Optimization of dosage regimen using a mechanism-based pharmacokinetic-pharmacodynamic modeling

使用基于机制的药代动力学-药效学模型优化剂量方案

• 批准号: 15590144
• 负责人: KAKEMI Masawo
• 金额: $ 1.98万
• 依托单位: Osaka University of Pharmaceutical Sciences
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590144/
• 关键词: tolbutamide; circadian rhythm; insulin; hypoglycemic effect; pharmacokinetics; pharmacodynamics; PK-PD Correlation; sulfonylureas; グルコーストランスポーター; スルホニルウレア; PK-PD解析

Pharmacokinetics (PK) and pharmacodynamics (PD) of hypoglycemic drugs may be influenced by dosage time, because plasma glucose level shows a remarkable circadian rhythm. The purpose of the present investigation was to evaluate the effect of circadian changes on the PK-PD relationship of tolbutamide (TB), a SU agent, in rats. Physiological level in plasma glucose showed a circadian rhythm with acrophase in the end of the light phase (ca.15:00 h). Plasma concentrations of free TB after i.v. bolus administration at 6:00 and 18:00 h were described using a two-compartment model, and no change of the PK parameters by the administration time was observed. The hypoglycemic effect after i.v. administration of TB at 18:00 h was larger than the 6:00 h dosage. The PK-PD model was constructed using link and E_<max> models with a circadian rhythm. However, the regression curves did not fit simultaneously the observed hypoglycemic effects at both dosage times well. For the insulin secretion by TB, plasma level and release from isolated pancreatic islets indicated that the spiked secretion of insulin enhanced at 18:00 h comparing with 6:00 h. The dosage of TB was therefore translated into the apparent dosage of insulin. To evaluate the relationship between the dosage of TB and the hypoglycemic effect, another model was then constructed using plasma level of insulin instead of TB. The model-estimated effect explained the observed data at both administration times simultaneously. These results suggest that a pharmacological change, which cannot be predicted from plasma drug concentration, might occur because of some biological circadian rhythms when SU agents are continued for a long time.

降糖药物的药代动力学（PK）和药效学（PD）可能会受到给药时间的影响，因为血浆葡萄糖水平表现出显着的昼夜节律。本研究的目的是评估昼夜节律变化对大鼠体内 SU 药物甲苯磺丁脲 (TB) PK-PD 关系的影响。血糖的生理水平显示出昼夜节律，在光相结束时（约 15:00 小时）出现顶峰期。静脉注射后游离结核的血浆浓度使用两室模型描述了 6:00 和 18:00 小时的推注给药，并且没有观察到给药时间引起的 PK 参数的变化。静脉注射后的降血糖作用18:00 时的 TB 给药剂量大于 6:00 时的剂量。 PK-PD模型是使用具有昼夜节律的link和E_<max>模型构建的。然而，回归曲线并不能很好地同时拟合两个剂量时间观察到的降血糖作用。对于结核病的胰岛素分泌，血浆水平和离体胰岛的释放表明，与6:00小时相比，18:00小时胰岛素的峰值分泌增强。因此，结核病的剂量被转化为胰岛素的表观剂量。为了评估TB剂量与降血糖效果之间的关系，使用血浆胰岛素水平代替TB构建了另一个模型。模型估计的效果同时解释了两个给药时间观察到的数据。这些结果表明，当长期持续使用SU药物时，由于某些生物昼夜节律，可能会发生无法从血浆药物浓度预测的药理学变化。

项目成果

サケ・カルシトニンのPharmacokinetics-pharmacodynamics に及ぼす日周リズムの影響

昼夜节律对鲑鱼降钙素药代动力学-药效学的影响

• 发表时间: 2005
• 期刊: TDM研究 22・1
• 作者: 岩永 一範;宮崎 誠
• 通讯作者: 宮崎 誠

Estimation of Bioavailability of Salmon Calcitonin from the Hypocalcemic Effect in Rats (II) : Effect of Protease Inhibitor on the Pharmacokinetic-Pharmacodynamic Relationship after Intranasal Administration.

从大鼠的低血钙效应估算鲑鱼降钙素的生物利用度（II）：蛋白酶抑制剂对鼻内给药后药代动力学-药效关系的影响。

• 发表时间: 2003
• 期刊: Drug Metabolism and Pharmacokinetics 18
• 作者: Makoto Miyazaki;Susumu Nakade;Kazunori Iwanaga;Kazuhiro Morimoto;Masawo Kakemi
• 通讯作者: Masawo Kakemi

Effect of Circadian Rhythm on Pharmacokinetics-Pharmacodynamics of Salmon Calcitonin in Rats

昼夜节律对鲑鱼降钙素在大鼠体内药代动力学-药效学的影响

• 发表时间: 2005
• 期刊: The Journal of Therapeutic Drug Monitoring 22
• 作者: Makoto MIYAZAKI;Naoya HOSHINO;Nobuhiro TAKEDA;Kazunori IWANAGA;Masawo KAKEMI
• 通讯作者: Masawo KAKEMI

サケカルシトニンのPharmacokinetics-Pharnacodynamicsに及ぼす日周リズムの影響

昼夜节律对鲑鱼降钙素药代动力学-药效学的影响

• 发表时间: 2005
• 期刊: TDM研究 22
• 作者: Makoto MIYAZAKI;Naoya HOSHINO;Nobuhiro TAKEDA;Kazunori IWANAGA;Masawo KAKEMI;宮崎 誠
• 通讯作者: 宮崎 誠

Estimation of Bioavailability of Salmon Calcitonin from the Hypocalcemic Effect in Rats (II) : Effect of Protease Inhibitor on the Pharmacokinetic - Pharmacodynamic Relationship after Intranasal Administration.

从大鼠的低血钙效应估算鲑鱼降钙素的生物利用度（II）：蛋白酶抑制剂对鼻内给药后药代动力学-药效关系的影响。

• 发表时间: 2003
• 期刊: Drug Metabolism and Pharmacokinetics 18
• 作者: Makoto MIYAZAKI;Toshiki FUJII;Kumiko MIYAKE;Kazunori IWANAGA;Masawo KAKEMI;宮崎 誠
• 通讯作者: 宮崎 誠