Quality And Efficacy Consistency Evaluation For Generic Cefaclor Based On PK/PD Characteristics Of Antibiotics

Antibacterial mainly act on pathogenic microorganisms in infected lesions directly or indirectly to produce antibacterial activity,thereby obtaining therapeutic efficacy.The bacterial etiological efficacy of antibacterial is an important basis for the diseases treatment.The effect of antibacterial can reflect the strength of the antibacterial activity but the anti-infective efficacy of antibacterial is not only related to the strength of antibacterial activity,but also related to the duration of antibacterial effect.Combining the pharmacokinetics（PK）and pharmacodynamics（PD）of antibacterial can reflect the change process of the drug concentration-effect in vivo over the time.Different types of antibacterial have different PK/PD effect characteristics.The PK/PD theory has been maturely applied to guide the rational clinical use of antibacteria.Based on the PK/PD analysis of antibacterial to formulate and optimize the dosing regimens are used to obtain the best clinical treatment efficacy.In view of the special action mechanism of antibacterial,the key PK/PD parameters can be used to evaluate the clinical therapeutic efficacy of antibacterial.But the main content of the current consistency evaluation for generic antimicrobial don’t evaluate the equivalence of PK/PD parameters which are closely related to pathogenic efficacy.Therefore,based on the PK/PD characteristics of antibacterial,this study chosedβ-lactam antibacterial cefaclor as the experimental object to compare the equivalence of PK/PD parameters between cefaclor originals and generics,and analyze the correlation between the key PK/PD parameters and quality consistency,in order to obtain more scientific new indicators for bioequivalence evaluation of antimicrobial and provide a new reference basis for the consistency evaluation of antimicrobial generic.Objective:Based on the PK/PD characteristics of antibacterial to compare the antibacterial activity between cefaclor generics and original reference drugs,simulate the probability of target attainment of the key PK/PD parameter for originals and generics,and explore the key role of PK/PD characteristics in achieving the efficacy consistency for antimicrobial generic.Methods:1.Collect 383 clinical isolates of bacteria from our hospital（including 186Staphylococcus strains,89 Escherichia coli strains,53 Streptococcus pneumoniae strains and55 Haemophilus influenzae strains）,use agar or broth double dilution method to determine the minimum inhibitory concentration of 5 cefaclor preparations（including 2 original localized preparations CEF-S1 and CEF-C1,3 domestic generic preparations CEF-S2,CEF-C2 and CEF-C3）against clinical strains,and compare the in vitro antibacterial activities of each preparation.2.Draw the killing time curve of cefaclor preparations against Streptococcus pneumoniae ATCC 49619 at each dilution concentration level in the range of 1/2 MIC to 8MIC,and compare the killing time effect of each preparation.3.Monte Carlo simulation method was performed to simulate the clinical efficacy target value f%T>MIC achieved by each preparation after the recommended dose of cefaclor was given to against pathogens,and to explore the possible impact of the rate of achievement of f%T>MIC target value on the curative efficacy for each preparation.Results:1.The results of in vitro susceptibility test showed that the MIC₅₀ were the same between cefaclor original and generic preparations against Staphylococcus bacteria,Escherichia coli,Streptococcus pneumoniae and Haemophilus influenzae,respectively 4μg/m L,2μg/m L,2μg/m L and 8μg/m L.The MIC₉₀ of original preparations against these strains wre 32μg/m L,4μg/m L,2μg/m L and 16μg/m L,respectively.The MIC₉₀ of generic preparations against these strains were one-fold higher than MIC₉₀ of original against these strains,which were 64μg/m L,8μg/m L,4μg/m L and 32μg/m L,respectively.2.The static sterilization efficiency of cefaclor original preparations against Streptococcus pneumoniae ATCC 49619 in the concentration range of 1/2 MIC to 8 MIC is higher than that of generics.3.For the f%T>MIC target value of 50%:when MIC≤0.25μg/m L,except CEF-C1,the PTA of each preparation reached more than 90%;when MIC=0.5μg/m L,the PTA of original CEF-S1 and generic CEF-S2 reached more than 90%,while the PTA of other preparations were all lower than 90%;when MIC=1μg/m L,only the PTA of original CEF-S1 reached 90%（were 95.51%）,the rest of preparations were all lower than 90%;when MIC≥2μg/m L,the PTA of all preparations were less than 90%.Within MIC range from 0.0625μg/m L to 4μg/m L,the PTA of original CEF-S1 was always higher than that of generic CEF-S2.Conclusion:The f%T>MIC of cefaclor with time-dependent antibacterial effects is a key PK/PD parameter closely related to the antibacterial efficacy.Theoretically,the higher f%T>MIC,the better curative efficacy.The generic CEF-S2 had been reported to be bioequivalent to the original CEF-S1.The simulated results show that,there was a difference in PTA of f%T>MIC for the clinical curative efficacy between two preparations after appling the same dosage regimen to against certain sensitive pathogens with MIC（0.5～2μg/m L）.The original CEF-S1 had the higher PTA values,which could mean that it is more likely to exert a better therapeutic efficacy.While the generic CEF-S2 with lower PTA values of f%T>MIC,it’s not easy to exert clinical treatment efficacy in vivo.Therefore,although the antimicrobial generic has passed the bioequivalent test,it can’t be guaranteed that generic could achieve absolute therapeutic equivalence with the original.It is recommended that when evaluating the consistency of antimicrobial generic with the original,the equivalence of PK/PD parameters closely related to antibacterial efficacy should be investigated,so as to further ensure the antimicrobial generic could produce the same therapeutic efficacy with original under the actual clinical bacterial resistance,in order to get closer to a real therapeutic equivalence.