Generic Drugs Based On The PK/PD Characteristics Of Levofloxacin Quality And Efficacy Evaluation Study

At present,the main content of the quality consistency evaluation of generic drugs includes pharmacological equivalence and bioequivalence.Bioequivalence is usually evaluated by pharmacokinetic endpoint indicators C_max and AUC.However,antibacterial drugs do not directly act on the human body,but on bacteria in the body,it may kill or inhibit the growth of bacteria,and may also cause them to multiply.Simply checking the pharmacokinetic parameters such as blood drug concentration in the body does not mean that the antibacterial activity of the antibacterial drugs is also consistent.To scientifically establish standards and evaluate the consistency of antimicrobial efficacy more objectively are a difficult problem in the existing consistency evaluation work.According to data from the National Antibacterial Drug Clinical Application Monitoring Network,in 2018,the consumption ratio of various types of antibacterial drugs ranked first in quinolones,and the widely used drug used was levofloxacin."Expert consensus on the clinical application of antimicrobial pharmacokinetics/pharmacodynamics theory"pointed out that,quinolones are concentration-dependent antibacterial drugs.To obtain good clinical efficacy and antibacterial effects,the PK/PD index that should be investigated is AUC_0-24/MIC,the PK/PD parameters of antibacterial drugs are the key technical parameters to evaluate their clinical efficacy,but the consistency evaluation of generic drugs does not evaluate the PK/PD parameters.Thus,the current conventional technical standards for the consistency evaluation of generic drugs can only indicate the PK parameters that are consistent,and it cannot be guaranteed to be consistent with the antibacterial effect of the branded drug.In recent years,in the study of optimizing the efficacy of quinolones,it is also necessary to evaluate the resistance mutation concentration MPC of antibacterial drugs,because it can show more effective restriction of drug resistance while taking into account the infection control and ability to select mutants.Therefore,this study is based on the PK/PD characteristics of the antibacterial drug levofloxacin,and compares and analyzes the in vitro antibacterial activity,anti-bacterial resistance mutation ability and PK/PD clinical efficacy target achievement of its generic and branded drugs,aiming to establish the correlation between the PK/PD parameter and the quality consistency of antimicrobial generic drugs.In order to obtain more scientific new indicators for bioequivalence research of antimicrobial drugs,this study aims to provide a new reference basis for the consistency evaluation of generic drugs.PurposeBased on the PK/PD characteristics of the antimicrobial drug,it requires investigation whether the generic drug levofloxacin is consistent with the branded drug in three aspects:in vitro antibacterial activity,anti-bacterial resistance mutation ability,and PK/PD clinical target value.In order to evaluate the clinical efficacy of the generic drug and the branded drug equivalence,important reference must be provided.Method1.The agar double dilution method recommended by CLSI was used to determine the effects of 17 Levofloxacin oral preparations of different manufacturers and specifications including branded research drugs and domestic generic drugs（It includes tablets and capsules,of which the branded drug manufacturer number is Levo 1,and the other manufacturers number is Levo 2-Levo 17）on six common clinical strains including Escherichia coli isolated from hospital,a total of 339 strains MIC and calculate their respective MIC₅₀,MIC₉₀and MIC range,and count the sensitivity rate and drug resistance rate of various strains.2.The agar double dilution method was used to determine the MPC of three Levofloxacin generic drugs（Levo 2、Levo 7、Levo 10）and branded drugs（Levo 1）against 76 strains of Escherichia coli and 60 strains of Klebsiella pneumoniae,the equivalent values of MPC₅₀ and MPC₉₀ are calculated,Then,the MPC₉₀ of each manufacturer was marked on the drug time curve of single oral administration of 500 mg levofloxacin,and the%T_>MPC was compared to analyze the anti-drug resistance mutation ability of the generic drugs and branded drugs.3.Combining the PK parameters of three generic Levofloxacin（Levo2、Levo 7、Levo 10）with the branded drug（Levo 1）from bioavailability tests,the PK/PD indexes C_max/MIC、AUC_0-24/MIC、C_max/MPC、AUC_0-24/MPC of four oral preparations including the original drug were compared by single point estimation method and Monte Carlo simulationapply single-point estimation and Monte Carlo simulation to analyze PTA and CFR of the compliance of the PK/PD clinical target value for the three generic drug manufacturers and the branded drug.Result1.In vitro antibacterial activity results show:For Staphylococcus aureus,The MIC₅₀ of Levo 1 is 0.125μg/m L,A total of three generic drugs,including Levo 2 were compared with Levo 1,with a difference of two times,which was 0.25μg/m L.The remaining generics are consistent with levo 1;The MIC₉₀ of Levo 1 is 0.5μg/m L,Three generics including Levo 10 were two-fold different compared to Levo 1,they were 1μg/m L,and the rest of the generics were the same as Levo 1;95.8%sensitive for Levo 1,93.7%less sensitive for six generics including Levo 10;0%resistant for Levo 1 and 4.2%resistant for 14generics including Levo 2.For Streptococcus pneumoniae,the MIC₅₀ of Levo 1 is 0.5μg/m L,11generics such as Levo 2 had a twofold difference compared with Levo1,they were 1μg/m L,the remaining generics are consistent with Levo 1;the MIC₉₀ of all manufacturers is 1μg/m L;the sensitivity rate of all manufacturers to Streptococcus pneumoniae was 100%,and the drug resistance rate was 0%.For Escherichia coli,the MIC₅₀ of all manufacturers is 0.25μg/m L.The MIC₉₀ of Levo 1 is 1μg/m L,12 generics including Levo 2 differ from Levo 1 by a factor of two,which is 2μg/m L,and the remaining generics are consistent with Levo 1;the sensitivity rate of Levo 1 is 85.5%and the sensitivity of 6 generics including Levo 2 is lower than that of Levo 1 by80.3%;The drug resistance rate of Levo 1 is the lowest at only 5.3%;The highest resistance rate was 14.5%with Levo 8.For Klebsiella pneumonia,the MIC₅₀ of Levo 1 is 0.03125μg/m L,the MIC₅₀ of Levo 12 is fourfold higher than Levo 1,which was 0.125μg/m L,15 generic drugs including Levo 2 were twice as many as Levo 1,which was 0.0625μg/m L;for MIC₉₀,Levo 1 is 0.5μg/m L,Levo 10 is twice as high as Levo 1,which is 1μg/m L,the remaining generics are consistent with Levo 1;the sensitivity rate of 17 Levofloxacin oral preparations to Klebsiella pneumonia peaked at 95%from Levo 1,and the lowest was Levo 10 at 88.3%.The drug resistance rate is low,with only 1.6%for Levo1,Levo 3、Levo 6 are consistent with Levo 1,Levo 2 was 5%,the remaining generics were 3.3%.For Haemophilus influenzae,The MIC₅₀ of all manufacturers is0.0156μg/m L.For MIC₉₀,Levo 1 and Levo 7 are at 0.25μg/m L,15 generics such as Levo 2 had a twofold difference compared with Levo 1,they were0.5μg/m L;the sensitivity rate of 17 Levofloxacin oral preparations to Haemophilus influenzae is 100%,and the drug resistance rate is 0%.For Pseudomonas aeruginosa,the MIC₅₀ of all manufacturers is0.5μg/m L;For MIC₉₀,Levo 1 is 1μg/m L,and the others are 2μg/m L.The sensitivity of 17 Levofloxacin oral preparations to Pseudomonas aeruginosa is significantly different.The highest is Levo 1 at 90.4%,and the lowest is Levo 9 and Levo 10 at only 73.1%.The resistance rate of some manufacturers to Pseudomonas aeruginosa is the same as that of the branded drug Levo 1,which is 0%,while the resistance rate of Levo 9 and Levo 10 is 5.7%.2.The results of the anti-drug resistance mutation study show:For Escherichia coli,the MPC₉₀ of Levo 1 is 3.2μg/m L,and the MPC₉₀ of Levo 2、Levo 7 and Levo 10 are 4.096μg/m L.For Klebsiella pneumoniae,the MPC₉₀ of Levo 1 is 4.096μg/m L,Levo 2 and Levo 7 are both 5.12μg/m L,and the MPC₉₀ of Levo 10 is 6.4μg/m L.For EC,the%T_>MPC of Levo 1 was 10.79%,which was higher than that of Levo 2and Levo 7;for KP,the%T_>MPC of Levo 1 was 4.25%,and that of other generic manufacturers was 0%.3.The single-point estimation method and Monte Carlo simulation results show:The PK/PD index results of the four manufacturers showed that for Staphylococcus aureus,the single-point estimate of AUC_0-24/MIC₉₀ reached the target,the branded drug Levo 1 was the highest at 95.8,and the generic Levo 10 was the lowest at 54.5;when AUIC is≥30,the CFR of all manufacturers is greater than 90%,and Levo 1 has the highest CFR,reaching 96.05%,Levo 10 has the lowest CFR,only 93.88%.For Streptococcus pneumoniae,the single-point estimate of AUC_0-24/MIC₉₀ reached the target,Levo 1 at 47.9,and the generics Levo 2and Levo 7 were lower than Levo 1,only 38.6 and 46.8;when AUIC is≥30,all manufacturers had the same CFR of more than 90%,of which Levo1 has the highest CFR,reaching 99.84%,Levo 2 has the lowest CFR,only90.41%.For Escherichia coli,the single-point estimate of AUC_0-24/MIC₉₀ did not reach the target.The highest value of the branded drug Levo 1 was 47.9,and the lowest was Levo 2 at only 19.3.When AUIC is≥125,the CFR of all manufacturers is less than 90%,and the highest CFR of Levo 1 is68.81%,the lowest CFR is Levo 2,only 48.90%.For Klebsiella pneumoniae,the single-point estimate of AUC_0-24/MIC₉₀ did not reach the target.The branded drug Levo 1 had the highest value of 95.8,and Levo 10 had the lowest value,which was only54.5.When AUIC is≥125,the CFR value of all manufacturers is less than90%,and the highest is still Levo 1 at 85.04%,the lowest CFR is Levo 7,only 73.31%.For Haemophilus influenzae,AUC_0-24/MIC₉₀ single-point estimation shows that the branded drug Levo 1 and the generic drug Levo 7 achieved the target at 191.6 and 187.2 respectively,while Levo 2 was the lowest at77.2;when AUIC is≥125,the CFR of Levo 1 and Levo 7 are 92.18%and90.70%respectively,Levo 10 has the lowest CFR,only 86.65%.For Pseudomonas aeruginosa,the single-point estimate of AUC_0-24/MIC₉₀ did not reach the target.The highest value of the branded drug Levo 1 was 47.9,on the other hand,Levo 2 was the lowest at only19.3;when AUIC is≥125,the CFR value of all manufacturers is very low,with Levo 1 being the highest at only 23.80%,Levo 10 has the lowest CFR,only 4.27%.Single-point estimation with Monte Carlo simulation based on MPC showed that for EC and KP,the AUC_0-24/MPC₉₀ was not greater than 22 in all manufacturers,but Levo 1 was still the highest,which was 74.91%and68.41%;when MPC was≤1.28μg/m L,the PTA of EC and KP in achieving AUPC≥22 was higher than 90%and above from each manufacturer.Conclusion1.In the study of in vitro antibacterial activity,it was found that the antibacterial ability of levofloxacin from various manufacturers in the market was uneven,and the antibacterial activity of some generic manufacturers was significantly different compared with the branded drug.Among the oral preparations of levofloxacin from 17 manufacturers,the MIC90 of the generic Levo 8,Levo 10,Levo 12 is higher than the branded drug Levo 1.The MIC₅₀ of Levo 12 to KP is 4 times higher than Levo 1;This is likely to cause treatment effects during clinical treatment.The results of the study show that the in vitro antibacterial activity of levofloxacin generic drugs from various manufacturers on clinically important pathogens is different from that of the branded drug.It is recommended that the PK/PD characteristics of antibacterial drugs should be combined with their PK/PD characteristics when evaluating the consistency of antibacterial drugs.The MIC is investigated to ensure that the generic drug has the same antibacterial activity as the branded drug under the actual clinical bacterial resistance.2.Among the commercially available levofloxacin oral preparations,there are generic drug manufacturers whose resistance to mutation prevention is lower than that of the branded drug.The MPC experiment compares the difference between the generic drug and the branded drug manufacturer in the ability to prevent drug resistance mutations.The manufacturer Levo 1 has better anti-drug resistance mutation ability than the other three manufacturers,while the generic drug Levo 10 has relatively poor anti-drug resistance mutation ability.The drug concentration time of the branded drug higher than MPC is the longest than any generic drug,especially for the clinical strain KP.Only the C_max of the branded drug exceeds MPC₉₀,while the C_max of the other three generic drugs are lower than MPC₉₀.The course of action is to determine the MPC of pathogenic bacteria and try to prolong the time during which the blood drug concentration is higher than MPC during the treatment period,which can inhibit both mutation and growth of drug-resistant mutants to the greatest extent.It is suggested that under the complex situation of real clinical drug-resistant bacteria,when evaluating the consistency of antimicrobial generic drugs,the consistency of their MPC parameters can be investigated,and the difference in the ability of generic drugs and branded research drugs to prevent drug resistance mutations can be explored.3.Combining the in vitro antibacterial activity and the anti-drug resistance mutation experiment of the first two parts of generic drugs Levo2,Levo 7,Levo 10 and the branded drug Levo 1 with their corresponding PK parameters,analyzes the final PK/PD indicators.The single-point estimation method was used to compare the PK/PD indicators of generic drug manufacturers and branded research drug manufacturers,and Monte Carlo simulation was used to compare the PTA and CFR of different bacteria of each manufacturer.The results showed that the PK/PD of the branded levofloxacin drug was different from that of the generic drug.Regardless of the bacteria,the branded drug Levo 1 always had the highest CFR.