In vivo pharmacokinetic evaluation of Molnupiravir in patients with severe chronic kidney disease

Yuanyuan Wang¹Qiong Chen^1,2Xuan Liu¹Ling Zhang¹Ming Chen¹Shuowen Wang¹Man Yang^1*Guorong Fan^1*Qiuling Fan^1*

• ¹Shanghai General Hospital, Shanghai, China
• ²Shanghai Jiao Tong University, Shanghai, China

Introduction: Molnupiravir (MPV) is an oral, potent ribonucleoside analog that inhibits the replication of SARS-CoV-2 and for adults with COVID-19. Patients with COVID-19 are at an elevated risk of adverse outcomes, underscoring the need for precise pharmacokinetic (PK) data . Renal impairment has minimal impact onPK profiles of MPV and its active metabolite NHC.However, there are no relevant pharmacokinetic studies in patients with severe renal insufficiency or patients requiring dialysis. This study aims to explore the concentration of MPV in patients with severe renal insufficiency, providing a basis for rational clinical use of drugs. Methods: LC-MS/MS was used to detect the plasma concentrations of 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 or 5 chronic kidney disease (CKD) were enrolled in the study. All patients received a standard oral dose of molnupiravir (MPV), and plasma samples were collected 12 hours post-administration (C₁₂ₕ) for analysis. Plasma concentrations of MPV itself were consistently low at 12 hours post-dose. In contrast, the 12-hour plasma concentration of N4-hydroxycytidine (NHC, the active metabolite of MPV) in patients with severe renal insufficiency (stage 4/5 CKD) was significantly higher than that in reference populations: compared with healthy subjects (NHC C₁₂ₕ: 16.7 ng/mL) and patients with mild to moderate renal impairment (NHC C₁₂ₕ: 31.1 ng/mL), the NHC C₁₂ₕ in the severe renal insufficiency group ranged from 43 to 1600 ng/mL. Notably, the patient with stage 5 CKD exhibited the highest NHC plasma concentration (1600 ng/mL) at 12 hours post-dose, which remained at a persistently elevated level. Conclusion: 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.