A semi-mechanistic model to characterize the pharmacokinetics of orally administered S-Ketamine in healthy human subjects
Muhammad Waqar Ashraf (1), Marko A. Peltoniemi (2), Miia Turpeinen (3), Pertti J. Neuvonen (4), Klaus T. Olkkola (5) , Teijo I. Saari (1,2)
(1) Department of Anaesthesiology and Intensive Care, University of Turku, Turku, Finland (2) Division of Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, Turku, Finland. (3) Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland. (4) Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland. (5) Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Objectives: S-Ketamine is a potent analgesic which can be effectively used in pain management as an adjuvant to enhance analgesia and reduce the need for opioids. The objective of this study was to develop a semi-mechanistic model to characterize the pharmacokinetics of orally administered S-Ketamine.
Methods: S-Ketamine concentration-time data was gathered from five placebo-controlled, blinded, randomized, crossover studies [1-5]. Nonlinear mixed effects modeling was performed with NONMEM software (version 7.3.0). A semi-mechanistic structural model was developed with differential equations for gut-wall, portal vein, and liver, alongside a three compartment model for describing the pharmacokinetics of S-Ketamine. Gut-wall clearance was modeled using Michaelis-Menten kinetics considering a limited amount of metabolizing enzymes, and hepatic clearance was specified through a well-stirred clearance model.
Results: Our results suggest that gut-wall does not play a significant role in the first pass metabolism of S-Ketamine contrary to the liver, which metabolizes S-Ketamine extensively during the first pass. The final structural model was constituted by applying only hepatic first-pass extraction. The use of an additive plus proportional residual variability model significantly reduced OFV value (?OFV=-195). Parameter estimates obtained with our final model were: Ka=8.94 hr-1, CL1=12.6 L/hr, V1=205 L, CL2=33 L/hr, V2=119 L, CL3=112 L/hr, V3=388 L (calculated as output compartment i.e. Vperiph2*Vperiph1). Our final model adequately captured the data leading to plausible values of parameter estimates, predicted concentrations and goodness of fit plots. The model was further evaluated with prediction-corrected visual predictive checks and Sampling Importance Resampling procedure [6], both of which proved the appropriateness of the final model.
Conclusions: The semi-mechanistic approach developed in the study adequately describes S-Ketamine pharmacokinetic data and inter-individual variability in healthy human volunteers. Our final model will be used for the optimization of S-Ketamine dosage regimen in acute postoperative pain management.
References:
[1] Hagelberg, N.M., Peltoniemi, M.A., Saari, T.I., Kurkinen, K.J., Laine, K., Neuvonen, P.J. & Olkkola, K.T. 2010, "Clarithromycin, a potent inhibitor of CYP3A, greatly increases exposure to oral S-ketamine", European Journal of Pain, vol. 14, no. 6, pp. 625-629.
[2] Peltoniemi, M.A., Saari, T.I., Hagelberg, N.M., Laine, K., Kurkinen, K.J., Neuvonen, P.J. & Olkkola, K.T. 2012, "Rifampicin has a Profound Effect on the Pharmacokinetics of Oral S-Ketamine and Less on Intravenous S-Ketamine", Basic and Clinical Pharmacology and Toxicology, vol. 111, no. 5, pp. 325-332.
[3] Peltoniemi, M.A., Saari, T.I., Hagelberg, N.M., Laine, K., Neuvonen, P.J. & Olkkola, K.T. 2012, "S-ketamine concentrations are greatly increased by grapefruit juice", European journal of clinical pharmacology, vol. 68, no. 6, pp. 979-986.
[4] Peltoniemi, M.A., Saari, T.I., Hagelberg, N.M., Laine, K., Neuvonen, P.J. & Olkkola, K.T. 2012, "St John's wort greatly decreases the plasma concentrations of oral S-ketamine", Fundamental and Clinical Pharmacology, vol. 26, no. 6, pp. 743-750.
[5] Peltoniemi, M.A., Saari, T.I., Hagelberg, N.M., Reponen, P., Turpeinen, M., Laine, K., Neuvonen, P.J. & Olkkola, K.T. 2011, "Exposure to Oral S-ketamine is unaffected by itraconazole but greatly increased by ticlopidine", Clinical pharmacology and therapeutics, vol. 90, no. 2, pp. 296-302.
[6] Bergstrand, and M. O. Karlsson. “Determination of Appropriate Settings in the Assessment of Parameter Uncertainty Distributions using Sampling Importance Resampling (SIR)”. In: PAGE 24 (2015) Abstr 3546 (2015). url: www.page-meeting.org/?abstract= 3546
