Ahmad Y Abuhelwa (1), Andrew Somogyi (2,3), Colleen K Loo (4,5,6,7), Paul Glue (8), David J.R Foster (1)
(1) University of South Australia, Adelaide, Australia (2) University of Adelaide, Adelaide, Australia, (3) Royal Adelaide Hospital, Adelaide, Australia, (4) University of New South Wales, Sydney, NSW, (5) Black Dog Institute, Randwick, NSW, (6) Wesley Hospital, Kogarah, NSW, (7) St George Hospital, Kogarah, NSW, (8) University of Otago, New Zealand
Introduction:
Major depressive disorders present a major clinical challenge with current antidepressant treatment achieving remission in only approximately 30% of patients [1]. Several recent trials suggested that a subanaesthetic dose of ketamine could provide a significant antidepressant effect in patients with depression (e.g.[2, 3]) and most studies have given ketamine at a fixed dose (0.5 mg/kg). A recently reported dose-titration pilot study evaluated low doses of ketamine administered across multiple routes of administration (IV, SC, IM) in patients with treatment refractory depression [4]. This analysis uses the data reported in by Loo et al. [4] to characterize the population PK-PD relationships for the effect of ketamine on the Montgomery–Asberg Depression Rating Scale (MADRS scores) and cardiovascular side effects of blood pressure and heart rate.
Objectives:
The objectives of this analysis were to:
- Develop population pharmacokinetic/pharmacodynamic (PK/PD) models that can effectively describe ketamine and norketamine pharmacokinetic and pharmacodynamic relationships for MADRS scores, blood pressure and heart rate after intravenous (IV), subcutaneous (SC), and intramuscular (IM) administration of ketamine in patients with treatment-refractory depression.
- Identify covariates that are predictive for the PK/PD of ketamine.
- Present the PKPD models as a web page application to facilitate interactive decision support of the use of ketamine for treatment of depression.
Methods:
Pharmacokinetic and pharmacodynamic data were collected from an active placebo-controlled pilot study in which 21 treatment-refractory depressed participants received ketamine (dose titration 0.1-0.5 mg/kg) by three routes of drug administration (IV, SC, IM) or midazolam (control treatment) in a multiple crossover design. Model development was conducted in a step-wise manner. The sequential 2-stage approach was used for development of both the metabolite PK model and the PD models using the final pharmacokinetic model [5]. Model development employed non-linear mixed effect modelling using NONMEM [6]. The final PK/PD models of ketamine, MADRS, blood pressure, and heart rate were implemented as a web application with user-friendly interface to facilitate communication of model results and allow for interactive decision support of the use of ketamine for treatment of depression.
Results:
The concentration-time data for ketamine and norketamine were adequately described using two-compartment models with first-order absorption after SC and IM administration. The model indicated that the bioavailability of ketamine after IM and SC is ~64%. Allometric scaling of body weight on all clearance and volume of distribution parameters for both ketamine and norketamine resulted in a significant improvement in the model fit. The delay in the concentration-response relationship for MADRS scores was best described using a turnover model, while for blood pressure and heart rate immediate effect model best described the data. For all PD effects, models of ketamine alone were superior to models with norketamine concentration linked to an effect. The estimated EC50 from the MDRDS score, blood pressure, and heart rate PKPD models were 0.439, 321, and 7580 ng/ml, respectively.
Conclusion:
PKPD models simulations suggest that a low-dose sustained release subcutaneous injection is a promising method of ketamine administration as the antidepressant effect and remission criteria can be achieved at low plasma concentrations (small EC50) while maintaining plasma concentration far below the EC50 for blood pressure and heart rate, and hence reducing the associated side effects. The shiny web application of the population PKPD models herein can be used as a practical tool for optimizing the antidepressant – side effects trade-off.
References:
[1] Dowlati, Y., et al., A meta-analysis of cytokines in major depression. Biological psychiatry, 2010. 67(5): p. 446-457.[2] Zarate Jr, C.A., et al., Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biological psychiatry, 2012. 71(11): p. 939-946.
[3] Murrough, J.W., et al., Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. American Journal of Psychiatry, 2013. 170(10): p. 1134-1142.
[4] Loo, C., et al., Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression. Acta Psychiatrica Scandinavica, 2016. 134(1): p. 48-56.
[5] Zhang, L., S.L. Beal, and L.B. Sheiner, Simultaneous vs. sequential analysis for population PK/PD data I: best-case performance. Journal of pharmacokinetics and pharmacodynamics, 2003. 30(6): p. 387-404.
[6] Beal, S., et al., NONMEM user’s guides, Part V. (1989-2009), Icon Development Solutions, Ellicott City, MD, USA, 2009.
Reference: PAGE 28 (2019) Abstr 9019 [www.page-meeting.org/?abstract=9019]
Poster: Drug/Disease Modelling - Other Topics