Population Pharmacokinetics And Pharmacodynamics Of Levofloxacin

In vitro and in vivo response-exposure studies have demonstrated that both dose and dosing schedules may influence the effect of an antimicrobial.Dosing optimization actually is the balance between the pharmacokinetics(PK) and the pharmcodynamics (PD).PK is the course of absorption,distribution,metabolism and elimination of the drug,which is considered to be 'how the body does to the drug'.PD is the course of the pharmacological effects against certain pathogen under the fluctuating concentrations in vivo,which can be stated as 'how the drug does to the microbial'.An appropriate regimen should attain a satisfactory PD endpoint and at the same time lowers the drug toxicity.However,it is not unusual that a fixed regimen in the target population can produce clinical failures to some patients because of under-dosage while causing toxicity to the other patients due to excessive dosing.The diversity of drug effects in an infection population comes from the hierarchies of PK variability and the hierarchies of the bactericidal effects of the antimicrobial against different pathogens.So it is always the physician's dream to find out the right dose for their patients.The population analysis method throws some light on this situation.The intrinsic character of the PPK method has the power to extract the essential information from the sparse clinical data and deduce some useful 'what if' hypothesis which tell the physician how to decide a regimen in different clinical situations.Besides,combining with the PD surrogates,such as fAUC/MICs or C_max/MICs,a stochastic simulation can be done according to the PPK model and figures out the probability that a certain dosage attains a certain clinical endpoint.The PPK/PD approaches are not only the promising alternatives to make the rational clinical decisions but also will bring an overwhelming revolution in the process of drug developments.Levofloxacin,the active(-)-S-isomer of the racemic drug substance of oxfloxacin, has excellent performance against most significant pathogens of the community-acquired lower respiratory infections.It is also highly active against some important pathogens that are resistant to the other type of antibiotics,such as penicillin intermittent Streptococcus pneumoniae(PISP) or penicillin resistant Streptococcus pneumoniae(PRSP),macrolide resistant Streptococcus pneumoniae and TEM-1β-lactamase producing Haemophilus influenzae.Levofloxacin has very good pharmacokinetic characteristics,including its complete oral bioavailability,wide distribution in the body,and high concentration in the infection sites.Its high bactericidal activity and its safety dosing make it one of the first choices of treating the community-acquired pneumoniae(CAP) and the acute extraction of the chronic bronchitis(AECB),which are the two common infection types and the significant morbility and morbidity causes of infectious diseases.However it is pity that till now we have little PK data of levofloxacin in the CAP and AECB patients.Most of the time,differences of PK data between the volunteer and the patients can not be ignored.The PK parameters of a drug in the patients usually have much wider distributions due to wider distributions of demographical baselines and complex clinical pathological conditions.If we arbitrary embed the PK parameters from the volunteer to the patients,the deviation of estimation might occur and this deviation might form the physician a wrong map of the drug in the patients and thus an improper clinical decision made.The aim of this thesis is to explore the PPK model of levofloxacin in CAP and AECB patients.The PPK model will then be used to characterize the source of PK variability in the target population quantitatively and form the rational regimens in different clinical situations.The PD data including the clinical and microbial responses as well as safety data are dedicatedly selected.The establishment of a PPK/PD model is expected to describe the relationship between the PK and the PD,which will be used for dosing optimization.The knowledge gained in the PPK/PD model push the study to a more mechanical exploration focusing on finding out a resolution of drug-resistant prevention strategy. Chapter1.Establishment and validation of the levofloxacin PPK modelObjective:To develop a PPK model of levofloxacin,which will be used to describe the PK characteristics of the drug in different subpopulations.Methods:A nonlinear mixed effects model was developed with NONMEMâ…¥(?) for 164 CAP/AECB patients and 18 healthy volunteers.The average 3～4 sparse drug concentration samples from each patient were collected on the drug absorption, distribution and elimination phases respectively.The data of the volunteer come from a phaseâ… clinical trial of which a density sampling strategy was adopted.The drug concentrations were determined by the reverse high performance liquid chromatography method.The detection limit of the method is 0.01 mg/L with a linear range from 0.01 mg/L to 5 mg/L.The effect of age,weight,sex,creatine clearance (CCR),food,disease status,and drug combinations on the PK parameters were evaluated.The bootstrap method was used to test the stability and predictive function of the model.Results:A two-compartment linear model with exponential residual errors best described the data collected.Both CCR and sex were found to significantly affect the apparent clearance while weight and sex affected the volume distribution of the central compartment.The typical population values of the apparent clearance(CL/F),volume distribution of the central compartment(V₂),the inter-compartment clearance(Q), volume distribution of the peripheral compartment(V₃) and the absorption rate constant (k_a) were 7.82 L/h,64.8 L,0.286 L/h,5.9 L and 1.36/h respectively.The inter-subject variances of CL/F and ka in the population were 15.52%and 79.94%respectively.In the process of bootstrapping validation,the narrow biases less than 10%of the PK parameters were found between the original data and the mean value of the bootstrap data sets,with an inverse Gaussian distribution of PK parameters in the bootstrap data sets.The MAE_imp and MSE_imp(%) were both fell within 5%indicated that the model had excellent prediction function.Conclusion:The PPK model was highly consistent with the physiological characteristics of levofloxacin.The model could robustly estimate the PK parameters by the sparse information.The inter-individual variance of CL/F is relatively narrow indicating its clinical application.The well-performance of the prediction ability of the model was the foundation of the stochastic simulations. Chapter2.Clinical application of the PPK modelObjective:To develop dosing strategies for levofloxacin in different demographical and pathological situations.Methods:The definition about the target population of levofloxacin was set according to the indications of the 500 mg once-daily regimen in this study.The variance-covariance matrix of the demographical baselines including age,weight and creatine clearance,the PK parameters and their inter-/intra- variances were embedded into NONMEM ADVAN6 TRANS1.Clinical trial simulation of levofloxacin with 1000 target population was conducted.Response surface analysis(full quadratic model) was then used to quantify the relationship between the covariances and the PK parameters to find out some special clinical situations that the adjustments of the regimen might be required.Results:The decreased creatine clearance caused a delayed elimination of the drug. A 10-days dosing simulation didn't find out significant accumulation of the drug in mild renal deterioration patients(creatine clearance ranged from 50～80 mL/min). Multiple doses of levofloxacin 500 mg once-daily caused mild accumulation in the moderate renal deterioration patients(creatine clearance ranged from 20～50 mL/min). When the creatine clearance fell below 20 mL/min(the severe renal deterioration),the obvious accumulation might occur on the third day of dosing which diminished if the regimen shifted to once every 48 h.There was a linear relationship between age and AUC_{0～∞},with r² = 0.4179.2mg.h/L of AUC_{0～∞} was escalated by every 5 years in the population,and the old age(70 y above) subgroup had a 20%higher AUC_{0～∞} than the average level of the population. The AUC_{0～∞} in the moderate renal deficient patient was also 20%higher than the average level,which implied that the physician could accommodate the amount of dosage with art for such patient.Gender might have some influences on AUC_{0～∞},that the AUC_{0～∞} in females were 10 mg.h/L higher than that in males.However such differences might have no significant clinical meanings.C_max was the only parameter that no surrogate was found to be predicted by.C_max was prone to have relatively flat distribution in the population which indicated that the parameter was related to the amount of dosage.Elevated dosing expected a higher C_max in the population.Conclusion:The present regimen of levofloxacin had a highly consistent performance in different subpopulations excepting the moderate and severe renal deficient patients.For the moderate renal deterioration patients,the physician could artistly adjust levofloxacin dosage from 500 mg once-daily to 250 mg once-daily on the second day.However,a strong indication for dosing adjustment was only in patients with severe renal deteriorations,in which the dosing intervals of levofloxacin should be every 48 h.Chapter3.The PPK/PD study of levofloxacin(clinical study)Objective:To illuminate the relationship between the drug exposure and the microbial responses as well as toxicity.Methods:PD study focusing on assessing the microbial responses was conducted on a subset of CAP and AECB patients with available MICs data of causative pathogens. PK parameters of each patient were determined by the Bayesian estimation method. The microbial responses were categorized as eradication,persistent,recurrent, re-infection and replacement.The categories of persistent and recurrent were considered to be microbial failure.The AUC_{0～∞}/MICs and C_max/MICs were obtained as the PPKUPD index.Stepwise logistic regression method was adopted to determine the PPK/PD breakpoint that predicting a positive microbial response.Since all infectious patients in the PPK study were safety evaluable,they were all entered into PD study focusing on assessing the relationship between drug exposure and the toxic responses. Stepwise logistic regression method was adopted to estimate the exposure and response (toxic) relationships.In the process of clinical trial simulation,the drug effects of different regimens of levofloxacin against Streptococcus pneumoniae,which was the most significant pathogen in CAP/AECB were extensively discussed.The probability of different regimens of levofloxacin attaining a positive microbial endpoint in the target population was assessed by stochastic simulations.The MICs distribution data of the wide type strains come from the EUCAST.Results:The regimen of levofloxacin 500 mg once-daily in this study had so excellent microbial responses that only 2 failure cases in the PPK/PD study which were both AECB patients with positive clinical responses,and the causative pathogens were both Pseudomonas aureginosa,which could be persistent in the bronchitis without any infectious symptoms.The stepwise regression analysis failed to find out a PPK/PD breakpoint for any significant pathogens due to patients' good endpoints in this study. In the safety PPK/PD study,a positive correlationship between the age and the ratio of central nervous system(CNS) adverse effect(AE) was found.However,most of the CNS adverse effect was mild and durable without stopping the use of the drug.The age also related to the transient decrease of white blood cell count.The stochastic simulation indicated that only the regimen of 500 mg once-daily could give a satisfactory target attainment rate against Streptococcus pneumoniae,with AUC_{0～∞} /MICs in 88.3%of the population well above 33.7.However,only 3.8%of the population's C_max/MICs were above 10.Conclusion:The regimen of levofloxacin in this study could attain pretty good clinical and microbial responses.Age was positively related to the CNS adverse effects as well as the transient decrease of white blood cell count.However,the AE was mild and the trade-off between the benefit and risk made the balance obviously to the benefit. No exposure related AE was found.Among the different regimens of levofloxacin,only the regimen of 500 mg once-daily could attain a satisfactory endpoint to Streptococcus pneumoniae.In the process of stochastic simulation,a relatively low C_max/MICs ratio in the population stressed necessity to further exploration.Chapter4.The PPK/PD study of levofloxaein(in-vitro study)Objective:To establish a mechanism-based mathematical model of levofloxacin's bactericidal effects against both susceptible and relatively resistant subpopulations of Streptococcus pneumoniae.To assess the antibiotic pressure against Streptococcus pneumoniae due to different levofloxacin regimens from a population view.Methods:Two strains of Streptococcus pneumoniae ATCC49619 and Streptococcus pneumoniae SPN00205,the latter of which was the clinical isolate in the PPK/PD study, were studied.The first step,the MICs and the MBCs of levofloxacin against the two strains were determined by a macrobroth dilution method with initial inoculums of～10⁵ CFU/mL.The second step,a 8 h and a 48 h in-vitro time kill curve studies were conducted for each isolate with different constant drug concentrations,including 1/2×MIC,1×MIC,2×MIC,3×MIC,4×MIC,8×MIC and 16×MIC.A drug free growth control group was set for each experiment.The bacteria count quantification of the susceptible group and the relative resistant group in different concentrations was determined on several time points.The data from the blank,1/2×MIC,1×MIC,2×MIC,4×MIC and 8×MIC concentrations was used to estimate the dummy PD parameters that describe the nonlinear growth rate of bacteria and nonlinear kill rate of the drug against the bacteria in a mechanism-based PK/PD model.The data from the 3×MIC and 16×MIC concentrations was used for model internal validation.A stochastic simulation was conducted to estimate the risk of screening the relative resistant Streptococcus pneumoniae by the different levofloxacin regimens from a population view.In the simulation,the PK data was the in vivo data from the PPK study and the PD parameters come from the time kill curve studies.The duration of drug-microbial interaction was set to 10 days which is the standard levofloxacin therapy course for CAP.Two initial microbial loads in the simulation were～10⁵ CFU/mL and～10⁸ CFU/mL,respectively.The remaining bacteria on the 10^th day in the population were summarised.Results:The PD parameters in the mechanism-based PK/PD model reflected the bactericidal characteristics of levofloxacin against Streptococcus pneumoniae.The model stated that the drug is a concentration-dependent antimicrobial,reaching the maximum bactericidal rate when the concentration attained 8 times of the MICs.The dummy PK parameter of EC₅₀ reflected the potency of drug against bacteria with approximately linear relationship to the MICs.In the stochastic simulation,only the regimen of 500 mg once-daily and 750 mg once-daily had limited bacteria selection pressure on the wide type population of Streptococcus pneumoniae.The simulation also indicated that the monitoring on the Streptococcus pneumoniae with the MICs of 2 mg/L should be emphasized.The MICs of 2 mg/L might be the PPK/PD breakpoint of levofloxacin against Streptococcus pneumoniae.Conclusion:The 500 mg once-daily should be the standard regimen of levofloxacin in clinical due to its excellent clinical/microbial responses and the potential ability to inhibit the development of drug resistance.The 750 mg once-daily short course regimen might perform even better than 500 mg regimen.It is of great value to assess the response and the safety of 750 mg regimen in Chinese population in future researches.