Study On The Safety And Pharmacokinetics Of Canine Itraconazole Preparation For Subcutaneous Injection

Itraconazole?ITZ?is a first-generation triazole antifungal drug.It can specifically bind to fungal CYP enzymes and interfere with the synthesis of a fungal cell membrane to kill fungi.It has sound effects on common clinical dermatophytosis,systemic fungal infections and other fungal infections.Hydroxypropyl-?-cyclodextrin?HP-?-CD?is a drug carrier widely used in clinics,which can effectively and stably carry ITZ.To determine the feasibility of administering this preparation by subcutaneous injection,we conducted a systematic preclinical study.Although Sporanox oral liquid and intravenous injection,commonly used in clinics,are ITZ preparations carried by HP-?-CD,the application is limited due to bioavailability and safety issues.In order to develop more convenient and safer ITZ preparations for veterinary use,we conducted a safety evaluation of the dog by setting different concentrations?2.5 mg/kg,7.5 mg/kg,12.5 mg/kg?for subcutaneous administration to purebred beagle dogs;the dogs were treated under the same administration frequency and frequency?once every three days,seven times in a row?.General clinical manifestations during administration,blood routine indexes,blood biochemical indexes,urine routine indexes,electrocardiogram,pathological anatomy,histopathological examination and adverse reactions were studied.According to test results,compared with the control group,the dogs in the three administration groups did not experience any adverse reactions.The transient increase of leukocytes in the drug administration groups occurred at different degrees,and the pain and swelling at the injection sites appeared in the middle and high dose groups.Histopathological examination revealed that the subcutaneous tissue in the sections had hyperemia and inflammation.No pathological changes occurred in other tissues and organs.Two weeks after the end of the administration,the swelling and pain at the injection sites disappeared,and the leukocyte-related indicators returned to normal.ITZ has very poor water solubility;however,the lipophilicity and keratinization make it accumulate in sebum and keratinous tissues?such as skin cuticle,nails,hair,etc.?in large amounts,these parts are mostly susceptible to dermatophytes;therefore,the local high concentration of ITZ is more suitable for the treatment of dermatophytosis.In order to explore the tissue distribution concentration and pharmacokinetic of the preparation,we established the high-performance liquid chromatography method to study the pharmacokinetics of single intravenous and subcutaneous injection of 12.5 mg/kg ITZ preparation,we obtained the absolute bioavailability of subcutaneous injection under this condition.Also,by establishing a reasonable sample processing method,the drug concentration in dog plasma and hair during multiple subcutaneous injections of 12.5 mg/kg ITZ preparation was studied,then we determined the steady-state concentration arrival time of the drug in plasma and related PK parameters.The results showed that the absolute bioavailability of subcutaneous administration at the dose of 12.5 mg/kg was 91.11%.Subcutaneous injection of the preparation,ITZ had a T_1/2 of?27.94±3.13 h?in dog plasma,T_max is?6±0 h?,MRT is?41.12±3.37 h?,Vd is?7.73±1.09 L/kg?;Intravenous injection of this preparation,ITZ had a T_1/2 of?45.10±15.67 h?in dog plasma,MRT is?59.50±19.39 h?,and Vd is?11.05±1.88 L/kg?.After the last subcutaneous injection,ITZ T_1/2?136.21±76.23 h?and AUC?164.18±9.03 h.?g/m L?in dog plasma increased significantly.No significant difference between T_max?6±0 h?and MRT?40.39±1.88 h?.The plasma drug concentration reached a steady state on the 15th day of subcutaneous injection,which was?1.41±0.12?g/m L?.Three days after the first dose,ITZ was detected in the hair?35.40±16.57?g/g?.Under steady-state plasma drug concentration,the drug concentration in the hair was36?44 times that of plasma.ITZ could still be detected in the hair tissue on the 61st day following the administration?2.12±0.40?g/g?.In summary,ITZ subcutaneous injection has excellent safety and tolerability,stable absorption,small individual differences,and can maintain sufficient plasma drug levels during longer dosing intervals.Compared to traditional preparations,the dosage of administration is reduced,reducing the treatment cost and the probability of adverse reactions.Moreover,subcutaneous administration is more comfortable to handle than an oral and intravenous injection,which is suitable for veterinary clinical application.