Perioperative Medicine  |   June 2018
Pharmacokinetic/Pharmacodynamic Model of CW002, an Investigational Intermediate Neuromuscular Blocking Agent, in Healthy Volunteers
Author Notes
  • From the Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (J.D.K., K.L.R.B.); Union University, Jackson, Tennessee (J.S.O.); Yale Medical School, New Haven, Connecticut (P.M.H.); Weill Cornell Medical College, New York, New York (C.A.L., J.J.S.); and Nuventra Pharma Sciences, Durham, North Carolina (V.D.S.).
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • Part of the work presented in this article has been presented at the American Society for Clinical Pharmacology and Therapeutics Annual Meeting, March 17, 2017, Washington, D.C.
    Part of the work presented in this article has been presented at the American Society for Clinical Pharmacology and Therapeutics Annual Meeting, March 17, 2017, Washington, D.C.×
  • Submitted for publication April 7, 2017. Accepted for publication February 1, 2018.
    Submitted for publication April 7, 2017. Accepted for publication February 1, 2018.×
  • Address correspondence to Dr. Schmith: Nuventra Pharma Sciences, Inc., 2525 Meridian Parkway, Suite 280, Durham, North Carolina 27713. gschmith@nuventra.com. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Clinical Science / Neuromuscular Diseases and Drugs / Pharmacology
Perioperative Medicine   |   June 2018
Pharmacokinetic/Pharmacodynamic Model of CW002, an Investigational Intermediate Neuromuscular Blocking Agent, in Healthy Volunteers
Anesthesiology 6 2018, Vol.128, 1107-1116. doi:10.1097/ALN.0000000000002157
Anesthesiology 6 2018, Vol.128, 1107-1116. doi:10.1097/ALN.0000000000002157
Abstract

Background: CW002 is an investigational nondepolarizing, neuromuscular blocking agent with a rapid onset and intermediate duration of action in animals. This is a single ascending dose, healthy subject study exploring tolerability, pharmacokinetics, and potency.

Methods: Population pharmacokinetic and pharmacokinetic/pharmacodynamic models were developed using plasma drug concentration data from a previously published dose–response study in 28 healthy subjects receiving single doses of CW002 during sevoflurane anesthesia. Subjects included in the models were from five different dose cohorts (cohorts 3, 4, 5, 6, and 8 receiving 0.04, 0.06, 0.08, 0.10, and 0.14 mg/kg, respectively). Serial arterial plasma concentrations and muscle twitch heights were monitored.

Results: A four-compartment model was fit to the concentration–time data, whereas a transit compartment with a sigmoid Emax model was fit to the pharmacokinetic/pharmacodynamic data. The population pharmacokinetics of CW002 was linear with very low interindividual variability in clearance (10.8%). Simulations were conducted to predict the onset and offset of effect at 2×, 3×, and 4× ED95. The time to 80% block was predicted to be 1.5, 0.8, and 0.7 min for 2×, 3×, and 4× ED95 doses, respectively. The simulated 25 to 75% recovery index was independent of dose.

Conclusions: CW002 has predictable pharmacokinetics and is likely to have a rapid onset with an intermediate duration of action at 3× ED95. This model provides information to inform critical decisions (e.g., dose, study design) for continued development of CW002.