The Study On The Pharmacokinetics And Bioequivalence Of Clarithromycin Soft Capsule Among Healthy Volunteers

Clarithromycin is semisynthetic marolide antibiotic,which has broadantibacterial spectrum and strong antibacterial activity. Its antibacterial activity issimilar with erythromycin in vitro, but stronger than erythromycin in vivo to somebacteria such as staphylococcus and streptococcus. Clarithromycin is mainly used totreat upper and lower respiratory tract infections, skin and soft tissue infections inclinic. Although capsule, tablet, dispersible tablet and sustained-release tablet ofclarithromycin have been on the market currently, there is still no new preparationclarithromycin soft capsule in China. In the present study, we used clarithromycintablet produced by Italy Abbott Laboratories Ltd, as reference preparation,clarithromycin soft capsules produced by xi' an Daheng Pharmaceutical Co. Ltd andBeijing Labbeiwang Pharmaceutical Technology Development Co. Ltd, as testpreparation. Pharmacokinetics and relative bioavailability of clarithromycin softcapsule were determined in healthy volunteers to guide the clinical use.Objective:To study pharmacokinetics and bioequivalence of clarithromycin soft capsulein healthy volunteers.Methods:A 2-way crossover design with one week washout was performed in 18healthy volunteers. The reference preparation was manufactured by Italy AbbottLaboratories Ltd. The test preparation was manufactured by xi' an DahengPharmaceutical Co. Ltd and Beijing Labbeiwang Pharmaceutical TechnologyDevelopment Co Ltd. Eighteen healthy male volunteers have taken single dose clarithromycin tablet as the reference preparation and clarithromycin soft capsule asthe test preparation orally with a dose of 0.5g in randomized crossover way. The timeinterval between two tests was one week. The character of volunteers included normalfunction of liver, renal, and heart, no history hypersceptibility. The volunteers wereforbidden using other drugs, starting from 2 weeks before the test to the end of the test.The drug was taken with 250ml boiled water in the morning. Two hours later they canhave water. Four hours later standard low fat diet were provided. Venous blood of 5mlwere collected separately before administration and 0.33h,0.67h,1h,1.5h,2h, 2.5h,3h,5h,8h,12h and 24h after administration. After heparin anticoagulation, plasma wereseparated and stored at -30℃.HPLC-MS was used to determined the plasma concentration. The plasmastandard curve was made and linear regression equation was obtained. Recovery ratetest, precision test and stability test were performed. The plasma concentration -timedata in volunteers was analyzed automatically with BAPP2.0 software using computer.Pharmacokinetic parameters included Tmax and Cmax were calculated. AUC wascaculated by trapezoidal rule. Relative bioavailability was calculated by usingformulas as follow (?).Results:The result showed that the method was highly specific. The impure substancedid not interfere with determination of clarithromycin. The linear regression equationis f = 0.003605 + 2.120×C, The quantitative low limit is 0.003021μg·ml-1,and thelinear range is 0.003021～5.035μg·ml-1 . Recover rate RSD is below 15%. The resultof stability test showed that plasma samples containing drug was stable at roomtemperature for 10h , in conditions of freezing and thawing three times and at -20℃for at least 2w. Detection of within and between batch precision showed RSD below10%. The results comply with the requirements analysis of biological samples.The data showed that blood concentration-time curves of two preparation weresimilar after 18 volunteers taken two preparations of single-dose clarithromycin andwere fitted to a one-compartment open model in volunteers. The main pharmacokinetic parameters of test and reference preparations were as follow:T_max(2.3±0.8) and (2.1±1.0)h; C_max((2.22±0.67) and (2.29±0.78)μg ? ml^-1;t_1/2(3.7±0.47) and (4.1±0.46)h; AUC_0-24 (14.89±4.73) and (15.6±5.96) mg·h·L^-1;AUC_0-∞(15.12±4.85) and (15.95±6.04) mg·h·L^-1. The relative bioavailability of thetest capsule to the reference one was F_0-t(98.4±15.0)% and F_0-∞(97.6±14.8)%respectively. AUC_0-24, AUC_0-∞ and C_max between the two preparation were analyzedwith a statistic analysis if ANOVA and two one-side test statistic analysis. T_max wasanalyzed with nonparameter statistic. The results showed that the two preparationwere bioequivalent.Conclusion:The pharmacokinetics of clarithromycin soft capsule in healthy volunteersis consistent with one-compartment open model. Clarithromycin soft capsule andclarithromycin tablet were bioequivalent.