmax (lg/mL) ClB (L/hkg) T½ (h) MRT (h) F (%)
Intravenous administration (mean SD)
Intramuscular administration (mean SD)
Subcutaneous administration (mean SD)
– – – – – 45.93 8.50
– – – – – 43.69 8.33
47.56 8.17*
45.52 9.01*
– – – – – – 8.43 0.13 0.31 0.43 22.99 0.34 1.13 1.79 79.70
– – – – – – 1.47 0.50 0.72 0.99 15.37 0.34 1.04 2.21 77.22
38.15 34.94 73.09 10.73 0.63 52.29
22.87 4.26 23.62 8.25 0.11 6.69
60.13 6.91 4.95 5.16 0.81 0.10 0.53 0.49 – – – – – 0.34 1.12 1.49 –
5.45 2.68 0.54 0.06 0.04 0.03
0.04 0.19 0.21
6.39† 0.09† 0.37† 0.20† 7.87† 0.04‡ 0.13 0.24† 14.43
0.38† 0.14† 0.32† 0.10† 3.07† 0.04‡ 0.23 0.23§ 21.41
*Significantly different (P < 0.05) i.v. vs i.m. and s.c. Significantly different (P < 0.05) i.m. vs s.c. ‡ ClB corrected by F. § Significantly different (P < 0.05) i.v. vs s.c. C1, C2, y-axis intercept terms; Cp(0), plasma concentration at 0 time; k1, distribution rate constant; k2, elimination rate constant; AUC(0–t), area under the plasma concentration vs time curve from 0 to time; AUC(0–∞), area under the plasma concentration vs time curve from 0 to infinite; K12, rate constant for passage from central to peripheral compartment; K21, rate constant for passage from peripheral to central compartment; t½(d), distribution half-life; Varea, volume of distribution of the elimination phase; V(d(ss)), volume of distribution at steady-state; Ka, absorption rate constant; t½(a), absorption half-life; MAT, mean absorption time; Tmax, time of maximum concentration; Cmax, maximum concentration; ClB, body clearance; t½, elimination half-life; MRT, mean residence time; F, bioavailability. †
et al., 2000; Zhao et al., 2012b) characterized by a fast distribution into the extracellular fluid and a relatively rapid renal excretion. The distribution process was rapid but, moderate in its extension (high rate constant, short half-life, and moderate volume of distribution). These pharmacokinetic parameters resulted rather similar to those reported for buffalo calves (Chaudhary et al., 1999), goats (Abo El-Sooud et al., 2000), and dogs (Zhao et al., 2012b). Also, pharmacokinetic parameters evaluating elimination process (high clearance, short halflife, and MRT) were very similar in the other studied species. Zhao et al. (2012b) studied cefuroxime disposition in dogs at © 2015 John Wiley & Sons Ltd
three intravenous doses (20, 40, and 80 mg/kg) demonstrating a linear pharmacokinetic. They report values of ClB of 0.31 L/hkg, t½ of 1.50 h, and MRT of 1.86 h, for the 20 mg/kg dosage. These values are slightly different than those found in the present study. Cefuroxime elimination lasted longer in the study of Zhao et al. (2012b); this difference is modest and could be explained by the more sensitive analytical method (triple-quadrupole tandem mass spectrometer) used by these authors. Cefuroxime ClB (0.34 L/hkg) was higher than glomerular filtration rate in dogs (0.24 L/hkg) (Baggot, 2001), indicating that other mechanisms (e.g., renal tubular secretion) are implicated in cefuroxime elimination as reported for humans and other species (Foord, 1976; Soback et al., 1989; Tsuji, 2006). Moderated pain was observed after i.m. administration, although no reaction at the injection site (intramuscular or subcutaneous) was clinically observed in any of the dogs. After i.m. administration, cefuroxime absorption was faster and Cmax higher than after s.c. administration. Moreover, after s.c. administration, cefuroxime remained in the plasma longer than after i.m. administration. These findings could be explained through the ‘flip-flop’ phenomenon, where terminal T½ is reflecting the ka rather than the k. This pharmacokinetic phenomenon would have clinical implications as it would prolong dosage intervals. The most common cause for retardation of drugs absorption, mainly after s.c. administration, is a local tissue reaction (irritation and inflammation) (Py€ or€ al€ a et al., 1994). In fact, for sodium cefuroxime a mild irritation, after subcutaneous administration to dogs, has been reported (Glaxo Laboratories, 1986). Cefuroxime bioavailability after both extravascular administration routes was equally high (i.m., 79.70% and s.c., 77.22%) without significant differences between them. The relatively longer permanence of cefuroxime in plasma when administered extravascularly (especially subcutaneously) could bring a bit more desirable plasma concentration profile in dogs than after intravenous administration. For beta-lactams, a T > MIC 50% of the dose interval has been established as optimal for bactericidal action. At the dose used in this study, a dose interval of 11 h (i.v., i.m.) or 12 h (s.c.) would be effective for treating bacteria with a MIC value of ≤1 lg/mL. However, for less susceptible bacteria (e.g., MIC ≤ 4 lg/mL), the dose interval should be shorter (8 h) (i.m., s.c.). More pharmacokinetic and pharmacodynamic studies are necessary to support the present results. Furthermore, clinical controlled trials are mandatory to establish proper cefuroxime dosing schedules in dogs.
ACKNOWLEDGMENTS The authors wish to thank to the personnel of Caniles, FCV, and UBA for the technical assistance with the dogs employed
44 G. A. Albarellos et al.
in this study. This work was supported by a Research Project UBACyT (Grant Numbers 20020100100745, 2011–2014 and 20020130100400, 2014–2017) of Secretarıa de Ciencia y Tecnica, Universidad de Buenos Aires, Argentina.
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veterinary medicine. Journal of Veterinary Pharmacology and Therapeutics, 27, 503–514. Prawez, S., Singh, M.K. & Jayachandran, C. (2001) Disposition kinetics, distribution and dosage regimen of cefuroxime in lactating goats after intramuscular administration. Indian Journal of Animal Research, 35, 108–111. Prawez, S., Jayachandran, C., Quasim, A. & Singh, M.K. (2004) Pharmacokinetics, distribution and dosage regimen of cefuroxime in lactating goats after intravenous administration. Indian Journal of Animal Research, 38, 107–111. Prescott, J.F. (2013) Beta-lactam antibiotics: cephalosporins. In Antimicrobial Therapy in Veterinary Medicine, 5th edn. Eds Giguere, S., Prescott, J.F. & Dowling, P.M., pp. 163–164. Wiley Blackwell, Ames, IA. Py€ or€ al€ a, S., Manner, E., Kesti, E. & Sandholm, M. (1994) Local tissue damage in cows after intramuscular injections of eight antimicrobial agents. Acta Veterinaria Scandinavia, 35, 107–110. Ruiz-Carretero, P., Nacher, A., Merino-Sanjuan, M. & Casabo, V.G. (2000) Pharmacokinetics and absolute bioavailability of oral cefuroxime axetil in the rat. International Journal of Pharmaceutics, 202, 89–96. Ryan, D.M., O0 Callaghan, C.H. & Muggleton, P.W. (1976) Cefuroxime, a new cephalosporin antibiotic activity in vivo. Antimicrobial Agents and Chemotherapy, 9, 520–525. Schwartz, G. (1978) Estimating the dimension of a model. Annals of Statistics, 6, 461–464. Soback, S., Ziv, G. & Kokue, E.I. (1989) Probenecid effect on cefuroxime pharmacokinetics in calves. Journal of Veterinary Pharmacology and Therapeutic, 12, 87–93. Toutain, P.L., Del Castillo, J.R.E. & Bousquet-Melou, A. (2002) The pharmacokinetic-pharmacodynamic approach to a rational dosage regimen for antibiotics. Research in Veterinary Science, 73, 105–114. Turnidge, J.D. (1998) The pharmacodynamics of ß-lactams. Clinical Infectious Diseases, 27, 10–22. Tsuji, A. (2006) Impact of transporter-mediated drug absorption, distribution, elimination and drug interactions in antimicrobial chemotherapy. Journal of Infection and Chemotherapy, 12, 241–250. von Eiff, C., Friedrich, A.W., Becker, K. & Peters, G. (2005) Comparative in vitro activity of ceftobiprole against staphylococci displaying normal and small-colony variant phenotypes. Antimicrobial Agents and Chemotherapy, 49, 4372–4374. Yamaoka, K., Nakagawa, T. & Uno, T. (1978) Application of Akaike0 s information criterion (AIC) in the evaluation of linear pharmacokinetic equations. Journal of Pharmacokinetics and Biopharmaceutics, 6, 165–175. Zhao, l., Yin, R., Wei, B., Li, Q., Jiang, Z., Chen, X. & Bi, K. (2012a) Comparative pharmacokinetics of cefuroxime lysine after single intravenous, intraperitoneal, and intramuscular administration to rats. Acta Pharmacologica Sinica, 33, 1348–1352. Zhao, L., Li, Q., Li, X., Yin, R., Chen, X., Geng, L. & Bi, K. (2012b) Bioequivalence and population pharmacokinetic modelling of two forms of antibiotic, cefuroxime lysine and cefuroxime sodium, after intravenous infusion in Beagle dogs. Journal of Biomedicine and Biotechnology, 2012, 9, Article ID 507294.
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Pharmacokinetics of cefuroxime after intravenous, intramuscular, and subcutaneous administration to dogs G. A. ALBARELLOS* L. MONTOYA* P. M. LORENZINI*
Albarellos, G. A., Montoya, L., Lorenzini, P. M., Passini, S. M., Lupi, M. P., Landoni, M. F. Pharmacokinetics of cefuroxime after intravenous, intramuscular, and subcutaneous administration to dogs. J. vet. Pharmacol. Therap. 39, 40–44.
S. M. PASSINI* M. P. LUPI* & M. F. LANDONI † *Catedra de Farmacologıa, Facultad de Ciencias Veterinarias, Universidad de Buenos Aires, Buenos Aires, Argentina; † Catedra de Farmacologıa, Facultad de Ciencias Veterinarias, Universidad Nacional de La Plata, Buenos Aires, Argentina
Cefuroxime pharmacokinetic profile was investigated in 6 Beagle dogs after single intravenous, intramuscular, and subcutaneous administration at a dosage of 20 mg/kg. Blood samples were withdrawn at predetermined times over a 12-h period. Cefuroxime plasma concentrations were determined by HPLC. Data were analyzed by compartmental analysis. Peak plasma concentration (Cmax), time-to-peak plasma concentration (Tmax), and bioavailability for the intramuscular and subcutaneous administration were (mean SD) 22.99 7.87 lg/mL, 0.43 0.20 h, and 79.70 14.43% and 15.37 3.07 lg/ mL, 0.99 0.10 h, and 77.22 21.41%, respectively. Elimination half-lives and mean residence time for the intravenous, intramuscular, and subcutaneous administration were 1.12 0.19 h and 1.49 0.21 h; 1.13 0.13 and 1.79 0.24 h; and 1.04 0.23 h and 2.21 0.23 h, respectively. Significant differences were found between routes for Ka, MAT, Cmax, Tmax, t½(a), and MRT. T > MIC = 50%, considering a MIC of 1 lg/mL, was 11 h for intravenous and intramuscular administration and 12 h for the subcutaneous route. When a MIC of 4 lg/mL is considered, T > MIC = 50% for intramuscular and subcutaneous administration was estimated in 8 h. (Paper received 15 December 2014; accepted for publication 22 April 2015) Gabriela A. Albarellos, Catedra de Farmacologıa, Facultad de Ciencias Veterinarias, Universidad de Buenos Aires, Chorroarın 280 (1427), Buenos Aires, Argentina. E-mail: [email protected]
INTRODUCTION Cefuroxime is a second-generation cephalosporin with a broader spectrum of activity. It is active against many grampositive (e.g., staphylococci and streptococci), gram-negative (Enterobacteriaceae), and some anaerobes bacteria (Prescott, 2013). Although there is no information on cefuroxime susceptibility of bacteria isolated from animals, reports from human medicine indicate that cefuroxime minimum inhibitory concentration (MIC) could be as low as 0.015 lg/mL (MIC90 for S. pyogenes) (Dohar et al., 2004). However, it is usually higher for other bacteria (MIC90 for staphylococci: 1 lg/mL and MIC90 for E. coli: 4 lg/mL) (von Eiff et al., 2005; Lerma et al., 2008). Susceptibility break point for human isolates is ≤0.5 lg/mL for Streptococcus pneumoniae and ≤8 lg/mL for Enterobacteriaceae (CLSI, 2014). Efficacy of cephalosporins is related to the time that plasma concentrations exceed the MIC, and a T > MIC of 40–60% of the dosing interval is the best efficacy predictor for assuring
40
therapeutic success (Craig, 1998; Turnidge, 1998; Toutain et al., 2002; McKellar et al., 2004). Cefuroxime pharmacokinetics has been studied in humans (Foord, 1976; Bundtzen et al., 1981), laboratory animals (Ryan et al., 1976; Ruiz-Carretero et al., 2000; Zhao et al., 2012a), goats (Abo El-Sooud et al., 2000; Prawez et al., 2001, 2004), buffalo calves (Chaudhary et al., 1999), calves (Soback et al., 1989), and dogs (Zhao et al., 2012b). After i.v. administration, cefuroxime is rapidly and widely distributed into the extravascular fluid, with a fast elimination by renal mechanisms (glomerular filtration and tubular secretion). It has a very short elimination half-life (1 h) (Soback et al., 1989; Abo El-Sooud et al., 2000; Ruiz-Carretero et al., 2000; Zhao et al., 2012b), and therefore, it requires frequent administrations. In human medicine, cefuroxime is used for the treatment of lower respiratory tract infections, urinary, and other soft tissue infections caused by susceptible bacteria. Cefuroxime could be a useful tool for the treatment of similar infections in companion animals’ medicine.
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Cefuroxime pharmacokinetics in dogs 41
Extravascular parenteral administration routes, such as intramuscular (i.m.) or subcutaneous (s.c.), have in small animal practice some advantages compared to intravascular routes. They are easier to administer, enabling ambulatory treatment and, for some antibiotics, could extend plasma concentrations allowing longer dosage intervals. To authors’ knowledge, there are no pharmacokinetic studies on cefuroxime after intramuscular or subcutaneous administration in dogs; therefore, the aim of this study was to describe cefuroxime pharmacokinetic after i.v., i.m., and s.c. administration in this species.
was separated by centrifugation (15 min at 3500 g) and stored at 20 °C until analysis. Blood sampling schedule was the same on the three phases of the study. Cefuroxime determination
Experimental animals were six adult Beagle dogs, 4 females, and 2 males, weighing 12.50 1.38 kg. All dogs were healthy as determined by clinical examination, complete blood and serum biochemical analysis and urinalysis. Animals were housed in the UBA Faculty of Veterinary Medicine facilities and allowed to acclimatize for 2 months before the experiment. Access to standard commercial dry food (Purina ProPlanâ, Nestle Argentina S.A., Buenos Aires, Argentina) and water was ad libitum. All animal procedures were approved by the Institutional Animal Care and Use Committee, School of Veterinary, University of Buenos Aires, Argentina.
Plasma cefuroxime concentrations were determined by HPLC according to the technique described by Al-Said et al. (2000). Briefly, 0.1 ml of 12.5% trichloroacetic acid was added to 0.4 ml of sample containing 20 lL of a 1000 lg/mL cephalexin solution (internal standard). The contents of the tube were mixed and then centrifuged at 3500 g for 10 min. A 50-lL aliquot was injected onto an HPLC system comprising an isocratic solvent delivery system (Thermo Scientific Dionex UltiMate, HPG-3200SD, Sunnyvale, CA, USA) and a variable UV/Vis detector (UV Visible MultiLength 151, Gilson Inc., WI, USA). The chromatograph consisted of a 125 9 4 mm, 5 lm LiChroCARTâ (Merck KGaA, Darmstadt, Germany) RP C18 column. The mobile phase was acetonitrile and 0.05 M potassium dihydrogen phosphate buffer (pH 4) (10:90). The flow rate was 2.0 mL/min and detection wavelength 280 nm. Cefuroxime standard curve was linear between 0.4 and 50 lg/mL, and the low limit of quantification (LLOQ) was 0.4 lg/mL. Intraday and interday LLOQ coefficient of variation were 1.6% and 2.3%, respectively.
Dosage forms
Pharmacokinetic analysis
An aqueous 10% cefuroxime sodium salt solution (Cefuroxâ 1.5 g; GlaxoSmithKline, Victoria, Buenos Aires, Argentina) was used. The formulation was prepared according to manufacturer’s instructions. Cefuroxime was administered i.v., i.m., and s.c. at a dosage of 20 mg/mL.
Individual cefuroxime plasma concentration vs. time curves was analyzed with a computer software (Phoenixâ WinNonlinâ 6.3, 2005–2012, Certara, L.P., Princeton, NJ, USA). Initial estimates were determined using the residual method (Gibaldi & Perrier, 1982) and refitted by nonlinear regression. The number of exponents needed for i.v., i.m., and s.c. administration data was determined by applying the Schwartz (Schwartz, 1978) and Akaike criterions (Yamaoka et al., 1978), and the residual distribution around the estimated concentrations. Most pharmacokinetic parameters were calculated using classic equations associated with compartmental analysis (distribution half-life, t½(d); elimination half-life, t½; absorption halflife, t½(a); microrate constants; intercepts; and rate constants) and noncompartmental methods (total body clearance, ClB; area under the curve from time 0 to time, AUC(0–t); area under the curve from time 0 to infinity, AUC(0-∞); mean residence time (MRT); mean absorption time (MAT); volume of distribution of the area during the elimination phase, Varea; volume of distribution at the steady-state, V(d(ss); maximum plasma concentration, Cmax; time of maximum plasma concentration, Tmax) (Gibaldi & Perrier, 1982). Cefuroxime bioavailability for extravascular administrations (F) was calculated by relating intramuscular and subcutaneous AUC to the intravenous one:
MATERIALS AND METHODS Experimental animals
Experimental design A three-period, three-treatment crossover design was used. As a result, each animal received cefuroxime i.v., i.m., and s.c. in a randomized sequence. For i.v. administration, cefuroxime was given via bolus (over a 2 min period) through a catheter placed in the left cephalic vein. For the i.m. route, the dose was administered in the dorsal lumbar muscles, and for the s.c. administration, the dose was injected under the lateral ribcage skin. A 2-week washout period elapsed between each phase. Blood sampling Samples (2.5 mL) were collected through a catheter placed in the right cephalic vein prior antibiotic administration and at 5, 10, 20, 30, 45 min and at 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 h. Samples were taken with heparinized syringes, placed into tubes, mixed, and kept on ice until plasma separation. Plasma
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42 G. A. Albarellos et al.
Fð%Þ ¼ ðAUCEV =AUCiv Þ 100;
Statistical analysis Pharmacokinetic parameters are expressed as mean standard deviation. Main estimated pharmacokinetic parameters were statistically compared for the different administration routes, applying an ANOVA test (AUC(0–t), AUC(0–∞), t½, MRT) or a t test (ka, t½(a), MAT, Tmax, Cmax, F) (GraphPad Prismâ, GraphPad Software, version 5.00, 2007, San Diego, CA, USA). Results were considered significant when P < 0.05.
IV IM SC
Plasma concentration ( g/mL)
where AUCEV and AUCiv are the areas under the concentration– time curves for the extravascular routes (i.m. or s.c.) and the i.v. administration, respectively.
100
10
MIC = 4 g/mL
MIC = 1 g/mL
1
0.1
PK/PD integration Time above the minimum inhibitory concentration (T > MIC) for the three studied administration routes was estimated by visual approximation from the plasma concentration vs. time curve. The MIC value applied was based on human reports (staphylococci MIC90 = 1 lg/mL; E. Coli MIC90 = 4 lg/mL) (von Eiff et al., 2005; Lerma et al., 2008).
RESULTS No adverse effects were recorded by physical examination in any of the dogs during or after cefuroxime administration. The applied blood sample withdrawal schedules after i.v., i.m., and s.c. cefuroxime administration allowed a proper description of the plasma concentrations vs. time curves as shown in Fig. 1. Estimated pharmacokinetic parameters are shown in Table 1. Cefuroxime plasma concentrations after intravascular and extravascular administrations were best fitted to a bicompartmental (i.v.) and a monocompartmental (with first-order input) model (i.m. and s.c.). After i.v. administration, cefuroxime showed a rapid distribution, reflected by the rate constant of the process (k1 10.73 8.25 h1) and its short half-life (T½(d) 0.10 0.06 h). However, the extent of distribution was moderate, with a volume of distribution (V(d(ss))) of 0.49 0.03 L/kg. After i.v. administration, cefuroxime was rapidly eliminated from the body as reflected by the high body clearance (ClB) (0.34 0.04 L/hkg), short elimination half-life (T½) (1.12 0.19 h), and short mean residence time (MRT) (1.49 0.21 h). Cefuroxime blood concentrations remained above the LLOQ for 4 h in only three dogs. Cefuroxime absorption was much slower after s.c. than after i.m. administration, and this was evident (P < 0.05) when parameters associated with this process (ka, T½(a), Tmax, and Cmax) were compared. However, extent of absorption was the same for both extravascular routes, with a bioavailability of
0
1
2
3
4
5
6
Time (h)
Fig. 1. Mean and SD cefuroxime plasma concentration–time profile after intravenous (i.v.) (■), intramuscular (i.m.) (▲), and subcutaneous (s.c.) (●) administration to dogs at a dosage of 20 mg/kg (n = 6).
79.70 14.43% and 77.22 21.41% for the i.m. and s.c. administration, respectively. Cefuroxime elimination after i.m. and s.c. administration was rather similar, with identical body clearance (0.34 0.04 L/hkg) and similar elimination half-life (1.13 0.13 h, i.m.; 1.04 0.23 h, s.c.). However, significant differences were found when MRT values were compared. As body clearances were identical for the three routes, observed MRT differences should be consequence of an absorption delay after extravascular administrations. Cefuroxime blood concentration was above 0.40 lg/mL (LLOQ) for 6 h after i.m. (5/6 dogs) and s.c. (6/6 dogs) administration. Cefuroxime plasma concentrations above the MIC are shown in Fig. 1. After i.m. and s.c. administration, T > MIC for more susceptible bacteria (MIC ≤1 lg/mL) was 5.5–6 h, while for less susceptible micro-organisms (MIC ≤ 4 lg/mL), this time was 3.5–4 h.
DISCUSSION Cefuroxime could be a good option to treat susceptible bacteria causing infections in dogs. However, the lack of pharmacokinetic information makes impossible the design of a rational administration schedule. The results obtained on this study would be useful to optimize cefuroxime parenteral use in dogs. Observed cefuroxime pharmacokinetic profile after i.v. administration was the expected for a beta-lactam and similar to that reported for dogs, goats, calves, and buffalo calves (Soback et al., 1989; Chaudhary et al., 1999; Abo El-Sooud
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Cefuroxime pharmacokinetics in dogs 43 Table 1. Mean (SD) pharmacokinetic parameters of cefuroxime after intravenous, intramuscular, and subcutaneous administration to dogs at a dosage of 20 mg/kg
Pharmacokinetic Parameter C1 (lg/mL) C2 (lg/mL) Cp(0) (lg/mL) k1 (h1) k2 (h1) AUC(0–t) (lgh/mL) AUC(0–∞) (lgh/mL) K12 (h1) K21 (h1) K12/k21 T½(d) (h) Varea (L/kg) V(d(ss)) (L/kg) ka (h1) T½(a) (h) MAT (h) Tmax (h) Cmax (lg/mL) ClB (L/hkg) T½ (h) MRT (h) F (%)
Intravenous administration (mean SD)
Intramuscular administration (mean SD)
Subcutaneous administration (mean SD)
– – – – – 45.93 8.50
– – – – – 43.69 8.33
47.56 8.17*
45.52 9.01*
– – – – – – 8.43 0.13 0.31 0.43 22.99 0.34 1.13 1.79 79.70
– – – – – – 1.47 0.50 0.72 0.99 15.37 0.34 1.04 2.21 77.22
38.15 34.94 73.09 10.73 0.63 52.29
22.87 4.26 23.62 8.25 0.11 6.69
60.13 6.91 4.95 5.16 0.81 0.10 0.53 0.49 – – – – – 0.34 1.12 1.49 –
5.45 2.68 0.54 0.06 0.04 0.03
0.04 0.19 0.21
6.39† 0.09† 0.37† 0.20† 7.87† 0.04‡ 0.13 0.24† 14.43
0.38† 0.14† 0.32† 0.10† 3.07† 0.04‡ 0.23 0.23§ 21.41
*Significantly different (P < 0.05) i.v. vs i.m. and s.c. Significantly different (P < 0.05) i.m. vs s.c. ‡ ClB corrected by F. § Significantly different (P < 0.05) i.v. vs s.c. C1, C2, y-axis intercept terms; Cp(0), plasma concentration at 0 time; k1, distribution rate constant; k2, elimination rate constant; AUC(0–t), area under the plasma concentration vs time curve from 0 to time; AUC(0–∞), area under the plasma concentration vs time curve from 0 to infinite; K12, rate constant for passage from central to peripheral compartment; K21, rate constant for passage from peripheral to central compartment; t½(d), distribution half-life; Varea, volume of distribution of the elimination phase; V(d(ss)), volume of distribution at steady-state; Ka, absorption rate constant; t½(a), absorption half-life; MAT, mean absorption time; Tmax, time of maximum concentration; Cmax, maximum concentration; ClB, body clearance; t½, elimination half-life; MRT, mean residence time; F, bioavailability. †
et al., 2000; Zhao et al., 2012b) characterized by a fast distribution into the extracellular fluid and a relatively rapid renal excretion. The distribution process was rapid but, moderate in its extension (high rate constant, short half-life, and moderate volume of distribution). These pharmacokinetic parameters resulted rather similar to those reported for buffalo calves (Chaudhary et al., 1999), goats (Abo El-Sooud et al., 2000), and dogs (Zhao et al., 2012b). Also, pharmacokinetic parameters evaluating elimination process (high clearance, short halflife, and MRT) were very similar in the other studied species. Zhao et al. (2012b) studied cefuroxime disposition in dogs at © 2015 John Wiley & Sons Ltd
three intravenous doses (20, 40, and 80 mg/kg) demonstrating a linear pharmacokinetic. They report values of ClB of 0.31 L/hkg, t½ of 1.50 h, and MRT of 1.86 h, for the 20 mg/kg dosage. These values are slightly different than those found in the present study. Cefuroxime elimination lasted longer in the study of Zhao et al. (2012b); this difference is modest and could be explained by the more sensitive analytical method (triple-quadrupole tandem mass spectrometer) used by these authors. Cefuroxime ClB (0.34 L/hkg) was higher than glomerular filtration rate in dogs (0.24 L/hkg) (Baggot, 2001), indicating that other mechanisms (e.g., renal tubular secretion) are implicated in cefuroxime elimination as reported for humans and other species (Foord, 1976; Soback et al., 1989; Tsuji, 2006). Moderated pain was observed after i.m. administration, although no reaction at the injection site (intramuscular or subcutaneous) was clinically observed in any of the dogs. After i.m. administration, cefuroxime absorption was faster and Cmax higher than after s.c. administration. Moreover, after s.c. administration, cefuroxime remained in the plasma longer than after i.m. administration. These findings could be explained through the ‘flip-flop’ phenomenon, where terminal T½ is reflecting the ka rather than the k. This pharmacokinetic phenomenon would have clinical implications as it would prolong dosage intervals. The most common cause for retardation of drugs absorption, mainly after s.c. administration, is a local tissue reaction (irritation and inflammation) (Py€ or€ al€ a et al., 1994). In fact, for sodium cefuroxime a mild irritation, after subcutaneous administration to dogs, has been reported (Glaxo Laboratories, 1986). Cefuroxime bioavailability after both extravascular administration routes was equally high (i.m., 79.70% and s.c., 77.22%) without significant differences between them. The relatively longer permanence of cefuroxime in plasma when administered extravascularly (especially subcutaneously) could bring a bit more desirable plasma concentration profile in dogs than after intravenous administration. For beta-lactams, a T > MIC 50% of the dose interval has been established as optimal for bactericidal action. At the dose used in this study, a dose interval of 11 h (i.v., i.m.) or 12 h (s.c.) would be effective for treating bacteria with a MIC value of ≤1 lg/mL. However, for less susceptible bacteria (e.g., MIC ≤ 4 lg/mL), the dose interval should be shorter (8 h) (i.m., s.c.). More pharmacokinetic and pharmacodynamic studies are necessary to support the present results. Furthermore, clinical controlled trials are mandatory to establish proper cefuroxime dosing schedules in dogs.
ACKNOWLEDGMENTS The authors wish to thank to the personnel of Caniles, FCV, and UBA for the technical assistance with the dogs employed
44 G. A. Albarellos et al.
in this study. This work was supported by a Research Project UBACyT (Grant Numbers 20020100100745, 2011–2014 and 20020130100400, 2014–2017) of Secretarıa de Ciencia y Tecnica, Universidad de Buenos Aires, Argentina.
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