In Vivo Pharmacokinetic Evaluation of Molnupiravir in Patients with Severe CKD

Background: This study aims to explore the plasma concentration of Molnupiravir in patients with severe renal insufficiency, providing a basis for rational clinical use of drugs. Methods: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to detect the plasma concentrations of MPV and NHC. Plasma working calibration standards for MPV and NHC were prepared by diluting 1.0, 5.0, 10.0, 50.0, 100, 500, 1000, and 2500 ng/mL in blank, drug-free plasma. Add 10 μl of internal standard solution to 100 μl of plasma sample. Quality control (QC) samples include high QC (HQC: 2000 ng/mL MPV and NHC), medium QC (MQC: 200 ng/mL MPV and NHC), low QC (LQC: 2.0 ng/mL MPV and NHC), and quantitative Limit (LLOQ: 1.0 ng/mL MPV and NHC). All analytes were extracted by protein precipitation using acetonitrile at a ratio equivalent to 3:1, and QMPV and QNHC were evaluated by calculating the ratio of plasma concentrations. Results: A total of four patients with stage 4/5 chronic kidney disease were included in the study. The blood samples collected 12 hours after taking the drug showed that the patients' MPV blood drug concentration was at a low level, while NHC and healthy subjects (C12h: Compared with patients with mild to moderate renal insufficiency (16.7 ng/mL) and patients with mild to moderate renal insufficiency (C12h: 31.1 ng/mL), patients with severe renal insufficiency have higher C12h than patients with mild to moderate renal insufficiency (43~1600 ng/mL). Among them, the NHC plasma concentration in patients with stage 5 chronic kidney disease is 1600 ng/mL, which is maintained at a relatively high level. Conclusion: After patients with severe renal insufficiency were administered 800 mg/12 hours according to the instructions, MPV was rapidly hydrolyzed to NHC in the body and maintained at a low level. The NHC is significantly higher than that of patients with mild to moderate symptoms, especially those with stage 5 chronic kidney disease. The blood drug concentration is equivalent to Cmax, which suggests that when used clinically in patients with uremia, the dosing interval should be adjusted to avoid drug accumulation and occurrence of AEs.