Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Clin Pharmacokinet. 2023 Sep;62(9):1305-1314. doi: 10.1007/s40262-023-01287-7. Epub 2023 Jul 28.
Voriconazole is an important broad-spectrum anti-fungal drug with nonlinear pharmacokinetics. The aim of this single centre fixed-sequence open-label drug-drug interaction trial in healthy participants (N = 17) was to determine whether microdosed probe drugs for CYP3A and CYP2C19 reliably predict voriconazole clearance (CL).
At baseline, a single oral microdose of the paradigm substrates midazolam (CYP3A) and omeprazole (CYP2C19) were given to estimate their clearances (CL). Thereafter, a single oral dose of voriconazole was administered (50, 100, 200 or 400 mg), followed by the microdosed probe drugs.
The clearances of midazolam (CL 790-2790 mL/min at baseline; 248-1316 mL/min during voriconazole) and omeprazole (CL 66.4-2710 mL/min at baseline; 30.1-1420 mL/min during voriconazole) were highly variable. CL [geometric mean ratio (GMR) 0.586 at 50 mg voriconazole decreasing to GMR 0.196 at 400 mg voriconazole] and CL (GMR 0.590 at 50 mg decreasing to GMR 0.166 at 400 mg) were reduced with higher voriconazole doses. CL was linearly correlated with CL (slope 1.458; adjusted R 0.528) as was CL (slope 0.807; adjusted R 0.898). Multiple linear regression resulted in an adjusted R of 0.997 for the relationship CL ~ log CL + log CL using data during voriconazole treatment and an adjusted R of 0.997 for the relationship CL ~ log CL + log CL + voriconazole dose, using baseline data for CL and CL.
Microdosed midazolam and omeprazole accurately described and predicted total CL TRIAL REGISTRATION: EudraCT No: 2020-001017-20, registered on March 5th, 2020. DRKS: DRKS00022547, registered on August 6th, 2020.
伏立康唑是一种重要的广谱抗真菌药物，具有非线性药代动力学特征。本研究是在健康志愿者（N=17）中开展的一项单中心固定序列开放性药物相互作用试验，旨在评估微剂量探针药物是否能够可靠地预测伏立康唑清除率（CL）。
在基线时，志愿者单次口服给予咪达唑仑（CYP3A）和奥美拉唑（CYP2C19）微剂量探针药物，以估算其清除率（CL）。随后，志愿者单次口服给予伏立康唑（50、100、200 或 400 mg），之后给予微剂量探针药物。
咪达唑仑（CL 在基线时为 790-2790 mL/min，在伏立康唑治疗期间为 248-1316 mL/min）和奥美拉唑（CL 在基线时为 66.4-2710 mL/min，在伏立康唑治疗期间为 30.1-1420 mL/min）的清除率存在高度变异性。随着伏立康唑剂量的增加，CL [50 mg 伏立康唑时的几何均数比值（GMR）为 0.586，400 mg 伏立康唑时的 GMR 为 0.196]和 CL（GMR 为 0.590，50 mg 伏立康唑时的 GMR 为 0.166，400 mg 伏立康唑时的 GMR 为 0.166）均降低。CL 与 CL（斜率 1.458；调整后 R 为 0.528）以及 CL（斜率 0.807；调整后 R 为 0.898）呈线性相关。使用伏立康唑治疗期间的数据，CLlog CL + log CL 关系的多元线性回归调整后 R 为 0.997，使用 CL 和 CL 的基线数据，CLlog CL + log CL + 伏立康唑剂量关系的多元线性回归调整后 R 为 0.997。
微剂量咪达唑仑和奥美拉唑可准确描述和预测总 CL。
EudraCT 编号：2020-001017-20，于 2020 年 3 月 5 日注册；DRKS：DRKS00022547，于 2020 年 8 月 6 日注册。
