Integrative population pharmacokinetic/pharmacodynamic analysis of nemonoxacin capsule in Chinese patients with community-acquired pneumonia

Introduction: Nemonoxacin is an innovative quinolone antibiotic for treatment of community-acquired pneumonia (CAP). As more data are available from clinical studies, it is necessary to perform an integrative pharmacokinetic/pharmacodynamic (PK/PD) analysis to support and justify the optimal dosing regimen of nemonoxacin in clinical practice. Methods and Results: We developed a population PK model using non-linear mixed effect model based on the data of 195 Chinese subjects receiving nemonoxacin in phase I to III clinical trials. The base model was a standard two-compartment PK model defined by clearance (12 L/h) and central volume of distribution (86 L). Covariates included creatinine clearance (CLcr), body weight (BW), sex, disease status and food. Compared to the subject with BW 60 kg, Cmax and AUC0‐24, ss reduced by 24% and 19% in the subject with BW 80 kg, respectively. Compared to the subject with CLcr 150 ml/min, AUC0‐24, ss and T1/2 increased by 28% and 24%, respectively in the subject with CLcr 30 ml/min. Compared to the fasted status, Tmax of nemonoxacin increased by 1.2 h in the subject with fed status. Effects of sex and disease status on PK parameters were small (change of PK parameters ≤19%). AUC0–24/MIC and %T > MIC were identified as the optimal PK/PD indices for predicting clinical efficacy. The AUC0-24/MIC target was 63.3, 97.8, and 115.7 against Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae, respectively. The %T > MIC target was 7.96% against Klebsiella pneumoniae. Monte Carlo simulation showed that treatment with nemonoxacin 500 mg q24 h could attain a PK/PD cutoff value higher than the MIC90 against S. pneumoniae and S. aureus. The corresponding cumulative fraction of response (CFR) was greater than 93%, while nemonoxacin 750 mg q24 h would provide higher PK/PD cutoff value against Haemophilus parainfluenzae, and higher CFR (83%) than 500 mg q24 h. Conclusion: Integrative PK/PD analysis justifies the reliable clinical and microbiological efficacy of nemonoxacin 500 mg q24 h in treating CAP caused by S. pneumoniae, S. aureus, and K. pneumoniae, irrespective of patient sex, mild renal impairment, empty stomach or not. However, nemonoxacin 750 mg q24 h would provide better efficacy than 500 mg q24 h for the CAP caused by H. parainfluenzae in terms of CFR.

creatinine ≥ 1.1 times the upper limit of normal (ULN); (7) Alanine or aspartate aminotransferase ≥ 3 times ULN within 48 h before enrollment; total bilirubin or direct bilirubin ≥ 1.1 times ULN; (8) Neutrophil count < 1500/mm 3 within 48 h before enrollment; (9) Received antibacterial agents for more than 24 hours within 72 hours before enrollment, or use of quinolones within 14 days and had history of allergy to these antibacterial agents; (10) Received other investigational drugs within 30 days before enrollment.

Efficacy evaluation
Clinical efficacy Clinical success: all symptoms and signs related to pneumonia disappeared. Results of chest X-ray and laboratory tests normalized after treatment and antibacterial therapy was no longer needed. Clinical success was also considered if the persistent clinical symptoms, signs, or laboratory abnormalities after therapy were part of the underlying disease rather than active infection.
Clinical failure was considered if a subject satisfied any of the following: (1) main symptoms or signs persisted or did not disappear completely or became worse after therapy; (2) emergence of new symptoms or signs related to pneumonia, or requiring treatment other than nemonoxacin; (3) had to switch to other antimicrobial treatment even though symptoms or signs were improved; (4) received other antimicrobial agents during the period from Visit 3 to Visit 4; (5) discontinued study drug therapy within 3 days after initiation of treatment due to adverse events.
Indeterminate was considered if a subject satisfied any of the following: (1) lacking post-treatment evaluation data; (2) additional antibacterial agents were used for other indication, which was not specified by study protocol; (3) discontinued study drug therapy due to reasons unrelated to nemonoxacin.

Microbiological efficacy
Microbiological efficacy was evaluated at Visit 3 (end of treatment) and Visit 4 (posttreatment follow-up Visit), which was recorded as: (1) eradication: baseline pathogen was negative in sputum culture at Visit 4; (2) assumed eradication: the disease under study was cured in the opinion of clinicians, but no sputum was available for culture; (3) assumed persistence: no sputum was available for culture in patients who were considered clinical failure; (4) persistence: baseline pathogen still positive in sputum culture at post-treatment follow-up Visit; (5) Indeterminate: microbiological efficacy could not be evaluated, e.g., follow-up visit was not performed on time.
SUPPLEMENTARY FIGURE 1 | Histogram of PK parameters of nemonoxacin based on bootstrap dataset. Bootstrap analysis of final PPK model was repeated 200 times.
SUPPLEMENTARY FIGURE 2 | Visual predictive check for the final population PK model of nemonoxacin. Blue circle: actual value; red solid line: mean of actual value; red dash line: 95% confidence interval for actual value; red area: 95% confidence interval for mean of simulations; blue area: 95% confidence interval for 5% or 95% percentile of simulations. CAP: community-acquired pneumonia; PK: pharmacokinetic.
SUPPLEMENTARY FIGURE 3 | Effect of covariate on Cmax of nemonoxacin at steady state. In each line, one covariate had the specified value, and value for other covariates came from the actual. Data was shown as mean±95% confidence interval. Nemonoxacin regimen: oral 500mg every 24h for 10 days. BW: body weight, DisStat: disease status, CAP: community-acquired pneumonia.
SUPPLEMENTARY FIGURE 4 | Effect of covariate on AUC0-24 of nemonoxacin at steady state. In each line, one covariate had the specified value, and value for other covariates came from the actual. Data was shown as mean±95% confidence interval. Nemonoxacin regimen: oral 500mg every 24h for 10 days. BW: body weight, DisStat: disease status, CAP: community-acquired pneumonia.
SUPPLEMENTARY FIGURE 5 | Effect of covariate on Tmax of nemonoxacin at steady state. In each line, one covariate had the specified value, and value for other covariates came from the actual. Data was shown as mean±95% confidence interval. Nemonoxacin regimen: oral 500mg every 24h for 10 days. BW: body weight, DisStat: disease status, CAP: community-acquired pneumonia. SUPPLEMENTARY FIGURE 6 | Effect of covariate on T1/2 of nemonoxacin at steady state. In each line, one covariate had the specified value, and value for other covariates came from the actual. Data was shown as mean±95% confidence interval. Nemonoxacin regimen: oral 500mg every 24h for 10 days. BW: body weight, DisStat: disease status, CAP: community-acquired pneumonia. SUPPLEMENTARY FIGURE 7 | Effect of covariate on CL/F of nemonoxacin at steady state. In each line, one covariate had the specified value, and value for other covariates came from the actual. Data was shown as mean±95% confidence interval. Nemonoxacin regimen: oral 500mg every 24h for 10 days. BW: body weight, DisStat: disease status, CAP: community-acquired pneumonia.
SUPPLEMENTARY FIGURE 8 | Effect of covariate on V/F of nemonoxacin at steady state. In each line, one covariate had the specified value, and value for other covariates came from the actual. Data was shown as mean±95% confidence interval. Nemonoxacin regimen: oral 500mg every 24h for 10 days. BW: body weight, DisStat: disease status, CAP: community-acquired pneumonia.
SUPPLEMENTARY FIGURE 9 | Effect of covariate on MRT0-inf of nemonoxacin at steady state. In each line, one covariate had the specified value, and value for other covariates came from the actual. Data was shown as mean±95% confidence interval. Nemonoxacin regimen: oral 500mg every 24h for 10 days. BW: body weight, DisStat: disease status, CAP: community-acquired pneumonia.
SUPPLEMENTARY FIGURE 10 | Effect of covariate on Cmin of nemonoxacin at steady state. In each line, one covariate had the specified value, and value for other covariates came from the actual. Data was shown as mean±95% confidence interval. Nemonoxacin regimen: oral 500mg every 24h for 10 days. BW: body weight, DisStat: disease status, CAP: community-acquired pneumonia.
SUPPLEMENTARY FIGURE 11 | Change in OBJ (deltaOBJ) for randomization test of final PPK model of nemonoxacin. Name of relation (i.e., covariate-parameter) was shown in the title of each panel. For each relation, the randomization was test 1000 times. During each test, only one covariate (for one parameter) was randomized, other four covariates were included in the model. In the final model, disease status was added on V3; food was added on KA, Tlag and F; CLcr was added on CL; sex was added on V2; body weight was added on CL, V2, V3 and Q. deltaOBJ = OBJ (test model) -OBJ (base model). OBJ means objective function value.
SUPPLEMENTARY FIGURE 12 | Correlation between nemonoxacin PK/PD index and clinical efficacy against each bacteria. The left, medium and right columns indicate results for Ln(AUC0-24/MIC), Ln(Cmax/MIC) and %>MIC, respectively. Each row represents results for one bacteria. In each panel, Y axis indicates probability of successful clinical efficacy. Red circle and blue line are actual data and fitting from logistic regression model, respectively. The box plot with light green characterize distribution of actual data: left limit, inner line and right limit of box are 25%, 50% and 75% percentile of actual data, respectively.  -IIV V2-IIV V3-IIV KA_IIV CL-IOV1 CL-IOV2 TLAG-IIV   V2   Concentration-dependent, PK/PD index maybe Cmax/MIC because P value is the lowest Slope and P value were based on logistic regression analysis. P value is for slope, the test statistic is Wald χ 2 , the formula is χ 2 =(slope/standard error(slope)) 2 . If P value is lower, the significance of the logistic regression model is higher. Note: ratio of AUC0-inf = AUC0-inf_CLcr=0/AUC0-inf_control. Nemonoxacin regimen: 500mg (q24h) for 10 days. The AUC0-inf was calculated based on 0-72h simulation data after last dose.