今日の論文
In the current analysis, the previously developed model for rats was used to analyze the pooled pharmacokinetic data obtained from four preclinical species (rat, rabbit, dog, and monkey) and to predict the pharmacokinetics of PEG-EPO in man through the implementation of the mixed-effects model for the interspecies scaling.
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- 具体的にどうしたかというと，
Since it is well known that the interspecies variability in the disposition of certain drugs is related to the body weight (WT), a power function of WT was used as allometric equation in order to characterize the interspecies variability in all pharmacokinetic parameters, except for bioavailability, which was estimated separately in rats, monkey, and dog.
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- したがって，BA だけはヒトに外挿できないので，いろいろな値に設定してみて，感度分析を行った．
- ブートストラップ・バリデーションについて．
This (bootstrap) process was repeated 1000 times with different random draws and the stability of the full model was evaluated by visual inspection of the distribution of the model parameter estimates. (...) Bootstrap runs where the minimization was not successful, were excluded from further analysis.
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- 1000 回のうち，155 回は失敗した．成功分 845 回だけ，と 1000 回すべて，のパラメータ推定値を用いて，平均，95% 信頼区間を見てみたところ，ほとんどの値はどちらで集計してもほぼ同じ値であった．Ka の allometric exponent の上限には 16% の違いが認められた．したがって，"This suggested that a number of unsuccessful minimizations in the bootstrap analysis may be due to an inaccurate estimation of the Ka exponent"．
- 最終的には，845 回分のみで集計しました．そして，
The bootstrap analysis clearly demonstrated the accuracy and precision of the parameter estimates, suggesting its robustness and usefulness in the extrapolation of the pharmacokinetic parameters of PEG-EPO from preclinical species to man.
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- ヒトへの外挿の際には，ブートストラップ分布を用いて，パラメータ推定値の uncertainty を考慮している．
The parameter estimates obtained by fitting the final model to every bootstrap replicate were used to calculate the pharmacokinetic parameters of PEG-EPO in man. (...) Individual WT and baseline EPO concentration for the virtual subjects were obtained by re-sampling from a dataset of 150 healthy adult males included in eight phase 1 studies with rHu-EPO. (...) Uncertainty in fixed and random parameter estimates was considered during the simulation by replicating the above-mentioned process 30 times using different values of fixed and random parameters, randomly selected from the estimates of the bootstrap replicates.
