581408 research-article2015
JFM0010.1177/1098612X15581408Journal of Feline Medicine and SurgeryLiang et al
Original Article
Pharmacokinetics and bioavailability of itraconazole oral solution in cats
Journal of Feline Medicine and Surgery 1–5 © ISFM and AAFP 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1098612X15581408 jfms.com
Chaoping Liang1, Qi Shan2, Jialian Zhong1, Wei Li1, Xiufeng Zhang1, Jing Wang3, Changfu Cao1 and Zhenling Zeng1
Abstract
Objectives The aim of this study was to describe the pharmacokinetics and bioavailability of itraconazole (ITR) oral solution in healthy cats. Methods The pharmacokinetics of ITR were studied in eight healthy, fasted cats after a single intravenous (IV) and oral (PO) administration at a dose of 5 mg/kg, in a two-period crossover design study. Blood was obtained at predetermined intervals for the determination of ITR concentrations with high-performance liquid chromatography. Pharmacokinetic characterisation was performed by a non-compartmental method using WinNonlin 5.2.1. Results After IV administration, the major pharmacokinetic parameters were as follows (mean ± SD): terminal elimination half-life (T1/2λz ) 15.8 ± 1.88 h; area under the curve from time zero to infinity (AUC0–∞) 13.9 ± 3.17 h·μg/ml; total body clearance 0.37 ± 0.08 l/h/kg; apparent volume of distribution 8.51 ± 1.92 l/kg; mean residence time 20.6 ± 3.95 h. After PO administration, the principal pharmacokinetic parameters were as follows (mean ± SD): T1/2λz 15.6 ± 3.20 h; AUC0–∞ 7.94 ± 2.83 h·μg/ml; peak concentration 0.70 ± 0.14 μg/ml; time of peak 1.43 ± 0.53 h. The absolute bioavailability of ITR oral solution after oral administration was 52.1 ± 11.6%. Conclusions and relevance The disposition of ITR oral solution in cats is characterised by a long terminal half-life, a short peak time and moderate bioavailability. Accepted: 19 March 2015
Introduction In recent years, an increasing number of fungal infections have been spread by animals. Almost 20% of fungal infections of human skin can be the result of close contact with cats and dogs. The infections not only endanger the health of cats and dogs, but also threaten human health.1,2 Itraconazole (ITR) is a first-generation synthetic triazole antifungal agent that is commonly used for a number of indications, including systemic and superficial mycosis.3,4 It has a wide antifungal spectrum, including moulds, dimorphic fungi, yeasts and dermatophytes.5 Similar to the mode of action of ketoconazole, ITR can selectively destroy cytochrome P-450-mediated ergosterol synthesis in fungal membranes, which leads to death of the fungal cells.6 Although a limited number of ITR products are licensed for use in animals, many of those available for the treatment of mycoses in humans are used by veterinary practitioners. Currently, the pharmacokinetics of ITR in rats, humans, dogs and horseshoe crabs have been reported.7–12 Although several studies on the determination of ITR in
cat plasma have been evaluated,13 a literature search revealed that pharmacokinetic evaluations after ITR oral solution to cats are scarce. The aim of this study was to assess the pharmacokinetics of ITR in eight cats after intravenous (IV) and oral (PO) administration, and to calculate the oral bioavailability of ITR oral solution in cats. 1National
Reference Laboratory of Veterinary Drug Residues (SCAU), College of Veterinary Medicine, South China Agricultural University, Guangzhou, China 2Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, China 3Guangzhou Senya Animal’s Pharmaceutical Co Ltd, Guangzhou, China Chaoping Liang and Qi Shan contributed equally to this work Corresponding author: Zhenling Zeng DVM, Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, South China Agricultural University, Wu shan Street, Tian he District, Guangzhou 510642, China Email: [email protected]
Downloaded from jfm.sagepub.com at CMU Libraries - library.cmich.edu on September 29, 2015
Journal of Feline Medicine and Surgery
2
Materials and methods Animals Eight healthy adult family cats (four females, four males) weighing (mean ± SD) 2.39 ± 0.18 kg were studied. They were kept individually in cages under the same standard laboratory conditions. The cats were fed the same regular volume of dry cat food without salt restriction twice a day. Water was freely available. Food was withheld before the experiment and until 10 h after drug delivery. The study was performed with the approval of the Institutional Animal Care and Use Committee of South China Agricultural University. Chemicals and reagents A standard of ITR (99.3% purity) was purchased from the National Institute for the Control of Pharmaceutical and Biological Products. The bulk of ITR (99.9% purity) and ITR oral solution (10 mg/ml) were provided by Shanghai Hanwei Bio-Pharmaceutical Technology Co. The ITR intravenous solution (10 mg/ml) was prepared by the College of Veterinary Medicine (South China Agricultural University). Analytical grade trifluoroacetic acid (TFA), n-hexane, acetic acid and methyl tert-butyl ether (MTBE) were purchased from Guangzhou Reagent Factory, and the other solvents were high-performance liquid chromatography (HPLC) grade and purchased from CNW Technologies GmbH. Experimental design On the day before an experiment, IV catheters (24 G, 4.8 cm) were placed in the right elbow vein of the cats and protected with an adhesive bandage. The cats were allowed to recover for 12 h. According to a single dose, two period crossover design with a washout of 15 days, the eight fasted cats were randomly divided into two groups for IV and PO administrations followed by a single dose of 5 mg/kg. After the 15 day washout period, the treatment was changed repeatedly. The first administration of ITR was delivered as an IV solution to the left cephalic vein using a plastic syringe fitted with an infusion set. The second administration was by instillation using a plastic syringe at the corners of the mouth within 10 s. Each cat was observed daily and abnormal findings were recorded during the experiments. Blood sampling After IV and PO administration, blood samples were collected into heparin tubes at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 9 h, 12 h, 24 h, 36 h, 48 h, 60 h, 72 h and 0.167 h, 0.25 h, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 9 h, 12 h, 24 h, 36 h, 48 h, 60 h, 72 h after treatment, respectively. All samples were immediately centrifuged at 2254 g/min for 10 mins and stored at –20ºC until analysis.
Sample preparation A 500 μl blood sample was placed into a 15 ml polypropylene centrifuge tube with 200 μl sodium hydroxide (1 mol/l) and extracted with 5 ml of MTBE. The mixture was vortexed for 5 mins and then centrifuged at 9016g/ min for 10 mins at 4ºC. The supernatants were transferred to another tube. The extract was concentrated up to dryness under nitrogen, and the residues were dissolved in 500 μl acetonitrile/aqueous solution of 6% acetic acid (2:3, v/v) and directly injected into the HPLC system. Instrumentation and analytical method ITR concentrations in serum were determined by using a slightly modified method adapted from Redmann and Charles.14 Briefly, the chromatographical system was a Waters 2475 Series HPLC and the column used was a reversed-phase Hypersil BDS C18 (5 μm, 250 mm × 4.6 mm). The mobile phase consisted of 0.2% TFA aqueous solution/acetonitrile (45:55, v/v). The elution was carried out on a C18 column with a flow rate of 1.0 ml/min. Excitation and emission wavelengths were 260 nm and 365 nm, respectively. The temperature was controlled at 25ºC and the injection volume was 20 μl. The calibration curve was linear over the concentration range of 0.02– 2.00 μg/ml, with a correlation coefficient (r) >0.999. The limit of quantification for ITR in plasma was 0.02 μg/ml. Both the inter- (n = 5) and intra-assay (n = 15) precision values were 0.05) to that of IV administration (15.8 ± 1.88 h), which is significantly shorter than in dogs (28.0 ± 2.90 h), and longer than in horses (11.3 ± 2.84 h), rabbits (9.40 ± 3.50 h) and rats (5.20 ± 1.80 h) following PO administration. The volume of distribution (corrected for bioavailability) after PO administration (15.1 ± 4.41 l/kg) was larger than that of IV administration (8.51 ± 1.92 l/kg) in cats and PO administration in horses (6.30 ± 0.94 l/kg). The large volume of distribution (corrected for bioavailability) observed after PO administration was likely due to ITR’s extensive distribution to nail, skin and tissue,17 and its slow release from peripheral tissue to the blood. In the present study, the oral solution bioavailability in fasted
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Journal of Feline Medicine and Surgery
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Table 2 Pharmacokinetic parameters of itraconazole after oral administration in different species15,16 Parameters
Cats
Dogs
Horses
Rats
Rabbits
Dose (mg/kg) Tmax (h) Cmax (μg/ml) T1/2λz (h) Vd /F (l/kg) Cl/F(l/h/kg)
5 1.43 ± 0.53 0.70 ± 0.14 15.6 ± 3.20 15.1 ± 4.41 0.70 ± 0.22
10.5 3.30 ± 2.10 0.37 ± 0.13 28.0 ± 2.90 82.2 ± 38.9 2.10 ± 0.90
5 3.33 ± 1.03 0.41 ± 0.13 11.3 ± 2.84 6.30 ± 0.94 —
15 5.20 ± 3.60 0.37 ± 0.11 5.20 ± 1.80 38.6 ± 3.40 6.00 ± 3.40
15 8.70 ± 3.00 1.23 ± 0.53 9.40 ± 3.50 7.90 ± 2.90 0.70 ± 0.40
Values are given as mean ± SD Tmax = time to maximum plasma concentration; Cmax = maximum plasma concentration; T1/2λz = terminal half-life; Vd/F = volume of distribution corrected for bioavailability; Cl/F = body clearance corrected for bioavailability
cats was only 52.1 ± 11.6%, which is lower than in horses (65.0 ± 26.3%)16 and in non-fasted cats (78.8 ± 28.0%).13 This may be owing to different species and its first-pass metabolism, which has been reported in humans, rats and dogs.18–20 Furthermore, it is very difficult to compare the bioavailability of oral solution in cats with that of other animals as no data regarding IV administration in other animals or humans have, to our knowledge, been published. Although the concentrations and bioavailability of oral solution in cats were low, the concentrations at the infection site were almost 10-fold higher than those in plasma concentrations.21,22 In addition, the geometric mean of minimum inhibitory concentration (MIC) values for 39 dermatophytic isolates was 0.078 μg/ml.23 In our study, the concentrations of the target side above the MIC were likely maintained over 24. Generally, common oral formulations of ITR are tablets and capsules. However, it is difficult to use these formulations to administer medicine to cats and dogs in veterinary clinics. ITR oral solution offers a significant advantage over capsules or tablets for veterinary use because cats may have difficulty in swallowing tablets or capsules, and it is very difficult to adjust the dosages of capsules or tablets for cats and dogs. Therefore, ITR oral solution is likely to have wide application in veterinary clinics, and there is a need to improve the absorption and bioavailability of the formulation continuously.
Conclusions This study describes the pharmacokinetic properties of ITR oral solution, and determines the absolute bioavailability of the formulation in cats. The results contribute to the data on the kinetic disposition of ITR in cats. Conflict of interest The authors do not have any potential conflicts of interest to declare.
Funding This study was supported financially by the Program for Changjiang Scholars and Innovative Research Team in
University of China (No. IRT13063) and the Natural Science Foundation of Guangdong Province, China (No. S2012030006590).
References 1 Rochette F, Engelen M and Vanden BH. Antifungal agents of use in animal health – practical applications. J Vet Pharmacol Ther 2003; 26: 31–53. 2 Richard JL, Debey MC, Chermette R, et al. Advances in veterinary mycology. J Med Vet Mycol 1994; 32 Suppl 1: 169–187. 3 Gupta AK, Sauder DN and Shear NH. Antifungal agents: an overview. Part II. J Am Acad Dermatol 1994; 30: 911–933. 4 Lestner J and Hope WW. Itraconazole: an update on pharmacology and clinical use for treatment of invasive and allergic fungal infections. Expert Opin Drug Metab Toxicol 2013; 9: 911–926. 5 Haria M, Bryson HM and Goa KL. Itraconazole. A reappraisal of its pharmacological properties and therapeutic use in the management of superficial fungal infections. Drugs 1996; 51: 585–620. 6 Hassan HA, Al-Marzouqi AH, Jobe B, et al. Enhancement of dissolution amount and in vivo bioavailability of itraconazole by complexation with β -cyclodextrin using supercritical carbon dioxide. J Pharmaceut Biomed 2007; 45: 243–250. 7 Lee U, Choi YH, Kim SH, et al. Pharmacokinetics of itraconazole in diabetic rats. Antimicrob Agents Chemother 2010; 54: 931–933. 8 Rabinow B, Kipp J, Papadopoulos P, et al. Itraconazole IV nanosuspension enhances efficacy through altered pharmacokinetics in the rat. Int J Pharm 2007; 339: 251–260. 9 Schmitt C, Perel Y, Harousseau JL, et al. Pharmacokinetics of itraconazole oral solution in neutropenic children during long-term prophylaxis. Antimicrob Agents Chemother 2001; 45: 1561–1564. 10 Abdel-Rahman SM, Jacobs RF, Massarella J, et al. Singledose pharmacokinetics of intravenous itraconazole and hydroxypropyl-cyclodextrin in infants, children, and adolescents. Antimicrob Agents Chemother 2007; 51: 2668–2673. 11 Mawby DI, Whittemore JC, Genger S, et al. Bioequivalence of orally administered generic, compounded, and innovator-formulated itraconazole in healthy dogs. J Vet Intern Med 2014; 28: 72–77.
Downloaded from jfm.sagepub.com at CMU Libraries - library.cmich.edu on September 29, 2015
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5
12 Allender MC, Schumacher J, Milam J, et al. Pharmacokinetics of intravascular itraconazole in the American horseshoe crab (Limulus polyphemus). J Vet Pharmacol Ther 2008; 31: 83–86. 13 Boothe DM, Herring I, Calvin J, et al. Itraconazole disposition after single oral and intravenous and multiple oral dosing in healthy cats. Am J Vet Res 1997; 58: 872–877. 14 Redmann S and Charles BG. A rapid HPLC method with fluorometric detection for determination of plasma itraconazole and hydroxy-itraconazole concentrations in cystic fibrosis children with allergic bronchopulmonary aspergillosis. Biomed Chromatogr 2006; 20: 343–348. 15 Yoo SD, Kang E, Shin BS, et al. Interspecies comparison of the oral absorption of itraconazole in laboratory animals. Arch Pharm Res 2002; 25: 387–391. 16 Davis JL, Salmon JH and Papich MG. Pharmacokinetics and tissue distribution of itraconazole after oral and intravenous administration to horses. Am J Vet Res 2005; 66: 1694–1701. 17 Matsumoto T, Tanuma H and Nishiyama S. Clinical and pharmacokinetic investigations of oral itraconazole in the treatment of onychomycosis. Mycoses 1999; 42: 79–91.
18 Mino Y, Naito T, Watanabe T, et al. Hydroxy-itraconazole pharmacokinetics is similar to that of itraconazole in immunocompromised patients receiving oral solution of itraconazole. Clin Chim Acta 2013; 415: 128–132. 19 Rabinow B, Kipp J, Papadopoulos P, et al. Itraconazole IV nanosuspension enhances efficacy through altered pharmacokinetics in the rat. Int J Pharm 2007; 339: 251–260. 20 Carrier A and Parent J. Liquid chromatographic-mass spectrometric determination of itraconazole and its major metabolite, hydroxyitraconazole, in dog plasma. J Chromatogr B Biomed Sci Appl 2000; 745: 413–420. 21 Morimoto K, Tanuma H, Kikuchi I, et al. Pharmacokinetic investigation of oral itraconazole in stratum corneum level of tinea pedis. Mycoses 2004; 47: 104–114. 22 Seishima M, Oyama Z, Oda M, et al. Distribution of an antifungal drug, itraconazole, in pathological and nonpathological tissues. Eur J Dermatol 2004; 14: 24–27. 23 Clayton YM. Relevance of broad-spectrum and fungicidal activity of antifungals in the treatment of dermatomycoses. Br J Dermatol 1994; 130 Suppl 43: 7–8.
Downloaded from jfm.sagepub.com at CMU Libraries - library.cmich.edu on September 29, 2015
JFM0010.1177/1098612X15581408Journal of Feline Medicine and SurgeryLiang et al
Original Article
Pharmacokinetics and bioavailability of itraconazole oral solution in cats
Journal of Feline Medicine and Surgery 1–5 © ISFM and AAFP 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1098612X15581408 jfms.com
Chaoping Liang1, Qi Shan2, Jialian Zhong1, Wei Li1, Xiufeng Zhang1, Jing Wang3, Changfu Cao1 and Zhenling Zeng1
Abstract
Objectives The aim of this study was to describe the pharmacokinetics and bioavailability of itraconazole (ITR) oral solution in healthy cats. Methods The pharmacokinetics of ITR were studied in eight healthy, fasted cats after a single intravenous (IV) and oral (PO) administration at a dose of 5 mg/kg, in a two-period crossover design study. Blood was obtained at predetermined intervals for the determination of ITR concentrations with high-performance liquid chromatography. Pharmacokinetic characterisation was performed by a non-compartmental method using WinNonlin 5.2.1. Results After IV administration, the major pharmacokinetic parameters were as follows (mean ± SD): terminal elimination half-life (T1/2λz ) 15.8 ± 1.88 h; area under the curve from time zero to infinity (AUC0–∞) 13.9 ± 3.17 h·μg/ml; total body clearance 0.37 ± 0.08 l/h/kg; apparent volume of distribution 8.51 ± 1.92 l/kg; mean residence time 20.6 ± 3.95 h. After PO administration, the principal pharmacokinetic parameters were as follows (mean ± SD): T1/2λz 15.6 ± 3.20 h; AUC0–∞ 7.94 ± 2.83 h·μg/ml; peak concentration 0.70 ± 0.14 μg/ml; time of peak 1.43 ± 0.53 h. The absolute bioavailability of ITR oral solution after oral administration was 52.1 ± 11.6%. Conclusions and relevance The disposition of ITR oral solution in cats is characterised by a long terminal half-life, a short peak time and moderate bioavailability. Accepted: 19 March 2015
Introduction In recent years, an increasing number of fungal infections have been spread by animals. Almost 20% of fungal infections of human skin can be the result of close contact with cats and dogs. The infections not only endanger the health of cats and dogs, but also threaten human health.1,2 Itraconazole (ITR) is a first-generation synthetic triazole antifungal agent that is commonly used for a number of indications, including systemic and superficial mycosis.3,4 It has a wide antifungal spectrum, including moulds, dimorphic fungi, yeasts and dermatophytes.5 Similar to the mode of action of ketoconazole, ITR can selectively destroy cytochrome P-450-mediated ergosterol synthesis in fungal membranes, which leads to death of the fungal cells.6 Although a limited number of ITR products are licensed for use in animals, many of those available for the treatment of mycoses in humans are used by veterinary practitioners. Currently, the pharmacokinetics of ITR in rats, humans, dogs and horseshoe crabs have been reported.7–12 Although several studies on the determination of ITR in
cat plasma have been evaluated,13 a literature search revealed that pharmacokinetic evaluations after ITR oral solution to cats are scarce. The aim of this study was to assess the pharmacokinetics of ITR in eight cats after intravenous (IV) and oral (PO) administration, and to calculate the oral bioavailability of ITR oral solution in cats. 1National
Reference Laboratory of Veterinary Drug Residues (SCAU), College of Veterinary Medicine, South China Agricultural University, Guangzhou, China 2Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou, China 3Guangzhou Senya Animal’s Pharmaceutical Co Ltd, Guangzhou, China Chaoping Liang and Qi Shan contributed equally to this work Corresponding author: Zhenling Zeng DVM, Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, South China Agricultural University, Wu shan Street, Tian he District, Guangzhou 510642, China Email: [email protected]
Downloaded from jfm.sagepub.com at CMU Libraries - library.cmich.edu on September 29, 2015
Journal of Feline Medicine and Surgery
2
Materials and methods Animals Eight healthy adult family cats (four females, four males) weighing (mean ± SD) 2.39 ± 0.18 kg were studied. They were kept individually in cages under the same standard laboratory conditions. The cats were fed the same regular volume of dry cat food without salt restriction twice a day. Water was freely available. Food was withheld before the experiment and until 10 h after drug delivery. The study was performed with the approval of the Institutional Animal Care and Use Committee of South China Agricultural University. Chemicals and reagents A standard of ITR (99.3% purity) was purchased from the National Institute for the Control of Pharmaceutical and Biological Products. The bulk of ITR (99.9% purity) and ITR oral solution (10 mg/ml) were provided by Shanghai Hanwei Bio-Pharmaceutical Technology Co. The ITR intravenous solution (10 mg/ml) was prepared by the College of Veterinary Medicine (South China Agricultural University). Analytical grade trifluoroacetic acid (TFA), n-hexane, acetic acid and methyl tert-butyl ether (MTBE) were purchased from Guangzhou Reagent Factory, and the other solvents were high-performance liquid chromatography (HPLC) grade and purchased from CNW Technologies GmbH. Experimental design On the day before an experiment, IV catheters (24 G, 4.8 cm) were placed in the right elbow vein of the cats and protected with an adhesive bandage. The cats were allowed to recover for 12 h. According to a single dose, two period crossover design with a washout of 15 days, the eight fasted cats were randomly divided into two groups for IV and PO administrations followed by a single dose of 5 mg/kg. After the 15 day washout period, the treatment was changed repeatedly. The first administration of ITR was delivered as an IV solution to the left cephalic vein using a plastic syringe fitted with an infusion set. The second administration was by instillation using a plastic syringe at the corners of the mouth within 10 s. Each cat was observed daily and abnormal findings were recorded during the experiments. Blood sampling After IV and PO administration, blood samples were collected into heparin tubes at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 9 h, 12 h, 24 h, 36 h, 48 h, 60 h, 72 h and 0.167 h, 0.25 h, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 9 h, 12 h, 24 h, 36 h, 48 h, 60 h, 72 h after treatment, respectively. All samples were immediately centrifuged at 2254 g/min for 10 mins and stored at –20ºC until analysis.
Sample preparation A 500 μl blood sample was placed into a 15 ml polypropylene centrifuge tube with 200 μl sodium hydroxide (1 mol/l) and extracted with 5 ml of MTBE. The mixture was vortexed for 5 mins and then centrifuged at 9016g/ min for 10 mins at 4ºC. The supernatants were transferred to another tube. The extract was concentrated up to dryness under nitrogen, and the residues were dissolved in 500 μl acetonitrile/aqueous solution of 6% acetic acid (2:3, v/v) and directly injected into the HPLC system. Instrumentation and analytical method ITR concentrations in serum were determined by using a slightly modified method adapted from Redmann and Charles.14 Briefly, the chromatographical system was a Waters 2475 Series HPLC and the column used was a reversed-phase Hypersil BDS C18 (5 μm, 250 mm × 4.6 mm). The mobile phase consisted of 0.2% TFA aqueous solution/acetonitrile (45:55, v/v). The elution was carried out on a C18 column with a flow rate of 1.0 ml/min. Excitation and emission wavelengths were 260 nm and 365 nm, respectively. The temperature was controlled at 25ºC and the injection volume was 20 μl. The calibration curve was linear over the concentration range of 0.02– 2.00 μg/ml, with a correlation coefficient (r) >0.999. The limit of quantification for ITR in plasma was 0.02 μg/ml. Both the inter- (n = 5) and intra-assay (n = 15) precision values were 0.05) to that of IV administration (15.8 ± 1.88 h), which is significantly shorter than in dogs (28.0 ± 2.90 h), and longer than in horses (11.3 ± 2.84 h), rabbits (9.40 ± 3.50 h) and rats (5.20 ± 1.80 h) following PO administration. The volume of distribution (corrected for bioavailability) after PO administration (15.1 ± 4.41 l/kg) was larger than that of IV administration (8.51 ± 1.92 l/kg) in cats and PO administration in horses (6.30 ± 0.94 l/kg). The large volume of distribution (corrected for bioavailability) observed after PO administration was likely due to ITR’s extensive distribution to nail, skin and tissue,17 and its slow release from peripheral tissue to the blood. In the present study, the oral solution bioavailability in fasted
Downloaded from jfm.sagepub.com at CMU Libraries - library.cmich.edu on September 29, 2015
Journal of Feline Medicine and Surgery
4
Table 2 Pharmacokinetic parameters of itraconazole after oral administration in different species15,16 Parameters
Cats
Dogs
Horses
Rats
Rabbits
Dose (mg/kg) Tmax (h) Cmax (μg/ml) T1/2λz (h) Vd /F (l/kg) Cl/F(l/h/kg)
5 1.43 ± 0.53 0.70 ± 0.14 15.6 ± 3.20 15.1 ± 4.41 0.70 ± 0.22
10.5 3.30 ± 2.10 0.37 ± 0.13 28.0 ± 2.90 82.2 ± 38.9 2.10 ± 0.90
5 3.33 ± 1.03 0.41 ± 0.13 11.3 ± 2.84 6.30 ± 0.94 —
15 5.20 ± 3.60 0.37 ± 0.11 5.20 ± 1.80 38.6 ± 3.40 6.00 ± 3.40
15 8.70 ± 3.00 1.23 ± 0.53 9.40 ± 3.50 7.90 ± 2.90 0.70 ± 0.40
Values are given as mean ± SD Tmax = time to maximum plasma concentration; Cmax = maximum plasma concentration; T1/2λz = terminal half-life; Vd/F = volume of distribution corrected for bioavailability; Cl/F = body clearance corrected for bioavailability
cats was only 52.1 ± 11.6%, which is lower than in horses (65.0 ± 26.3%)16 and in non-fasted cats (78.8 ± 28.0%).13 This may be owing to different species and its first-pass metabolism, which has been reported in humans, rats and dogs.18–20 Furthermore, it is very difficult to compare the bioavailability of oral solution in cats with that of other animals as no data regarding IV administration in other animals or humans have, to our knowledge, been published. Although the concentrations and bioavailability of oral solution in cats were low, the concentrations at the infection site were almost 10-fold higher than those in plasma concentrations.21,22 In addition, the geometric mean of minimum inhibitory concentration (MIC) values for 39 dermatophytic isolates was 0.078 μg/ml.23 In our study, the concentrations of the target side above the MIC were likely maintained over 24. Generally, common oral formulations of ITR are tablets and capsules. However, it is difficult to use these formulations to administer medicine to cats and dogs in veterinary clinics. ITR oral solution offers a significant advantage over capsules or tablets for veterinary use because cats may have difficulty in swallowing tablets or capsules, and it is very difficult to adjust the dosages of capsules or tablets for cats and dogs. Therefore, ITR oral solution is likely to have wide application in veterinary clinics, and there is a need to improve the absorption and bioavailability of the formulation continuously.
Conclusions This study describes the pharmacokinetic properties of ITR oral solution, and determines the absolute bioavailability of the formulation in cats. The results contribute to the data on the kinetic disposition of ITR in cats. Conflict of interest The authors do not have any potential conflicts of interest to declare.
Funding This study was supported financially by the Program for Changjiang Scholars and Innovative Research Team in
University of China (No. IRT13063) and the Natural Science Foundation of Guangdong Province, China (No. S2012030006590).
References 1 Rochette F, Engelen M and Vanden BH. Antifungal agents of use in animal health – practical applications. J Vet Pharmacol Ther 2003; 26: 31–53. 2 Richard JL, Debey MC, Chermette R, et al. Advances in veterinary mycology. J Med Vet Mycol 1994; 32 Suppl 1: 169–187. 3 Gupta AK, Sauder DN and Shear NH. Antifungal agents: an overview. Part II. J Am Acad Dermatol 1994; 30: 911–933. 4 Lestner J and Hope WW. Itraconazole: an update on pharmacology and clinical use for treatment of invasive and allergic fungal infections. Expert Opin Drug Metab Toxicol 2013; 9: 911–926. 5 Haria M, Bryson HM and Goa KL. Itraconazole. A reappraisal of its pharmacological properties and therapeutic use in the management of superficial fungal infections. Drugs 1996; 51: 585–620. 6 Hassan HA, Al-Marzouqi AH, Jobe B, et al. Enhancement of dissolution amount and in vivo bioavailability of itraconazole by complexation with β -cyclodextrin using supercritical carbon dioxide. J Pharmaceut Biomed 2007; 45: 243–250. 7 Lee U, Choi YH, Kim SH, et al. Pharmacokinetics of itraconazole in diabetic rats. Antimicrob Agents Chemother 2010; 54: 931–933. 8 Rabinow B, Kipp J, Papadopoulos P, et al. Itraconazole IV nanosuspension enhances efficacy through altered pharmacokinetics in the rat. Int J Pharm 2007; 339: 251–260. 9 Schmitt C, Perel Y, Harousseau JL, et al. Pharmacokinetics of itraconazole oral solution in neutropenic children during long-term prophylaxis. Antimicrob Agents Chemother 2001; 45: 1561–1564. 10 Abdel-Rahman SM, Jacobs RF, Massarella J, et al. Singledose pharmacokinetics of intravenous itraconazole and hydroxypropyl-cyclodextrin in infants, children, and adolescents. Antimicrob Agents Chemother 2007; 51: 2668–2673. 11 Mawby DI, Whittemore JC, Genger S, et al. Bioequivalence of orally administered generic, compounded, and innovator-formulated itraconazole in healthy dogs. J Vet Intern Med 2014; 28: 72–77.
Downloaded from jfm.sagepub.com at CMU Libraries - library.cmich.edu on September 29, 2015
Liang et al
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12 Allender MC, Schumacher J, Milam J, et al. Pharmacokinetics of intravascular itraconazole in the American horseshoe crab (Limulus polyphemus). J Vet Pharmacol Ther 2008; 31: 83–86. 13 Boothe DM, Herring I, Calvin J, et al. Itraconazole disposition after single oral and intravenous and multiple oral dosing in healthy cats. Am J Vet Res 1997; 58: 872–877. 14 Redmann S and Charles BG. A rapid HPLC method with fluorometric detection for determination of plasma itraconazole and hydroxy-itraconazole concentrations in cystic fibrosis children with allergic bronchopulmonary aspergillosis. Biomed Chromatogr 2006; 20: 343–348. 15 Yoo SD, Kang E, Shin BS, et al. Interspecies comparison of the oral absorption of itraconazole in laboratory animals. Arch Pharm Res 2002; 25: 387–391. 16 Davis JL, Salmon JH and Papich MG. Pharmacokinetics and tissue distribution of itraconazole after oral and intravenous administration to horses. Am J Vet Res 2005; 66: 1694–1701. 17 Matsumoto T, Tanuma H and Nishiyama S. Clinical and pharmacokinetic investigations of oral itraconazole in the treatment of onychomycosis. Mycoses 1999; 42: 79–91.
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