A Mechanism-based Pharmacokinetic Model Describing the Interaction Between Sugammadex and Rocuronium in Patients with Normal and Impaired Renal Function
J. Smeets(1), B. Ploeger(1), A. Strougo(1), L. Liefaard(1), T. Kerbusch(2)
(1)LAP&P Consultants BV, Leiden, The Netherlands; (2)N.V. Organon, a part of Schering-Plough Corporation, Oss, The Netherlands
Objectives: Sugammadex is a novel neuromuscular block reversal agent that acts by encapsulating steroidal neuromuscular blocking agents, specifically rocuronium. Complex formation causes an increase of total (bound plus free) plasma concentrations of rocuronium. Reduction of free rocuronium causes redistribution of rocuronium to the plasma. Furthermore, the clearance of total rocuronium is decreased because sugammadex and the complex are primarily renally excreted at a slower rate than free rocuronium, which is also hepatically excreted. These processes were modelled based on phase I, II, and III clinical data using population pharmacokinetic (PK) analysis with NONMEM.
Methods: Firstly, the PK of rocuronium alone was modelled based upon 238 subjects from seven trials, including patients with severly impaired renal function. Secondly, the PK interaction between rocuronium and sugammadex was modelled based upon 147 patients with normal and severely impaired renal function, from three trials, who received 0.1-8.0 mg/kg sugammadex at various time points after rocuronium. The model was validated using internal and external data sets.
Results: A three-compartment model was developed for rocuronium. The PK interaction was further described by three compartments for free sugammadex and three compartments for the complex. Complex formation occurs in the central compartment and is described by association and dissociation rate constants K1 and K2, which are related to the in-vitro association constant of the complex as Ka=K1/K2. The PK parameters of sugammadex and the complex were estimated simultaneously based on plasma concentrations of sugammadex and rocuronium. Clearance of free rocuronium and sugammadex were 44 and 90% lower in severely renally impaired patients than in normal patients.
Conclusion: The presented model could accurately describe the observed PK of rocuronium and sugammadex in a series of clinical trials, confirming the mechanism of PK interaction.