Mona Darwish PhD, Kenneth Tempero MD, PhD, John G. Jiang PhD, Philip G. Simonson PhD
{"title":"健康日本志愿者多次服用400µg芬太尼含片后芬太尼蓄积程度","authors":"Mona Darwish PhD, Kenneth Tempero MD, PhD, John G. Jiang PhD, Philip G. Simonson PhD","doi":"10.1111/j.1753-5174.2008.00008.x","DOIUrl":null,"url":null,"abstract":"<p><b>Objective. </b> This study was conducted to characterize the pharmacokinetics, including extent of accumulation, and safety and tolerability of fentanyl following multiple doses of fentanyl buccal tablet (FBT) in healthy Japanese volunteers.</p><p><b>Methods. </b> Healthy Japanese adults received 10 successive doses of open-label FBT 400 µg at 6-hour intervals. Naltrexone was given to minimize the opioid effects of fentanyl. FBT was placed above a molar tooth between the gum and cheek. Peak serum fentanyl concentration (C<sub>max</sub>), time to C<sub>max</sub> (t<sub>max</sub>), and area under the serum fentanyl concentration-time curve from 0 to 6 hours (AUC<sub>0–6</sub>) were summarized using descriptive statistics. Accumulation ratio was calculated as C<sub>max</sub> for dose 10/C<sub>max</sub> for dose 1, and was calculated similarly for AUC<sub>0–6</sub>.</p><p><b>Results. </b> Fourteen volunteers (mean age 33 years) were enrolled, and 13 completed the study. After doses 1 and 10, respectively, mean (SD) C<sub>max</sub> was 1.70 (0.49) ng/mL and 1.97 (0.42) ng/mL, AUC<sub>0–6</sub> was 4.46 (1.14) ng·h/mL and 6.81 (0.90) ng·h/mL, and median (range) t<sub>max</sub> was 50 (30–110) minutes and 30 (15–120) minutes. Following 10 successive doses, systemic exposure (AUC<sub>0–6</sub>) was 55% higher than after dose 1, and C<sub>max</sub> was 23% higher. Steady state was achieved within 3 days of dosing at 6-hour intervals, i.e., prior to dose 10. The most frequent adverse events (AEs) were somnolence (N = 9), decreased oxygen saturation (N = 4), headache (N = 3), application-site pain (N = 8), application-site erythema (N = 6), and application-site reaction (N = 5). All AEs were mild or moderate.</p><p><b>Conclusions. </b> Following administration of FBT at 6-hour intervals to healthy Japanese volunteers, at steady state, fentanyl exposure was higher by 55% (AUC<sub>0–6</sub>) and 23% (C<sub>max</sub>) than after a single dose of FBT. Adverse events were mild or moderate.</p>","PeriodicalId":8181,"journal":{"name":"Archives of Drug Information","volume":"1 2","pages":"50-55"},"PeriodicalIF":0.0000,"publicationDate":"2008-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/j.1753-5174.2008.00008.x","citationCount":"4","resultStr":"{\"title\":\"Extent of Fentanyl Accumulation Following Multiple Doses of Fentanyl Buccal Tablet 400 µg in Healthy Japanese Volunteers\",\"authors\":\"Mona Darwish PhD, Kenneth Tempero MD, PhD, John G. Jiang PhD, Philip G. Simonson PhD\",\"doi\":\"10.1111/j.1753-5174.2008.00008.x\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><b>Objective. </b> This study was conducted to characterize the pharmacokinetics, including extent of accumulation, and safety and tolerability of fentanyl following multiple doses of fentanyl buccal tablet (FBT) in healthy Japanese volunteers.</p><p><b>Methods. </b> Healthy Japanese adults received 10 successive doses of open-label FBT 400 µg at 6-hour intervals. Naltrexone was given to minimize the opioid effects of fentanyl. FBT was placed above a molar tooth between the gum and cheek. Peak serum fentanyl concentration (C<sub>max</sub>), time to C<sub>max</sub> (t<sub>max</sub>), and area under the serum fentanyl concentration-time curve from 0 to 6 hours (AUC<sub>0–6</sub>) were summarized using descriptive statistics. Accumulation ratio was calculated as C<sub>max</sub> for dose 10/C<sub>max</sub> for dose 1, and was calculated similarly for AUC<sub>0–6</sub>.</p><p><b>Results. </b> Fourteen volunteers (mean age 33 years) were enrolled, and 13 completed the study. After doses 1 and 10, respectively, mean (SD) C<sub>max</sub> was 1.70 (0.49) ng/mL and 1.97 (0.42) ng/mL, AUC<sub>0–6</sub> was 4.46 (1.14) ng·h/mL and 6.81 (0.90) ng·h/mL, and median (range) t<sub>max</sub> was 50 (30–110) minutes and 30 (15–120) minutes. Following 10 successive doses, systemic exposure (AUC<sub>0–6</sub>) was 55% higher than after dose 1, and C<sub>max</sub> was 23% higher. Steady state was achieved within 3 days of dosing at 6-hour intervals, i.e., prior to dose 10. The most frequent adverse events (AEs) were somnolence (N = 9), decreased oxygen saturation (N = 4), headache (N = 3), application-site pain (N = 8), application-site erythema (N = 6), and application-site reaction (N = 5). All AEs were mild or moderate.</p><p><b>Conclusions. </b> Following administration of FBT at 6-hour intervals to healthy Japanese volunteers, at steady state, fentanyl exposure was higher by 55% (AUC<sub>0–6</sub>) and 23% (C<sub>max</sub>) than after a single dose of FBT. Adverse events were mild or moderate.</p>\",\"PeriodicalId\":8181,\"journal\":{\"name\":\"Archives of Drug Information\",\"volume\":\"1 2\",\"pages\":\"50-55\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2008-09-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1111/j.1753-5174.2008.00008.x\",\"citationCount\":\"4\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Archives of Drug Information\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/j.1753-5174.2008.00008.x\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Archives of Drug Information","FirstCategoryId":"1085","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/j.1753-5174.2008.00008.x","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Extent of Fentanyl Accumulation Following Multiple Doses of Fentanyl Buccal Tablet 400 µg in Healthy Japanese Volunteers
Objective. This study was conducted to characterize the pharmacokinetics, including extent of accumulation, and safety and tolerability of fentanyl following multiple doses of fentanyl buccal tablet (FBT) in healthy Japanese volunteers.
Methods. Healthy Japanese adults received 10 successive doses of open-label FBT 400 µg at 6-hour intervals. Naltrexone was given to minimize the opioid effects of fentanyl. FBT was placed above a molar tooth between the gum and cheek. Peak serum fentanyl concentration (Cmax), time to Cmax (tmax), and area under the serum fentanyl concentration-time curve from 0 to 6 hours (AUC0–6) were summarized using descriptive statistics. Accumulation ratio was calculated as Cmax for dose 10/Cmax for dose 1, and was calculated similarly for AUC0–6.
Results. Fourteen volunteers (mean age 33 years) were enrolled, and 13 completed the study. After doses 1 and 10, respectively, mean (SD) Cmax was 1.70 (0.49) ng/mL and 1.97 (0.42) ng/mL, AUC0–6 was 4.46 (1.14) ng·h/mL and 6.81 (0.90) ng·h/mL, and median (range) tmax was 50 (30–110) minutes and 30 (15–120) minutes. Following 10 successive doses, systemic exposure (AUC0–6) was 55% higher than after dose 1, and Cmax was 23% higher. Steady state was achieved within 3 days of dosing at 6-hour intervals, i.e., prior to dose 10. The most frequent adverse events (AEs) were somnolence (N = 9), decreased oxygen saturation (N = 4), headache (N = 3), application-site pain (N = 8), application-site erythema (N = 6), and application-site reaction (N = 5). All AEs were mild or moderate.
Conclusions. Following administration of FBT at 6-hour intervals to healthy Japanese volunteers, at steady state, fentanyl exposure was higher by 55% (AUC0–6) and 23% (Cmax) than after a single dose of FBT. Adverse events were mild or moderate.