Cox Donna S, Rehman Muhammad, Khan Tahira, Ginman Katherine, Salageanu Joanne, LaBadie Robert R, Wan Katty, Damle Bharat
Pfizer Inc. Global Product Development, Collegeville, Pennsylvania, USA.
Pfizer Inc. Global Product Development, Andover, Massachusetts, USA.
Br J Clin Pharmacol. 2023 Nov;89(11):3352-3363. doi: 10.1111/bcp.15835. Epub 2023 Jul 12.
To evaluate pharmacokinetics (PK) and safety after coadministration of nirmatrelvir/ritonavir or ritonavir alone with midazolam (a cytochrome P450 3A4 substrate) and dabigatran (a P-glycoprotein substrate).
PK was studied in 2 phase 1, open-label, fixed-sequence studies in healthy adults. Single oral doses of midazolam 2 mg (n = 12) or dabigatran 75 mg (n = 24) were administered alone and after steady state (i.e. ≥2 days) of nirmatrelvir/ritonavir 300 mg/100 mg and ritonavir 100 mg. Midazolam and dabigatran plasma concentrations and adverse events were analysed for each treatment.
After administration of midazolam with nirmatrelvir/ritonavir (test) or alone (reference), midazolam geometric mean area under the concentration-time curve extrapolated to infinity (AUC ) and maximum plasma concentration (C ) increased 14.3-fold and 3.7-fold, respectively. Midazolam coadministered with ritonavir (test) or alone (reference) resulted in 16.5-fold and 3.9-fold increases in midazolam geometric mean AUC and C , respectively. After administration of dabigatran with nirmatrelvir/ritonavir (test) or alone (reference), dabigatran geometric mean AUC and C increased 1.9-fold and 2.3-fold, respectively. Dabigatran coadministered with ritonavir (test) or alone (reference) resulted in a 1.7-fold increase in dabigatran geometric mean AUC and C . Midazolam or dabigatran exposures were generally comparable when coadministered with nirmatrelvir/ritonavir or ritonavir alone, with a slightly higher dabigatran C with nirmatrelvir/ritonavir vs. ritonavir alone. Nirmatrelvir/ritonavir was generally safe when administered with or without midazolam or dabigatran. No serious or severe adverse events were reported.
Coadministration of midazolam or dabigatran with nirmatrelvir/ritonavir increased systemic exposure of midazolam or dabigatran. Midazolam exposures were comparable when coadministered with nirmatrelvir/ritonavir or ritonavir alone, suggesting no incremental effect of nirmatrelvir. Dabigatran C was slightly higher when coadministered with nirmatrelvir/ritonavir compared with of ritonavir alone, suggesting a minor incremental effect of nirmatrelvir.
评估奈玛特韦/利托那韦或单独使用利托那韦与咪达唑仑（一种细胞色素P450 3A4底物）和达比加群（一种P-糖蛋白底物）合用时的药代动力学（PK）及安全性。
在两项针对健康成年人的1期开放标签固定序列研究中对PK进行了研究。单独及在奈玛特韦/利托那韦300mg/100mg和利托那韦100mg达到稳态（即≥2天）后，分别口服单剂量2mg咪达唑仑（n = 12）或75mg达比加群（n = 24）。分析每种治疗的咪达唑仑和达比加群血浆浓度及不良事件。
咪达唑仑与奈玛特韦/利托那韦（试验组）或单独使用（参照组）合用时，咪达唑仑浓度-时间曲线外推至无穷大时的几何平均曲线下面积（AUC）和最大血浆浓度（Cmax）分别增加了14.3倍和3.7倍。咪达唑仑与利托那韦（试验组）或单独使用（参照组）合用时，咪达唑仑几何平均AUC和Cmax分别增加了16.5倍和3.9倍。达比加群与奈玛特韦/利托那韦（试验组）或单独使用（参照组）合用时，达比加群几何平均AUC和Cmax分别增加了1.9倍和2.3倍。达比加群与利托那韦（试验组）或单独使用（参照组）合用时，达比加群几何平均AUC和Cmax增加了1.7倍。与单独使用利托那韦相比，咪达唑仑或达比加群与奈玛特韦/利托那韦合用时的暴露量总体相当，且与单独使用利托那韦相比，奈玛特韦/利托那韦使达比加群Cmax略高。奈玛特韦/利托那韦与咪达唑仑或达比加群合用时总体安全。未报告严重或重度不良事件。
咪达唑仑或达比加群与奈玛特韦/利托那韦合用时增加了咪达唑仑或达比加群的全身暴露量。咪达唑仑与奈玛特韦/利托那韦或单独与利托那韦合用时的暴露量相当，提示奈玛特韦无增量效应。与单独使用利托那韦相比，达比加群与奈玛特韦/利托那韦合用时Cmax略高，提示奈玛特韦有轻微增量效应。
