A note on post-marketing safety study design to characterise time-dependent adverse events.

PURPOSE: To investigate a suitable post-marketing safety study design, that is number of patients and duration of exposure, to well characterise adverse events (AEs) profiles under limited resources, fixed patient-months. METHODS: A simulation study is conducted to investigate a suitable study design that can appropriately characterise the shape of the hazard function of AEs using the Weibull model. The reliability of the estimates is evaluated by referring their bias and mean squared error (MSE). RESULTS: In general, patients should be followed for a longer period even if the number of patients is relatively small for characterising delayed AEs. Patients' drop-out affects the estimation and deteriorates its reliability. For AEs that are likely to occur soon after the exposure, a study with relatively shorter duration and large number of patients is preferable. CONCLUSIONS: It is important to evaluate statistically the appropriate study design in planning a safety study so that a good estimate of the hazard function would be obtained.

An estimation method of the half-life for a one-compartment model of a single bolus intravenous injection by a single sampling.

In clinical trials, sometimes only a single drug concentration can be measured from a patient because of the patient's burden. In this case, the sampling point is usually identical for all patients. From a single concentration, we cannot generally obtain point-estimates of each pharmacokinetic parameter. In this paper, we propose a method to estimate the half-life of a one-compartment model of a single bolus intravenous injection from a single concentration at a sampling point of or after three half-lives. We analytically show that the later the sampling point is the better estimate of the half-life we can get. This approach is illustrated by simulated concentration-data and nicorandil concentration-data. Therefore, we compared the performance of the proposed method with that of the Bayesian approach.

Treatment of thoracic esophageal carcinoma invading adjacent structures.

T4 esophageal cancer is defined as the tumor invading adjacent structures, using tumor-node-metastasis (TNM) staging. For clinically T4 thoracic esophageal carcinoma, multimodality therapy, that is, neoadjuvant chemoradiotherapy (CRT) followed by surgery or definitive CRT, has generally been performed. However, the prognosis of patients with these tumors remains poor. Another strategy is needed to achieve curative treatment. In the present article, the treatment strategies employed to date are reviewed. Furthermore, the strategies for these malignancies are reassessed, based on our experiences. R1/2 and R0 resections are regarded as those with residual and no tumor after surgery. The present data show that patients who underwent R1/2 resection after neoadjuvant CRT experienced little survival benefit, while complete response (CR) cases after definitive CRT had comparatively better results. Therefore, curative surgery should not be attempted without down-staging, and definitive CRT should be the initial treatment. Then surgery is indicated for the eradication of residual cancer cells. Close surveillance is essential for early detection of relapse even after CR, because the operation will gradually become increasingly difficult due to post-CRT fibrosis. In conclusion, multimodality therapy consists of definitive CRT followed by R0 resection, which can be the treatment of choice for T4 esophageal carcinoma. These challenging treatments have the potential to constitute the most effective therapeutic strategy.

Profile likelihood-based confidence intervals using Monte Carlo integration for population pharmacokinetic parameters.

Population pharmacokinetic (PPK) analysis usually employs nonlinear mixed effects models using first-order linearization methods. It is well known that linearization methods do not always perform well in actual situations. To avoid linearization, the Monte Carlo integration method has been proposed. Moreover, we generally utilize asymptotic confidence intervals for PPK parameters based on Fisher information. It is known that likelihood-based confidence intervals are more accurate than those from the usual asymptotic confidence intervals. We propose profile likelihood-based confidence intervals using Monte Carlo integration. We have evaluated the performance of the proposed method through a simulation study, and analyzed the erythropoietin concentration data set by the method.

Extended information criterion (EIC) approach for linear mixed effects models under restricted maximum likelihood (REML) estimation.

In clinical data analysis, the restricted maximum likelihood (REML) method has been commonly used for estimating variance components in the linear mixed effects model. Under the REML estimation, however, it is not straightforward to compare several linear mixed effects models with different mean and covariance structures. In particular, few approaches have been proposed for the comparison of linear mixed effects models with different mean structures under the REML estimation. We propose an approach using extended information criterion (EIC), which is a bootstrap-based extension of AIC, for comparing linear mixed effects models with different mean and covariance structures under the REML estimation. We present simulation studies and applications to two actual clinical data sets.

A note on population pharmacokinetic studies with a single sampling design.

The choice of sampling time point in a population pharmacokinetic study with severe limitation on the number of samples per study subject (single sampling design) is critical in obtaining reliable parameter estimates. The authors have investigated the relationship between the timing as well as the degree of distribution of a sampling point among study subjects and the reliability of the estimates of pharmacokinetic parameters in a population pharmacokinetic study. This was achieved through a simulation, assuming an intravenously administered drug whose pharmacokinetic profile follows a 1-compartment model. The convergence rate of the NLMIXED procedure as well as the values of bias and MSE for the estimated parameters showed great variability depending on the sampling schedules. The results indicate that, in the case of a single sampling design, the sampling points should be distributed as widely as possible over a time range along the concentration-time profile to obtain reliable parameter estimates.

Evaluation of Bayesian estimation of pharmacokinetic parameters.

The validity of pharmacokinetic parameters estimated by the maximum a posteriori probability (MAP) Bayesian method was investigated by simulation studies. A 1-compartment model with bolus intravenous administration was used as a pharmacokinetic model, and the coefficients of variation for the parameters and residual error were set at 30% and 10%, respectively. The accuracy of the posterior modes of pharmacokinetic parameters estimated by the MAP Bayesian method was assessed by the difference between the true value and the estimated value. The results showed that the accuracy of the Bayesian estimation depended on sampling times and on the differences between the prior means and individual true parameter values. For assessing the reliability and accuracy of the Bayesian estimation, the authors suggest using the whole posterior distribution of the pharmacokinetic parameters to describe the 95th percentile range for predicted blood concentration profiles. The authors believe that the proposed procedures provide helpful information for evaluating the Bayesian estimation of pharmacokinetic profiles.

Observation of time-dependent adverse events and the influence of drop-out thereon in long-term safety studies--simulation study under the current practice of post-marketing safety evaluation in Japan.

Safety assessment of a new drug should be continuously carried out in the premarketing phase as well as in the postmarketing phase. Considering the actual conditions and problems of postmarketing safety studies in Japan, i.e., the lack of attention to the extent of patients' exposure to the drug (duration and the number of patients), we simulated the number of adverse events to be observed after specified intervals of exposure. This was done by applying different sets of hazard functions for a Weibull distribution under the circumstances that a certain number of patients has dropped out, focusing on rare and delayed adverse events associated with chronically used drugs. By using the result of these simulations, we point out potential problems of underestimating adverse event rates in situations where the hazard rate of the event escalates over time. Patients drop-out from the study also deteriorates the ability to observe such time-dependent adverse events. The simulation can also serve as a useful tool to examine the necessary sample size and the duration of exposure in order to observe and characterize potentially expected adverse events. It is important to take the two key factors into consideration: the change of hazard function over time and the effect of drop-out in designing, analyzing, and evaluating safety studies for new drugs.

A simulation-based confidence band for drug concentrations in blood: an application to a clinical phase I trial.

Since drug concentrations in blood are usually related to the effectiveness and toxicity, a confidence band for the drug concentrations gives useful information for the treatment. This paper proposes a simulation-based approach for constructing confidence bands for drug concentrations in blood. The confidence band covers the whole profile of the drug concentrations with a specified probability. The proposed approach presupposes that actual concentrations of a subject fluctuate randomly around a curve specified by an appropriate pharmacokinetic model and the subject-specific pharmacokinetic parameters. The confidence band is constructed by taking into account both the random fluctuations of the actual concentrations and the statistical uncertainty of the parameter estimates. The proposed approach is applied to a simulation study and an actual phase I trial.

An experimental study of jejunal pouch replacements following total gastrectomy.

BACKGROUND/AIMS: The nutritional effects of pouch replacement after total gastrectomy remain clinically controversial. Two previous experiments failed to show any nutritional benefit. However, the pouches applied clinically and examined experimentally so far were all of anti-peristaltic type. METHODOLOGY: Male 7- or 8-week-old Wistar rats were divided into 3 experimental groups after total gastrectomy. For group 1 and 2 rats, Roux-en-Y reconstructions and Hunt-Lawrence pouches, i.e., anti-peristaltic type, were performed, respectively. Group 3 rats underwent a new type of iso-peristaltic pouch replacement. Food intake was recorded daily and all rats were weighed once a week. At the end of the 12-week experimental period, there were 9 rats in group 1, 10 in group 2, and 8 in group 3. The volumes of the gastric reservoirs were measured, and blood samples were taken. Five 20-week-old rats served as control of weight, food intake, and laboratory data. RESULTS: The volumes of the gastric reservoirs in group 2 and 3 rats were significantly larger than in group 1 animals. However, there were no intergroup differences in weight change or food intake. The weights and the food intakes of the 3 experimental groups were significantly lower than those of the control rats. No superiority in the results of blood samples was observed among the experimental groups. Correlations between weight gain and food intake were shown in all groups. But, a correlation between the volume of the gastric reservoir and food intake was observed only for group 3 rats. CONCLUSIONS: The present study showed no nutritional benefits of an iso- as well as an anti-peristaltic pouch replacement.

Penetration of Pazufloxacin into the Fluid of Suction Blisters Induced in Human Skin.

We investigated the pharmacokinetics of pazufloxacin (PZFX) in the fluid of suction blisters induced in the skin of 6 healthy male volunteers after a 200mg oral dose of PZFX. The time to reach the maximum concentration (tmax) of PZFX in plasma was 0.7 hours, and the maximum concentration (Cmax) was 2.95µg/mL. The half-life of the elimination phase (t1/2) in plasma was 1.75 hours, and the area under the concentration-time curve (AUC) was 6.70µg·h/mL. The tmax, Cmax, t1/2 and AUC values in the suction blister fluid were 2.0 hours, 1.52µg/mL, 1.95 hours and 6.28µg·h/mL, respectively. The ratio of the AUC of PZFX in blister fluid to the AUC in plasma was almost 1.0. Thus, excellent penetration of PZFX into suction blister fluid was observed.