Pharmacokinetics and Safety of Fospropofol Disodium for Injection in Subjects with Hepatic Impairment Compared with Healthy Matched Controls: A Prospective Cohort Study.

PURPOSE: Fospropofol disodium for injection (FospropofolFP) is a new water-soluble propofol prodrug for procedural sedation and general anesthesia. This prospective cohort study aimed to characterize the pharmacokinetics and safety of FospropofolFP in subjects with hepatic impairment compared with healthy matched participants during general anesthesia.

PATIENTS AND

METHODS

Twenty-three patients were enrolled and divided into three cohorts according to liver function: normal liver function (n = 10), moderate hepatic impairment (n = 10), and severe hepatic impairment (n = 3). They received a single bolus of FospropofolFP 10 mg/kg i.v. Venous blood samples were collected from each patient 14 time points. The plasma concentrations of FospropofolFP and active metabolite propofol were determined by liquid chromatography tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters were calculated by non-compantmental analysis (NCA) using Phoenix WinNonlin software.

RESULTS

Compared with matched healthy controls, patients with moderate hepatic impairment exhibited significant reduced exposure and increased elimination for FospropofolFP: the area under the curve (AUC) decreased by approximately 43% and clearance (CL) increased by 60%. The AUC of patients with severe hepatic impairment exhibited a significant decrease by approximately 55%. Notably, propofol (active metabolite) clearance decreased by approximately 15% and 33% in moderate and severe impairment, respectively. Multivariate analysis identified preoperative albumin (ALB) as an independent predictor of FospropofolFP exposure.

CONCLUSION

Our study is the first to report altered PK of FospropofolFP in patients with moderate-to-severe hepatic impairment, report a reverse pattern of increased elimination of FospropofolFP and slow elimination of the metabolite propofol, and identify ALB as an independent predictor of FospropofolFP's PK. No unexpected adverse events related to FospropofolFP were seen in subjects with hepatic impairment after a single dose and that repeated dosing may need further evaluation.