To the Editor:—
We read with great interest the article by Dr. Gijsenbergh et al.1
about the reversal of rocuronium-induced neuromuscular block by Org 25969. The described reversal mechanism is highly promising both for the clinical application and in research endeavors.
This being the first description of the pharmacokinetics of Org 25969, we hoped to reconstruct the time course of the plasma concentrations of Org 25969 using the provided data. Unfortunately, the combination of the pharmacokinetic parameters (tables 6 and 7) does not permit such a reconstruction, in part due to a nonstandard method of analysis. The authors do not mention whether an exponential equation or a compartmental model was fitted to the concentrations of Org 25969 in plasma. Was either approach even attempted? The terminal elimination half-life (t½β) could be appropriate for either a biexponential or a triexponential equation. The reported values for the areas under the plasma concentration curves are, in concept, dose dependent, and the reported values apparently reflect this. Presumably, the authors used areas under the plasma concentration curves to justify the claim of “dose-linear pharmacokinetics,” but this was not explicitly stated in the text. The reported “volume of distribution during the terminal phase” (VZ) is not routinely reported, and a comparison with the standard volumes, i.e., the initial volume of distribution for a multiexponential equation (Vc), the volume of the central compartment in compartmental interpretation (V1), or the volume of distribution at steady state (VSS), is difficult if not impossible. Furthermore, because VZ was evaluated from VZ = CL/−β, VZ is a function of t½β and, hence, provides no additional information. Of the routinely reported parameters, the authors provide only the estimates for the systemic clearance (CL) and the mean residence time. These two parameters do not suffice to reconstruct the time course of the plasma concentrations.
It would have been informative had the authors compared the doses of Org 25969 with the dose of rocuronium using molar units. The dose of rocuronium, 0.6 mg/kg, corresponds to approximately 1 · 10−6
mol · kg−1
. Given the molecular weight of Org 25969 of 2,000 Da,2
the doses of Org 25969, 0.1 to 8.0 mg/kg, correspond to (0.05 to 4) · 10−6
mol · kg−1
. If one molecule of Org 25969 binds to one molecule of rocuronium and assuming that the whole dose of rocuronium is still present in the body 3 min after injection, then Org 25969 doses of less than 1 · 10−6
mol · kg−1
, corresponding to less than 2 mg/kg, would, on theoretical basis, have little chance to reverse the neuromuscular block completely. As documented by the authors, only the molar doses of Org 25969 higher than the molar dose of rocuronium produced the desired reversal. Therefore, Org 25969 doses of 4.0 and 8.0 mg/kg efficiently reversed the block (table 9); on the molar basis, the two doses are two and four times higher than the dose of rocuronium. The Org 25969 dose of 2 mg/kg is equimolar to that of rocuronium and produced only a marginal reversal of neuromuscular block. Consideration of the doses in molar terms strengthens the authors' conclusion and explains why lower doses of Org 25969 could not have produced the reversal (table 9).
Vladimir Nigrovic, M.D.,*
Shashi B. Bhatt, M.D.
Anton Amann, Ph.D.
*Medical University of Ohio, Toledo, Ohio. firstname.lastname@example.org
1. Gijsenbergh F, Ramael S, Houwing N, van Iersel T: First human exposure of Org 25969, a novel agent to reverse the action of rocuronium bromide. Anesthesiology 2005; 103:695–703
2. Adam JM, Bennett DJ, Bom A, Clark JK, Feilden H, Hutchinson EJ, Palin R, Prosser A, Rees DC, Rosair GM, Stevenson D, Tarver GJ, Zhang MQ: Cyclodextrin-derived host molecules as reversal agents for the neuromuscular blocker rocuronium bromide: Synthesis and structure-activity relationships. J Med Chem 2002; 45:1806–16
© 2006 American Society of Anesthesiologists, Inc.