Cox Donna S, Van Eyck Lien, Pawlak Sylvester, Beckerman Bruce, Linn Carlos, Ginman Katherine, Thay Cha Youliny, LaBadie Robert R, Shi Haihong, Damle Bharat
Global Product Development, Pfizer Inc., Collegeville, Pennsylvania, USA.
Clinical Research Unit, Pfizer Inc., Brussels, Belgium.
Br J Clin Pharmacol. 2023 Sep;89(9):2867-2876. doi: 10.1111/bcp.15788. Epub 2023 May 31.
The objective of this study was to evaluate the effects of a strong cytochrome P450 family (CYP) 3A4 inhibitor (itraconazole) and inducer (carbamazepine) on the pharmacokinetics and safety of nirmatrelvir/ritonavir.
Pharmacokinetics were measured in two phase 1, open-label, fixed-sequence studies in healthy adults. During Period 1, oral nirmatrelvir/ritonavir 300 mg/100 mg twice daily was administered alone; during Period 2, it was administered with itraconazole or carbamazepine. Nirmatrelvir/ritonavir was administered as repeated doses or one dose in the itraconazole and carbamazepine studies, respectively. Nirmatrelvir and ritonavir plasma concentrations and adverse event (AE) rates in both periods were analysed.
Each study included 12 participants. Following administration of nirmatrelvir/ritonavir with itraconazole (Test) or alone (Reference), test/reference ratios of the adjusted geometric means (90% CIs) for nirmatrelvir AUC and C were 138.82% (129.25%, 149.11%) and 118.57% (112.50%, 124.97%), respectively. After administration of nirmatrelvir/ritonavir with carbamazepine (Test) or alone (Reference), test/reference ratios (90% CIs) of the adjusted geometric means for nirmatrelvir AUC and C were 44.50% (33.77%, 58.65%) and 56.82% (47.04%, 68.62%), respectively. Nirmatrelvir/ritonavir was generally safe when administered with or without itraconazole or carbamazepine. No serious or severe AEs were reported.
Coadministration of a strong CYP3A4 inhibitor with a strong CYP3A inhibitor used for pharmacokinetic enhancement (i.e., ritonavir) resulted in small increases in plasma nirmatrelvir exposure, whereas coadministration of a strong inducer substantially decreased systemic nirmatrelvir and ritonavir exposures suggesting a contraindication in the label with CYP3A4 strong inducers. Administration of nirmatrelvir/ritonavir alone or with itraconazole or carbamazepine was generally safe.
本研究的目的是评估强效细胞色素P450家族（CYP）3A4抑制剂（伊曲康唑）和诱导剂（卡马西平）对奈玛特韦/利托那韦药代动力学和安全性的影响。
在两项针对健康成年人的1期开放标签固定序列研究中测量药代动力学。在第1阶段，单独每日两次口服300mg/100mg奈玛特韦/利托那韦；在第2阶段，将其与伊曲康唑或卡马西平联合给药。在伊曲康唑和卡马西平研究中，奈玛特韦/利托那韦分别以重复剂量或单剂量给药。分析两个阶段的奈玛特韦和利托那韦血浆浓度以及不良事件（AE）发生率。
每项研究包括12名参与者。奈玛特韦/利托那韦与伊曲康唑联合给药（试验组）或单独给药（参照组）后，奈玛特韦AUC和C的调整几何均数（及90%置信区间）的试验组/参照组比值分别为138.82%（129.25%，149.11%）和118.57%（112.50%，124.97%）。奈玛特韦/利托那韦与卡马西平联合给药（试验组）或单独给药（参照组）后，奈玛特韦AUC和C的调整几何均数的试验组/参照组比值（及90%置信区间）分别为44.50%（33.77%，58.65%）和56.82%（47.04%，68.62%）。无论是否与伊曲康唑或卡马西平联合给药，奈玛特韦/利托那韦总体上都是安全的。未报告严重或重度不良事件。
将强效CYP3A4抑制剂与用于药代动力学增强的强效CYP3A抑制剂（即利托那韦）联合使用，导致血浆奈玛特韦暴露量略有增加，而强效诱导剂联合使用则显著降低了奈玛特韦和利托那韦全身暴露量，提示在药品标签中应将CYP3A4强效诱导剂列为禁忌。单独或与伊曲康唑或卡马西平联合使用奈玛特韦/利托那韦总体上是安全的。
