今日の論文
- Bradley, Dudley, and Drusano (2003) Pediatr Infect Dis J, "Predicting efficacy of antiinfectives with pharmacodynamics and Monte Carlo simulation"
- 雑誌が雑誌ですから，いつも読んでいるような論文とは視点が少し違って，興味深い．
- 'Objective' として次のようなことが挙げてある．
To recall that the data used to describe the variables in a published Monte Carlo simulation in a journal may not necessarily reflect the data that would be used to describe those variables for a particular pysician's own patient.
-
- これはここにつながるんでしょうね，きっと．
A few years later, in your own institution, the resistance of P. aeruginosa to ceftazidime is twice that of organisms isolated in the earlier study. By placing your institution's Pseudomonas MIC distribution into your analysis, your are able to determine what dose of ceftazidime is needed for your own population of patients. (...) In this way the recognized differences in susceptibility in organisms among countries, regions, cities, hospitals and wards within a hospital can be taken into account. We need only enter the accurate microbiologic data into the simulation to obtain relevant advice for our patients.
-
- 患者の免疫能の問題について．
Monte Carlo simulation can also calculate appropriate dosages of antibiotics for immunocompromisd populations. Understanding that most antibiotics are tested in normal, immunocompetent hosts before FDA approval, these dosing recommendations apply only to normal hosts. The cure for most bacterial infections depends on the host immune system, particularly polymorphonuclear leukocytes, to help eradicate the pathogens. When the host response is absent or severely compromised, as in a child with neutropenia, it would be expected that the overall dosage of antibiotic required to achieve a cure would be greater.
-
- そして，あえてこういう記述があるのが面白い．
The FDA can evaluate the safety and efficacy of the drug only for the indications submitted by the pharmaceutical sponsor; the FDA will usually not express an opinion, positive or negative, regarding indications for which data were not submitted. (...) A certain antibiotic may appear very helpful for treatment of a specific infection in children but may never have been studied by the pharmaceutical company or submitted to the FDA for that indication or particular age group. In these situations Phase IV studies in children investigate antibiotic therapy in types of infections not previously studied.
- Sandstrom, ..., and Karlsson (2005) JCO, "Model describing the relationship between pharmacokinetics and hematologic toxicity of the epirubicin-docetaxel regimen in breast cancer patients"
- よくできました．
- Minami 先生のコメント論文も入門用としてわかりやすくてよいです．
- 本論にはあまり関係ないのだが，両薬剤ともに３−コンパートメントモデルが当てはまることがわかっていたので，それを採用した．ただし，エピルビシンのデータは３−コンパートメントモデルには不足していたので，NONMEM の PRIOR 機能を利用した．
- Minami, Sasaki, et al. (2001) Jpn J Cancer Res, "Pharmacodynamic modeling of the entire time course of leukopenia after a 3-hour infusion of paclitaxel"
- Brendel, ..., Mentre, et al. (2005) Fandam Clin Pharmacol, "Population pharmacokinetic analysis of indinavir in HIV-infected patient treated with a stable antiretroviral therapy"
- オーソドックスな PPK 解析．ただし，WinNONMIX を用いて，inter-occasion variability を推定するために若干の工夫をしている．
- 定量限界以下のデータに関して，"we fixed them to LOQ/2" とした．
- また，シミュレーションで濃度の 10%点，90% 点を求めている．
The simulations were done using the final model of indinavir. We used, in the simulations the total variability (inter plus intra) of the random effects and the residual error variability in order to mimic the observations.
We kept in each group of simulation the same distribution of the significant covariates as in the study population.
The 10th and 90th predicted percentiles for the 1000 simulations in each group were compared with the observed concentrations. (...) It should be noted that in order to evaluate the non-parametric 10th and 90th percentiles, a rather large sample of simulated patients is needed.
