Quantitative comparison of the efficacies and safety profiles of three first-line non-platinum chemotherapy regimens for advanced non-small cell lung cancer.

Objectives: The purpose of this study was to quantify the efficacies and safety profiles of the three first-line non-platinum chemotherapy regimens recommended in the National Comprehensive Cancer Network guidelines. Materials and Methods: The PubMed and Cochrane Library databases were searched comprehensively, and clinical trials involving patients with advanced non-small cell lung cancer treated with one of three first-line non-platinum regimens (gemcitabine combined with vinorelbine, gemcitabine combined with docetaxel, or gemcitabine alone) were included in the analysis. A parametric proportional hazard survival model was established to analyze the time course of overall survival (OS). The objective response rate (ORR) and incidence rates of grade 3-4 adverse events (AEs) were summarized using a single-arm meta-analysis with a random-effects model. Results: Seventeen studies met the inclusion criteria. Age and performance status (PS) scores were significant predictors of OS. For each 10-years increase in age, mortality risk increased by 18.5%, and the mortality risk increased by 4% for every 10% increase in the proportion of patients with a PS score of 2. After correcting for the above factors, we found that the three first-line non-platinum chemotherapy regimens did not differ based on OS or toxicity. Conclusion: There was no significant difference in OS or toxicity among the three first-line non-platinum chemotherapy regimens. Age and PS scores were significant predictors of OS, and their heterogeneity across different studies should be considered in cross-study comparisons and sample size estimations when designing clinical trials.

Development and Application of the Placebo Response Model in Clinical Trials for Primary Sjögren's Syndrome.

This study aimed to develop a placebo response model for pharmaceutical clinical trials of primary Sjogren's syndrome,and to quantitatively analyze the distribution and related factors influencing the placebo response to further optimize the design of clinical trials and evaluate the results of single-arm clinical trials. Public databases, including PubMed, Embase, and Cochrane Library were searched for reports on randomized placebo-controlled trials for Sjögren's syndrome which used the change from baseline in ESSDAI score as the primary outcome. The model-based meta-analysis method was used to evaluate the time course and the related influencing factors of the placebo response for ESSDAI in such clinical trials. A virtual placebo control group was constructed based on the final placebo response model to determine the treatment efficacy of belimumab and cyclosporine A for primary Sjögren's syndrome in a single-arm study. A total of 12 studies involving 450 subjects were included in the analysis. The established model described the time-course characteristics of the changes in ESSDAI score from the baseline in the 48 weeks placebo group. We found that the onset time of placebo response was approximately 12 weeks, and its efficacy plateaued at 48 weeks. The baseline ESSDAI score had a significant effect on the maximum value of the placebo response; the maximum value of the placebo response decreased by 0.552 for every 1 score rise in the baseline ESSDAI score. The efficacy of belimumab and cyclosporine A in the single-arm trial was comparable to that of the placebo response at the same baseline; no significant therapeutic advantage was observed. The placebo response model established in this study could provide a basis for designing clinical trials for primary Sjogren's syndrome in the future. It may also provide a reliable external efficacy control standard for single-arm clinical trials.

Relationship between antofloxacin concentration and QT prolongation and estimation of the possible false-positive rate.

PURPOSE: To elucidate the relationship between antofloxacin (AT) plasma concentration and QT interval prolongation, compare the effects of different correction and analytical methods on conclusions, and estimate the possible false-positive rate in thorough QT (TQT) studies. METHODS: Twenty-four healthy Chinese volunteers from a four-period crossover TQT study orally received 200 mg/d AT, 400 mg/d AT, 400 mg/d moxifloxacin, and a placebo in a random order for 5 d for each. QT interval samples were collected on d 1 and d 5. Population models were established describing the relationship between QT and AT concentration. The yardstick from ICH E14 guidelines was used to measure the effect of drugs on QT prolongation both in biostatistical and modeling analyses. A possible false-positive rate was estimated by constructing a 1000-time bootstrap to obtain the rate-of-difference values between d 1 and d 5 over 5 ms in the placebo period. RESULTS: In the modeling analysis, the QT prolongation estimate at the mean maximal concentration of AT (4.51 µg/mL) was 3.84 ms, and its upper bound of the one-sided 95 % CI was 7.04 ms, which showed a negative effect on QT interval prolongation. The estimation for the false-positive rate was 31 % in this study. CONCLUSION: The effect of AT on QT interval prolongation may not have been significant at the dosage of 400 mg. Baseline and placebo adjustments were necessary in TQT studies. Population modeling has demonstrated clear superiority in making full use of data to accurately analyze the relationship between drugs and QT intervals.

Comparative Efficacy of Drugs for the Treatment of Chronic Constipation: Quantitative Information for Medication Guidelines.

BACKGROUND: Quantitative information is scarce with regard to guidelines for currently prescribed medications for constipation. Furthermore, these guidelines do not reflect the differences in the number of bowel movements caused by each drug. GOALS: In this study, we used a model-based meta-analysis to quantitatively estimate the deviations from the baseline number of spontaneous bowel movements (SBMs) and complete spontaneous bowel movements (CSBMs) associated with pharmacotherapy for chronic constipation to bridge the knowledge gap in the guidelines for current medications. STUDY: A comprehensive survey was conducted using literature databases. In this study, we also included randomized placebo-controlled trials on chronic constipation. Pharmacodynamic models were established to describe the time course of the numbers of SBMs and CSBMs produced by each drug. RESULTS: Data from 20 studies (comprising 9998 participants and 8 drugs) were used to build this model. The results showed that bisacodyl had the greatest effect on increasing the frequency of bowel movements, whereas plecanatide yielded the lowest increase in the number of SBMs and CSBMs. After eliminating the placebo effect, the maximal increase in bowel movement frequency associated with bisacodyl was 6.8 for SBMs (95% confidence interval: 6.1-7.6) and 4.7 for CSBMs (95% confidence interval: 4.3-5.1) per week. These numbers are ∼4 times higher than the number of bowel movements produced by plecanatide. The change in the frequency of SBMs and CSBMs for other drugs, such as sodium picosulfate, velusetrag, linaclotide, elobixibat, lubiprostone, and prucalopride, was similar. The highest increases in the frequency of SBM and CSBM were 2.5 to 4 and 1 to 2.1 per week, respectively. Bisacodyl had the most noticeable loss of efficacy between week 1 and week 4; it reduced the frequencies of SBMs and CSBMs by 2.3 and 2.2, respectively. By contrast, the changes in the frequencies of SBMs and CSBMs were not as great with other drugs. CONCLUSIONS: The data provided in this study may be a valuable supplement to the medication guidelines for the treatment of chronic constipation.

Population pharmacokinetics of moxifloxacin and its concentration-QT interval relationship modeling in Chinese healthy volunteers.

Moxifloxacin (MX) is an 8-methoxyquinolone antimicrobial drug, which is often used as a positive control in thorough QT (TQT) studies. In the present study we established the population pharmacokinetics model of MX and the relationship of MX concentrations with the QT and various corrected QT (QTc) intervals, and compared the results with other ethnicities. The MX data used for modeling were obtained from a published TQT interval prolongation study of antofloxacin with MX as the positive control. In this four-period crossover study, 24 adult Chinese healthy volunteers received either 200 or 400 mg of oral antofloxacin once daily, 400 mg of MX, or a placebo. Population concentration-effect models were used to investigate the relationship between MX concentrations and QT interval prolongation, baseline-adjusted QTc (ΔQTc), or ΔQTc adjusted with time-matched placebo corrections (ΔΔQTc). The influencing factors of MX PK and the concentration-QTc relationship were determined through covariate screening. Simulation studies were conducted in R2.30 by using the final model with the estimated population mean and intra-individual and inter-individual variability. The estimated pharmacokinetic parameters and the estimated slope of the MX concentration-QT/ΔQTc/ΔΔQTc relationship were described using models and were compared to results for other ethnicities from the literature. We showed that the population pharmacokinetic parameter estimates for total plasma clearance (CL/F), the volume of distribution of central compartment (Vc/F), the distributional clearance in plasma (Q), the volume of distribution of peripheral compartment (Vp/F), and the absorption rate constant (Ka) were 8.22 L/h, 104 L, 3.98 L/h, 37.7 L, and 1.81 1/h, respectively. There was no significant covariate included in the final model. QT interval prolongation of MX estimates ranging from 9.77 to 12.91 ms at the mean average maximum concentration of MX (4.36 µg/mL) and a mean slope ranging from 2.33 to 2.96 ms per µg/mL. In conclusion, no ethnic differences were observed for the MX pharmacokinetic parameters and QT interval prolongation.

Random sparse sampling strategy using stochastic simulation and estimation for a population pharmacokinetic study.

The purpose of this study was to use the stochastic simulation and estimation method to evaluate the effects of sample size and the number of samples per individual on the model development and evaluation. The pharmacokinetic parameters and inter- and intra-individual variation were obtained from a population pharmacokinetic model of clinical trials of amlodipine. Stochastic simulation and estimation were performed to evaluate the efficiencies of different sparse sampling scenarios to estimate the compartment model. Simulated data were generated a 1000 times and three candidate models were used to fit the 1000 data sets. Fifty-five kinds of sparse sampling scenarios were investigated and compared. The results showed that, 60 samples with three points and 20 samples with five points are recommended, and the quantitative methodology of stochastic simulation and estimation is valuable for efficiently estimating the compartment model and can be used for other similar model development and evaluation approaches.

Bioequivalence evaluation of two formulations of pidotimod using a limited sampling strategy.

The aim of this study was to develop a limited sampling strategy (LSS) to assess the bioequivalence of two formulations of pidotimod. A randomized, two-way, cross-over study was conducted in healthy Chinese volunteers to compare two formulations of pidotimod. A limited sampling model was established using regression models to estimate the pharmacokinetic parameters and assess the bioequivalence of pidotimod. The model was internally validated by the Jack-knife method and graphical methods. The traditional non-compartmental method was also used to analyze the data and compared with LSS method. The results indicate that following oral administration of a single 800 mg dose, the plasma AUC(0-12 h) and C(max) of pidotimod can be predicted accurately using only two to four plasma samples. The bioequivalence assessment based on the LSS models provided results very similar to that obtained using all the observed concentration-time data points and indicate that the two pidotimod formulations were bioequivalent. A LSS method for assessing the bioequivalence of pidotimod formulations was established and proved to be applicable and accurate. This LSS method could be considered appropriate for a pidotimod bioequivalence study, providing an inexpensive cost of sampling acquisition and analysis. And the methodology presented here may also be applicable to bioequivalence evaluation of other medications.

Limited sampling strategy models for estimating the AUC of gliclazide in Chinese healthy volunteers.

The aim of this work is to reduce the cost of required sampling for the estimation of the area under the gliclazide plasma concentration versus time curve within 60 h (AUC0-60t ). The limited sampling strategy (LSS) models were established and validated by the multiple regression model within 4 or fewer gliclazide concentration values. Absolute prediction error (APE), root of mean square error (RMSE) and visual prediction check were used as criterion. The results of Jack-Knife validation showed that 10 (25.0 %) of the 40 LSS based on the regression analysis were not within an APE of 15 % using one concentration-time point. 90.2, 91.5 and 92.4 % of the 40 LSS models were capable of prediction using 2, 3 and 4 points, respectively. Limited sampling strategies were developed and validated for estimating AUC0-60t of gliclazide. This study indicates that the implementation of an 80 mg dosage regimen enabled accurate predictions of AUC0-60t by the LSS model. This study shows that 12, 6, 4, 2 h after administration are the key sampling times. The combination of (12, 2 h), (12, 8, 2 h) or (12, 8, 4, 2 h) can be chosen as sampling hours for predicting AUC0-60t in practical application according to requirement.

Quantitative analysis and simulation of anti-inflammatory effects from the active components of Paino Powder () in rats.

OBJECTIVE: To explore different combinations of the active ingredients of Paino Powder ()), including paeoniflorln, naringin, neohesperidln and platyeodin-D, which are responsible for the inhibition of carrageenin-induced edema in rats, and to evaluate the performance of the orthogonal simulation method in quantitative analysis and the simulation of the combinations. METHODS: A 1-level (used) and 2-level (unused) orthogonal design was applied to assign 7 combinations of active components. Aspirin and saline were set as the two controls. The carrageen In-Induced edema in the right hind paws of rats was established as the acute inflammation model The efficacy indices were expressed by the area under the curve (AUC) and the peak value of the swelling change (%) over time in rats. RESULTS: Compared with the saline group, the rats in active component combinations showed a significant reduction of AUG and peak value in the swelling (P<0.05). The maximum anti-inflammatory effect was from the whole four-ingredient combination. Among the four ingredients, naringin showed a dominant contribution to the combination, while paeoniflorin > platycodin-D > naringin contributed in succession. These results are consistent with the results of computer simulation. CONCLUSIONS: A single component from Paino Powder does not exhibit any anti-inflammatory effect, but some combinations show such effect. The strongest inhibition to edema comes from the full 4-ingredient combination. The orthogonal simulation method is feasible in the research on decomposed formulas of Chinese medicine.

[Comparative pharmacokinetic analysis based on nonlinear mixed effect model].

Comparative pharmacokinetic (PK) analysis is often carried out throughout the entire period of drug development, the common approach for the assessment of pharmacokinetics between different treatments requires that the individual PK parameters, which employs estimation of 90% confidence intervals for the ratio of average parameters, such as AUC and Cmax, these 90% confidence intervals then need to be compared with the pre-specified equivalent interval, and last we determine whether the two treatments are equivalent. Unfortunately in many clinical circumstances, some or even all of the individuals can only be sparsely sampled, making the individual evaluation difficult by the conventional non-compartmental analysis. In such cases, nonlinear mixed effect model (NONMEM) could be applied to analyze the sparse data. In this article, we simulated a sparsely sampling design trial based on the dense sampling data from a truly comparative PK study. The sparse data were analyzed with NONMEM method, and the original dense data were analyzed with non-compartment analysis. Although the trial design and analysis methods are different, the 90% confidence intervals for the ratio of PK parameters based on 1000 Bootstrap are very similar, indicated that the analysis based on NONMEM is a reliable method to treat with the sparse data in the comparative pharmacokinetic study.

Race differences: modeling the pharmacodynamics of rosuvastatin in Western and Asian hypercholesterolemia patients.

AIM: To evaluate race differences in the pharmacodynamics of rosuvastatin in Western and Asian hypercholesterolemia patients using a population pharmacodynamic (PPD) model generated and validated using published clinical efficacy trials. METHODS: Published studies randomized trials with rosuvastatin treatment for at least 4 weeks in hypercholesterolemia patients were used for model building and validation. Population pharmacodynamic analyses were performed to describe the dose-response relationship with the mean values of LDL-C reduction (%) from dose-ranging trials using NONMEM software. Baseline LDL-C and race were analyzed as the potential covariates. Model robustness was evaluated using the bootstrap method and the data-splitting method, and Monte Carlo simulation was performed to assess the predictive performance of the PPD model with the mean effects from the one-dose trials. RESULTS: Of the 36 eligible trials, 14 dose-ranging trials were used in model development and 22 one-dose trials were used for model prediction. The dose-response of rosuvastatin was successfully described by a simple E(max) model with a fixed E(0), which provided a common E(max) and an approximate twofold difference in ED(50) for Westerners and Asians. The PPD model was demonstrated to be stable and predictive. CONCLUSION: The race differences in the pharmacodynamics of rosuvastatin are consistent with those observed in the pharmacokinetics of the drug, confirming that there is no significant difference in the exposure-response relationship for LDL-C reduction between Westerners and Asians. The study suggests that for a new compound with a mechanism of action similar to that of rosuvastatin, its efficacy in Western populations plus its pharmacokinetics in bridging studies in Asian populations may be used to support a registration of the new compound in Asian countries.

Population pharmacokinetics of rhTNFR-Fc in healthy Chinese volunteers and in Chinese patients with Ankylosing spondylitis.

AIM: To investigate the population pharmacokinetics of recombinant human tumor necrosis factor receptor-Fc fusion protein (rhTNFR-Fc) administered via subcutaneous (SC) injection in healthy Chinese volunteers and in Chinese patients with ankylosing spondylitis (AS). METHODS: Thirty-two healthy volunteers were randomly assigned to receive a single SC injection of 12.5, 25, 37.5, or 50 mg of rhTNFR-Fc. Twenty male patients with moderate AS were randomly assigned to receive seven consecutive SC injections of rhTNFR-Fc at either 25 mg twice a week (BIW) or 50 mg once a week (QW). Population pharmacokinetic (PK) analysis was applied to obtain PK parameters of rhTNFR-Fc by the NONMEM method. RESULTS: The data were best described by a one-compartment model with lag time. We found that gender had a significant effect on the apparent clearance (CL/F), with the male CL/F ratio being only 0.665 times the female ratio; the absorption coefficient (F) of multiple dosages of rhTNFR-Fc was only 0.674 times that of a single dosage. The outcome parameters were CL/F (female: 0.168 L/h, male: 0.110 L/h), the apparent volume of distribution (Vd/F: 15.5 L), the absorption rate constant (Ka) (single dosage: 0.0605 h⁻¹, multiple dosage: 0.0408 h⁻¹), and the lag time (T(lag): 1.03 h). The inter-individual variability in the CL/F, Vd/F, Ka, and T(lag) were 33.3%, 42.7%, 55.6%, and 81.8%, respectively. CONCLUSION: Chinese females have a higher CL/F than Chinese males, and multiple dosings can significantly decrease the absorption of rhTNFR-Fc (SC). The population PK parameters of rhTNFR-Fc in healthy Chinese volunteers and patients with AS were similar to those reported for subjects in published American studies.

[In vitro pharmacodynamic interactions of antitumor effect of the combination of adriamycin and curcumin evaluated by the parameter method and the response surface].

The paper aimed to find the optimal combination and evaluation of the interactions of antitumor effect of the curcumin (Cur) and adriamycin (ADM) in vitro. According to the factorial design and data characteristics, the parameter method combined with the response surface approach were used to analyze the pharmacodynamic interactions of in vitro antitumor effects of the combination of Cur and ADM at different dosages. The results showed that the dose-effect relationship of the combination with the ratio of ADM-Cur 1:3 showed significant differences in comparison with either used alone. The dose-effect curve was shift left in combination. The combination of adriamycin (ADM, 0.693-2.132 micromol L(-1)) and curcumin (Cur, 2.047-6.304 micromol L(-1)) with a fixed ratio (1:3) showed a synergism. With increasing doses of the combination, there is an additive effect. Computer simulation showed a trend of decreasing difference between the observed and expected effects with the dose increasing in Cur from 6.304 to 16.0 micromol L(-1) and ADM from 2.132 to 5.3 micromol L(-1). The response surface analysis showed the optimal combination to be Cur 18.50 micromol L(-1) and ADM 3.89 micromol L(-1) with a ratio of 5:1. This study suggests that the parameter method combined with the response surface analysis provides richer and more reasonable information, and is helpful for quantitative design of drug combination therapy and to describe the nature and degree of drug interaction.

[Anti-inflammatory effects and quantitative study of the combinations of active ingredients of Painong powder in mice].

OBJECTIVE: To study the anti-inflammatory effects of the combinations of active components of Painong powder, a compound traditional Chinese herbal medicine, and the quantitative analysis of their interactions. METHODS: The mouse model of acute inflammation with increase of capillary permeability was induced by intraperitoneal injection of acetic acid. An orthogonal design with 2 levels (used and unused) was applied to assign the combinations groups of active ingredients including naringin and neohesperidin, peoniflorin, and platycodin. Aspirin and normal saline were administered as control. The pharmacodynamic interactions were analyzed by the optical density (OD) of infiltrated Evans blue. RESULTS: The different combinations of active ingredients showed anti-inflammatory effect with different degree, and the predicted values of OD varied from 0.115 to 0.170. The maximum anti-inflammatory effect was from the combination of naringin, neohesperidin, paeoniflorin and platycodin, better than that of the saline group (P < 0.01). However, there was no significant difference as compared with the aspirin group (P > 0.05). Paeoniflorin showed a dominant contribution to the formula, and platycodin the least. The combination of all active components exhibited synergism. CONCLUSION: The results suggest that all the ingredients are efficacious constituents of the formula, and paeoniflorin shows a dominant contribution to the formula. More information about prescription compatibility can be obtained by the orthogonal simulation method.