Iñaki F. Trocóniz1, Robert A. Dean2, Gemma L. Dickinson3, Kjell Svensson4, Steven Swanson5, Gunnar Flik6, Kimberley Jackson3.
1, Pharmacometrics and Systems Pharmacology, Department of Pharmacy, School of Pharmacy, University of Navarra, Pamplona 31080, Spain; 2 Tailored Therapeutics, Eli Lilly and Company, Indianapolis, Indiana, USA; 3 Global PK/PD, Eli Lilly and Company, Indianapolis and Windlesham, UK; 4 Discovery Biology, Eli Lilly and Company, Indianapolis; 5 Drug Disposition, Eli Lilly and Company, Indianapolis; 6 Brains On-Line, Groningen, Netherlands.
Objectives: The goal of the current analysis is to develop a semi-physiologically based PK model for S(+)-Ketamine (S-Ket) in rats that can be used in the future to develop PK-PD models and to translate pharmacological effects to humans.
Methods: Twenty-two Sprague-Dawley (SD) rats dosed with S-Ket were included in the study. A MetaQuant slow flow microdialysis probe was implanted in the PFC, a CSF probe in the aquaduct, and a catheter placed in the jugular vein. S-Ket was administered SC at doses of 10 mg/kg (n=10) and 25 mg/kg (n=12). Concentrations of Ket and norketamine (Nket) were measured in plasma, CSF and dialysate using HPLC and tandem mass spectrometry (MS/MS) detection. Samples were obtained at the following times (h) post dose: 0.25, 0.5, 1, 2, 3, and 4 (plasma), 0.25, 1.25, 2.25 and 4.25 (CSF). After 2 h prestabilisation, microdialysis samples (40 ml) were collected over 30 minute periods for 4 h.
The population approach in NONMEM 7.2 (Icon Development Solutions, Hanover, Maryland) was used for this analysis. The plasma PK of Ket and Nket were described using compartmental models. For concentrations in dialysate and CSF, semi-physiologically based models were evaluated where input and output rates were defined as the product of the flow and CPxfu or CTu/KP, respectively; where CP=predicted total analyte concentration in plasma, fu, = unbound fraction in plasma obtained from literature, CTu=unbound concentration in CSF or dialysate, and KP=partition coefficient between unbound concentrations in plasma and tissue at equilibrium. Tissue volumes were taken from literature.
Results: Absorption after SC injection was described by a first order rate model. Bioavailability was 28% lower for the 25 mg/kg S(+)-Ket dose compared with the 10 mg/kg dose. Plasma profiles of Ket and Nket were described with compartmental models. The fraction of total plasma clearance of Ket corresponding to Nket formation was 93%. Disposition of Ket and NKet in dialysate and CSF were described adequately with the use of partial physiologically-based PK models with estimates of the partition coefficient for both analytes close to one.
Conclusions: An integrated PK model for Ket and Nket has been developed to describe disposition in plasma, dialysate, and CSF in rats following SC administration of S(+)-Ketamine. This model framework will be used to develop PK-PD models, and given the semi-physiological basis of the model, translation to other species will be attempted.
References:
[1] Icon Development Solutions, Hanover, Maryland
Reference: PAGE 23 (2014) Abstr 3102 [www.page-meeting.org/?abstract=3102]
Poster: Drug/Disease modeling - CNS