Newly Published
Perioperative Medicine  |   May 2018
Combined Recirculatory-compartmental Population Pharmacokinetic Modeling of Arterial and Venous Plasma S(+) and R(–) Ketamine Concentrations
Author Notes
  • From the Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado (T.K.H.); the Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado (T.K.H.); the Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois (M.J.A., T.C.K.); the Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands (A.D., E.O.); and the Department of Laboratory Medicine, Division of Clinical Pharmacology (L.L.G.), and the Department of Clinical Science, Intervention and Technology, Division of Anesthesiology (J.P.), Karolinska Institute at Karolinska University Hospital, Stockholm, Sweden.
  • 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).×
  • Submitted for publication November 28, 2017. Accepted for publication April 9, 2018.
    Submitted for publication November 28, 2017. Accepted for publication April 9, 2018.×
  • Acknowledgments: The authors thank Evan D. Kharasch, M.D., Ph.D., Washington University in St. Louis, St. Louis, Missouri, for his valuable insights regarding the pharmacokinetic modeling of arterial-venous drug concentration data.
    Acknowledgments: The authors thank Evan D. Kharasch, M.D., Ph.D., Washington University in St. Louis, St. Louis, Missouri, for his valuable insights regarding the pharmacokinetic modeling of arterial-venous drug concentration data.×
  • Research Support: Support was provided solely from institutional and/or departmental sources.
    Research Support: Support was provided solely from institutional and/or departmental sources.×
  • Competing Interests: The authors declare no competing interests.
    Competing Interests: The authors declare no competing interests.×
  • Correspondence: Address correspondence to Dr. Henthorn, Department of Anesthesiology, University of Colorado School of Medicine, Campus Box B-113, 12705 E Montview Blvd., Suite 200, Aurora, Colorado 80045. thomas.henthorn@ucdenver.edu 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 / Pharmacology
Perioperative Medicine   |   May 2018
Combined Recirculatory-compartmental Population Pharmacokinetic Modeling of Arterial and Venous Plasma S(+) and R(–) Ketamine Concentrations
Anesthesiology Newly Published on May 15, 2018. doi:10.1097/ALN.0000000000002265
Anesthesiology Newly Published on May 15, 2018. doi:10.1097/ALN.0000000000002265
Abstract

Background: The pharmacokinetics of infused drugs have been modeled without regard for recirculatory or mixing kinetics. We used a unique ketamine dataset with simultaneous arterial and venous blood sampling, during and after separate S(+) and R(–) ketamine infusions, to develop a simplified recirculatory model of arterial and venous plasma drug concentrations.

Methods: S(+) or R(–) ketamine was infused over 30 min on two occasions to 10 healthy male volunteers. Frequent, simultaneous arterial and forearm venous blood samples were obtained for up to 11 h. A multicompartmental pharmacokinetic model with front-end arterial mixing and venous blood components was developed using nonlinear mixed effects analyses.

Results: A three-compartment base pharmacokinetic model with additional arterial mixing and arm venous compartments and with shared S(+)/R(–) distribution kinetics proved superior to standard compartmental modeling approaches. Total pharmacokinetic flow was estimated to be 7.59 ± 0.36 l/min (mean ± standard error of the estimate), and S(+) and R(–) elimination clearances were 1.23 ± 0.04 and 1.06 ± 0.03 l/min, respectively. The arm-tissue link rate constant was 0.18 ± 0.01 min–1, and the fraction of arm blood flow estimated to exchange with arm tissue was 0.04 ± 0.01.

Conclusions: Arterial drug concentrations measured during drug infusion have two kinetically distinct components: partially or lung-mixed drug and fully mixed-recirculated drug. Front-end kinetics suggest the partially mixed concentration is proportional to the ratio of infusion rate and total pharmacokinetic flow. This simplified modeling approach could lead to more generalizable models for target-controlled infusions and improved methods for analyzing pharmacokinetic-pharmacodynamic data.