Population Pharmacokinetics And Pharmacokinetic/Pharmacodynamic Study Of A New NFQ Nemonoxacin

In recent years, drug resistance rate of Gram-positive bacteria to β-lactams and erythromycin increased rapidly in clinical treatment of community-acquired pneumonia (CAP). Amount of drug-resistant S. pneumoniae (DRSP) and community-acquired methicillin-resistant S. aureus (CA-MRSA) also increased daily. Meanwhile, some Haemophilus influenzae was found to be ampicillin-resistant but with negative β-lactamase. So appropriate antimicrobial agents and optimum regimens have become the only solution for increasing drug effectiveness and inhibiting bacteria resistance. Drawing up an effective regimen is based on combined consideration of pharmacokinetics and pharmacodynamics and consequently obtain enough drug concentration in infection sites to get ride of bacteria and achieve the best clinical and microbial effect. Hence, it is necessary to conduct population pharmacokinetic and pharmacokinetic/pharmacodynamic studies in clinical trials for assessment of new antimicrobial agents with respect to international standards to acquire pharmacokinetics characteristics of the new agents in patients with different infection and draw up the best dose regimen combined pharmacodynamic data.Quinolones have wide spectrum, low toxicity, high oral bioavailability and excellent tissue permeability, especially in lung the tissue drug concentrations are2to9fold higher than plasma concentration. Nowadays quinolones have been widely used in clinical practice for the efficient treatment of CAP patients.Nemonoxacin, a novel non-fluorinated quinolone (NFQ) acts by inhibiting bacterial DNA gyrase. In vitro activity results showed it retained potent broad-spectrum activities against a variety of gram-positive organisms like Penicillin-susceptible, Penicillin-intermediate and Penicillin-resistant Streptococcus pneumonia (PSSP, PISP, PRSP), and methicillin-resistant Staphylococcus aureus (MRSA), gram-negative organisms like Moraxelle catarrhalis and Haemophilus influenzae, atypical pathogens like Legionella, Mycoplasma pneumonia and Chlamydia pneumonia.The study is based on model based drug development (MBDD) technique which is a bench-to-bedside piece-wise knowledge integration pharmacokinetic/pharmacodynamic (PK/PD) platform. A oral nemonoxacin PPK model was developed with the data integrates the data in PPK study throughout phase Ⅱ and phase Ⅲ clinical trial and the data from healthy subjects in phase I clinical trial. The PPK model was applied for quantitation of influence of physiological and pathological factors on absorption, distribution, metabolism and elimination of nemonoxacin in CAP patients. Bayesian feedback was used to obtain individual PK parameters of each subject which were then combined with pharmacodynamic parameter (minimum inhibitory concentration, MIC) to build a PK/PD model. Monte Carlo simulation was conducted to screen the optimal dose regimen of nemonoxacin in CAP patients and give a support to application of the drug safely and effectively. Meanwhile, another aim of the study is to develop a MBDD platform throughout phase Ⅰ to Ⅲ clinical trial based on PPK and PK/PD modeling and simulation going with the tide of world development.The project includes the following4parts:Part1Pharmacokinetic study of nemonoxacin capsule following single and multiple doses in healthy subjectsThe pharmacokinetic study of nemonoxacin following single dose included three stages. The first stage was a randomized, open, placebo-controlled, three periods, three doses of cross-over study in which to evaluate the safety and pharmacokinetics of nemonoxacin.12subjects (male:female=6:6) were randomized to three groups and administered orally250mg,500mg and750mg nemonoxacin under fasting. After washout of seven days, these12subjects received500mg nemonoxacin with high-fat meal to study the food effect in second stage. Twenty four subjects were enrolled in the third stage to study pharmacokinetics after multiple doses of500mg and750mg nemonoxacin. These subjects administered500mg or750mg nemonoxacin orally once daily for10days. The plasma and urine samples were collected on schedule. Non-compartmental and compartmental pharmacokinetic parameters were calculated using WinNonlin6.0software (Pharsight Corp.CA USA). LC-MS/MS method was used to determine the concentration of nemonoxacin in plasma and urine. Following oral administration of250mg,500mg and750mg nemonoxacin, Cmax was rapidly reached (within1to1.5h), values were3.237±0.667μg/mL,5.909±1.349μg/mL, and8.525±1.739μg/mL, respectively. AUC0-(?) were21.52±3.36μg·h/mL,42.41±5.83μg·h/mL, and66.54±7.90μg·h/mL, respectively. The values of T1/2were10.73h,12.83h and11.01h, respectively. It shows that AUC0-∞AUC0-72h and Cmax were linear comparatively with dose increase proportion over the dose range of250mg to750mg. In the fed state, the absorption of nemonoxacin was slowed and decreased, Tmax delayed2.5h, Cmax and AUC0-∞decreased20%and18%. It indicated the drug should be administered under fasting. Nemonoxacin was not found to be accumulated in subjects after multiple doses of both500mg and750mg. About70%drug eliminated from urine. Part2Pharmacokinetic study of nemonoxacin capsule in CAP patientsIn phase Ⅱ clinical trial, an open design of study were conducted to enroll18CAP patients to study pharmacokinetics of CAP patients following oral administration of nemonoxacin500mg (n=12) or750mg (n=6) once daily for7to10days. The plasma and urine samples were collected on schedule. Non-compartmental and compartmental pharmacokinetic parameters were calculated using WinNonlin6.0software (Pharsight Corp.CA USA). LC-MS/MS method was used to determine the concentration of nemonoxacin in plasma and urine. Following oral administration of multiple dose of500mg and750mg nemonoxacin in CAP patients, Cmax was rapidly reached (within1.7to1.9h), values were5.42±2.12μg/mL and8.49±3.4μg/mL, respectively. AUC0-∞were54.5±18.25(μg·h/mL and71.2±16.15μg·h/mL, respectively. The values of T1/2were9.15±1.37and8.87±h, respectively. It shows that AUC0-∞and Cmax were linear comparatively with dose increase proportion over the dose range of500mg to750mg in CAP patients. Following multiple dose of500mg and750mg nemonoxacin, there was no statistical difference in the primary non-compartmental parameters (Tmax, Cmax, Cmin, Cave and AUC0-∞) between healthy subjects and CAP patients with same dose. The difference of compartmental parameter T1/2,Ka between healthy subjects and CAP patients in both500mg and750mg group was statistically significant. Absorption of nemonoxacin was slower in CAP patients than in healthy subjects expressed in3-5fold prolonged T1/2,Ka-This is might because of no restriction on diet in CAP patients compared to under fasting in healthy subjects. It indicates that the drug should be administered in patients under fasting. This result is different to that in part1that dining slowed down the absorption of nemonoxacin. Although the drug absorbtion was delayed1.25-1.5h in CAP patients, AUC was similar between CAP patients and healthy subjects. That indicate that CAP patients may not need fasting before drug administration The urine cumulative excretion rate of nemonoxacin in CAP patients and healthy subjects are similar.Part3Population pharmacokinetic study of nemonoxacin capsule in CAP patientsIn phase II and phase II clinical trial of nemonoxacin capsule, totally56and57CAP patients were enrolled for PPK study with463plasma samples. Including1528plasma samples from phase I clinical trial, totally1991plasma concentrations were used to develop and validate a PPK model using NONMEM program, PDXPOP software, R program and XPOSE program. The basic model is two compartment model adding inter-individual variation of CL、V2、Q、 V3and Ka with multiplicative model, intra-individual (residual) was expressed by a multiplicative model. Twenty nine covariates were screened using forward inclusion and backward elimination. It was found that CL is influenced by disease status and creatinine clearance (CLcr). Body weight, basic disease and age influenced V2. Ka is influenced by whether patients are fasting or not. The final modeling is as following:The typical value of CL/F、V2、F、Q/F、V3/F and Ka were12.8L/h、91.9L、1.14L/h、21.6L and2.531/h. Stability of the final PPK model was accepted by Bootstrapping for1000times with99.8%convergence and overlapped95%confidence interval (CI). Individual PPK parameters were calculated using Bayesian calculation with layered covariate. The results indicate that physiological and pathological status influenced absorption, distribution, metabolism and elimination of nemonoxacin in human. Clearance of nemonoxacin decreased in patients with mild kidney function impairment, basic disease, over60years old and low body weight (<60kg). Central volume of distribution of nemonoxacin decreased in patients with fasting status, basic disease, younger than40years old and low body weight (<60kg). Ka decreased in patients with CAP and dining, which indicates dining may decrease absorption of nemonoxacin in human. The results are similar to that of part2of this study.Part4Population pharmacokinetic/pharmacodynamic study of nemonoxacin capsule in CAP patientsBasing on the PPK model developed in part3, concentration data were simulated following multiple doses of500mg once daily and750mg once daily in113CAP patients who attended phase II and phase III clinical trial. Simulated plasma concentrations of2260individuals were obtained to calculated individual PK parameters with WinNonlin software. Matlab software was used to carry on Monte Carlo simulation of PTA and CFR for2regimens with combination of MIC results of302strains including PSSP、PISP、PRSP. Haemophilus influenzae, Moraxelle catarrhalis、MSSA、MRSA. The results for CFR calculation indicate that when AUC/MIC90and Cmax/MIC90target were fixed as25and5, both regimens achieve over95%of CRF. When AUC/MIC90and Cmax/MIC90target were fixed as63and8, both regimens achieve over90%of CRF except that CRF of the regimen of500mg to MRSA was lower than90%(88.5%and83.4%). The results for PTA calculation indicate that when MIC90of the main pathogenic bacteria for CAP was lower than lmg/L, both regimens achieve PTA level over90%for PK/PD taget of AUC24/MIC9o=25and Cmax/MIC-5. If PK/PD taget of AUC24/MIC90and Cmax/MIC90are63and8, MIC90of pathogenic bacteria need to be lower than0.5mg/L for ideal drug effect. Overall, both of the regimens for nemonoxacin capsule,500mg and750mg once daily for7to1Odays, can give optimal clinical and microbiological effect for CAP patients.