Merck & Co., Inc., Rahway, New Jersey, USA.
Br J Clin Pharmacol. 2023 Jul;89(7):2122-2130. doi: 10.1111/bcp.15677. Epub 2023 Feb 12.
Letermovir, a cytomegalovirus (CMV) DNA terminase complex inhibitor, is a substrate of ABCB1 (P-glycoprotein; P-gp), organic anion transporting polypeptide (OATP)1B1/3, UDP-glucuronosyltransferase (UGT)1A1, UGT1A3 and possibly ABCG2 (breast cancer resistance protein; BCRP). A study was conducted to evaluate the effects of itraconazole, a prototypic ABCB1/ABCG2 inhibitor, on letermovir pharmacokinetics (PK) and the effects of letermovir on itraconazole PK.
In an open-label, fixed-sequence study in 14 healthy participants, 200 mg oral itraconazole was administered once daily for 4 days. Following a 10-day washout, 480 mg oral letermovir was administered once daily for 14 days (Days 1-14) and then coadministered with 200 mg itraconazole once daily for 4 days (Days 15-18). Intensive PK sampling was performed for letermovir and itraconazole. PK and safety were evaluated.
Letermovir geometric mean ratio (GMR; 90% confidence interval [CI]) for area under the concentration-time curve from time 0 to 24 h (AUC ) was 1.33 (1.17, 1.51) and for maximum concentration (C ) was 1.21 (1.05, 1.39) following administration with/without itraconazole. Itraconazole GMR (90% CI) for AUC was 0.76 (0.71, 0.81) and for C was 0.84 (0.76, 0.92) following administration with/without letermovir. Coadministration of letermovir with itraconazole was generally well tolerated.
The increase in letermovir exposure with coadministration of itraconazole is likely predominantly due to inhibition of intestinal ABCB1 and potentially ABCG2 transport. The mechanism for the decrease in itraconazole exposure is unknown. The modest changes in letermovir and itraconazole PK are not considered clinically meaningful.
来特莫韦是一种巨细胞病毒 (CMV) DNA 末端酶复合物抑制剂，是 ABCB1（P-糖蛋白；P-gp）、有机阴离子转运多肽 (OATP)1B1/3、UDP-葡萄糖醛酸转移酶 (UGT)1A1、UGT1A3 和可能的 ABCG2（乳腺癌耐药蛋白；BCRP）的底物。进行了一项研究，以评估伊曲康唑（一种典型的 ABCB1/ABCG2 抑制剂）对来特莫韦药代动力学 (PK) 的影响，以及来特莫韦对伊曲康唑 PK 的影响。
在 14 名健康参与者中进行了一项开放标签、固定序列研究，参与者每日口服 200mg 伊曲康唑，连续 4 天。在 10 天洗脱期后，参与者每日口服 480mg 来特莫韦，连续 14 天（第 1-14 天），然后每日一次同时口服 200mg 伊曲康唑，连续 4 天（第 15-18 天）。对来特莫韦和伊曲康唑进行了强化 PK 采样。评估了 PK 和安全性。
来特莫韦与伊曲康唑合用/不合用时，AUC 从 0 到 24 小时的几何平均比（GMR；90%置信区间 [CI]）为 1.33（1.17，1.51），C 最大值（C ）为 1.21（1.05，1.39）。伊曲康唑与来特莫韦合用/不合用时，AUC 的 GMR（90%CI）为 0.76（0.71，0.81），C 为 0.84（0.76，0.92）。来特莫韦与伊曲康唑合用通常耐受良好。
来特莫韦与伊曲康唑合用后暴露量增加，可能主要是由于肠 ABCB1 和潜在的 ABCG2 转运的抑制。伊曲康唑暴露减少的机制尚不清楚。来特莫韦和伊曲康唑 PK 的适度变化在临床上没有意义。
