Portenoy R K, Southam M A, Gupta S K, Lapin J, Layman M, Inturrisi C E, Foley K M
Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Anesthesiology. 1993 Jan;78(1):36-43. doi: 10.1097/00000542-199301000-00007.
The transdermal therapeutic system (fentanyl), or TTS(fentanyl), continuously delivers fentanyl for up to 72 h. The transdermal therapeutic system (fentanyl)-100 delivers approximately 100 micrograms/h. The repeated dose pharmacokinetics of this drug using the recommended dosing interval have not been evaluated previously and were determined in the present study.
Blood samples were obtained from ten opioid-tolerant cancer patients who received five applications of TTS(fentanyl) at 72-h intervals. A sample of venous blood was taken before each dose; multiple samples were taken during and after the fifth application. A gas chromatographic/mass spectrometry method was used to assay fentanyl (limit of detection 0.2 ng/ml).
For the fifth dose, the mean (SD) maximum concentration was 2.6 (1.3) ng/ml and the mean (SD) area under the serum fentanyl concentration-time curve (0-72 h) was 116.9 (59.9). Following removal of the system, the mean (SD) apparent half-life was 21.9 (8.9) h. There were no differences among the serum fentanyl concentrations measured before the second through fifth doses. Fentanyl absorption was 47% complete at 24 h, 88% complete at 48 h, and 94% complete at 72 h. The mean (SD) dose delivered during the 72-h period was 4.3 (1.1) mg. A first-dose trough concentration predicted from fifth-dose kinetics and the actual first-dose trough concentration were very similar. Adverse effects ascribed to the transdermal system were minimal.
These results suggest that steady-state serum concentrations are approached by the second dose of TTS(fentanyl) and that the kinetics are stable with repeated dosing. The apparent half-life following system removal is relatively long, indicating ongoing absorption from a subcutaneous depot.
透皮治疗系统（芬太尼），即TTS（芬太尼），可持续释放芬太尼长达72小时。透皮治疗系统（芬太尼）-100每小时释放约100微克。此前尚未评估过使用推荐给药间隔时该药物的重复剂量药代动力学，本研究对此进行了测定。
从10名阿片类药物耐受的癌症患者中采集血样，这些患者每隔72小时接受5次TTS（芬太尼）给药。每次给药前采集静脉血样；在第5次给药期间和之后采集多个血样。采用气相色谱/质谱法测定芬太尼（检测限为0.2纳克/毫升）。
对于第5剂，平均（标准差）最大浓度为2.6（1.3）纳克/毫升，血清芬太尼浓度-时间曲线（0至72小时）下的平均（标准差）面积为116.9（59.9）。取下系统后，平均（标准差）表观半衰期为21.9（8.9）小时。第2剂至第5剂给药前测得的血清芬太尼浓度之间无差异。芬太尼在24小时时吸收完成47%，48小时时完成88%，72小时时完成94%。72小时期间的平均（标准差）给药剂量为4.3（1.1）毫克。根据第5剂药代动力学预测的首剂谷浓度与实际首剂谷浓度非常相似。归因于透皮系统的不良反应极少。
这些结果表明，第二次给予TTS（芬太尼）时可达到稳态血清浓度，且重复给药时药代动力学稳定。取下系统后的表观半衰期相对较长，表明皮下储库持续吸收。
