Semimechanistic Population Pharmacokinetic Model to Predict the Drug–Drug Interaction Between <i>S</i>‐ketamine and Ticlopidine in Healthy Human Volunteers

Ashraf, Muhammad Waqar; Peltoniemi, Marko A.; Olkkola, Klaus T.; Neuvonen, Pertti J.; Saari, Teijo I.

doi:10.1002/psp4.12346

Cited by 15 publications

(18 citation statements)

References 43 publications

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“…However, since CYP3A4 is more abundant than CYP2B6, CYP3A4 is considered to be the main CYP subtype in this metabolic pathway. Ashraf et al report that CYP2B6 is the main enzyme responsible for ketamine metabolism [29].…”

Section: Metabolitesmentioning

confidence: 99%

Pharmacokinetic and pharmacodynamic considerations for NMDA-receptor antagonist ketamine in the treatment of chronic neuropathic pain: an update of the most recent literature

Kamp

Olofsen

et al. 2019

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: Chronic neuropathic pain (NP) is an incapacitating illness caused by a lesion of the somatosensory nervous system and is associated with several diseases or syndromes. Since current treatment options lack adequate efficacy in the majority of patients, ketamine is often administered to treat refractory NP. Areas covered: This review gives an overview of new ketamine pharmacokinetic data including data on intranasal and inhaled ketamine. The outcome of seven systematic reviews and meta-analyses, published since 2012, on ketamine efficacy in NP is discussed. The reader will additionally get an understanding of ketamine's complex metabolism with emphasis on the metabolite hydroxynorketamine. Expert opinion: Proof of sustained, large effects of ketamine in the treatment of NP from randomized controlled clinical trials is lacking, although we cannot exclude selective ketamine efficacy in patients with central sensitization, opioid-induced hyperalgesia or opioid tolerance. Interestingly, data from observational trials and case series do suggest the efficacy of ketamine in producing effective pain relief in NP with positive patient-related outcome measures. Additional randomized trials in often illdefined groups of chronic pain patients are not useful and we suggest to conduct future studies in NP patients with central sensitization and/or with opioid refractory severe NP.

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Section: Metabolitesmentioning

confidence: 99%

Pharmacokinetic and pharmacodynamic considerations for NMDA-receptor antagonist ketamine in the treatment of chronic neuropathic pain: an update of the most recent literature

Kamp

Olofsen

et al. 2019

Expert Opinion on Drug Metabolism & Toxicology

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“…35 A CYP2D6 inhibitor (ticlopidine) conversely slowed metabolism of IV esketamine, though any relevance to the intranasal preparation is unclear. 36 An in vitro study of esketamine showed modest induction of CYP2D6 and 3A4. 11 The mean terminal half-life for esketamine ranges between 7 and 12 h, though there is a period of rapid decline in plasma concentrations over 2-4 h following the C max .…”

Section: Therapeutic Advances In Drug Safety 11mentioning

confidence: 99%

Section: Pharmacokineticsmentioning

confidence: 99%

Esketamine: new hope for the treatment of treatment-resistant depression? A narrative review

Salahudeen

Wright

Peterson

2020

Therapeutic Advances in Drug Safety

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This narrative review aims to provide an overview of the current literature on the pharmacology, safety, efficacy and tolerability of intranasal esketamine, the S-enantiomer of ketamine, for the treatment of treatment-resistant depression (TRD). A literature search using Medline, Embase, PsycINFO and Cochrane Central was conducted (January 2000 to July 2019). Product information and www.clinicaltrials.gov were also reviewed. The literature search was limited to human studies published in English. Phase I, II, and III studies of intranasal esketamine for TRD were reviewed. About a third of patients with major depressive disorder fail to achieve remission despite treatment with multiple antidepressants. This article examines the trials that led to the approval of esketamine in the United States, as well as other recent studies of esketamine for TRD. The findings from limited phase III trials illustrate that intranasal esketamine is effective and safe in reducing depressive symptoms and achieving clinical response in patients with TRD. The optimum duration and frequency of use are not fully understood. Although the nasal spray is a convenient dosage form, its use in practice may be limited by cost and administrative regulation. While it may prove beneficial to many patients who suffer from TRD, further long-term data are required, along with comparative trials with the R-isomer (arketamine). In the interim, care and monitoring should be exercised in its use in clinical practice.

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“…Population models were specified with differential equations that were solved with ADVAN13 subroutine and parameters estimated using first-order conditional estimation with interaction. A sequential PK-PD approach was used as described previously [23,24]. In the first step, a PK model was developed using IV administration data only, followed by the implementation of a semi-mechanistic absorption model for SC administration.…”

Section: Model Developmentmentioning

confidence: 99%

Population Modelling of Dexmedetomidine Pharmacokinetics and Haemodynamic Effects After Intravenous and Subcutaneous Administration

et al. 2020

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Background and Objective Dexmedetomidine is a potent agonist of α 2-adrenoceptors causing dose-dependent sedation in humans. Intravenous dexmedetomidine is commonly used perioperatively, but an extravascular route of administration would be favoured in palliative care. Subcutaneous infusions provide desired therapeutic plasma concentrations with fewer unwanted effects as compared with intravenous dosing. We aimed to develop semi-mechanistic population models for predicting pharmacokinetic and pharmacodynamic profiles of dexmedetomidine after intravenous and subcutaneous dosing. Methods Non-linear mixed-effects modelling was performed using previously collected concentration and haemodynamic effects data from ten (eight in the intravenous phase) healthy human subjects, aged 19-27 years, receiving 1 µg/kg of intravenous or subcutaneous dexmedetomidine during a 10-min infusion. Results The absorption of dexmedetomidine from the subcutaneous injection site, and distribution to local subcutaneous fat tissue was modelled using a semi-physiological approach consisting of a depot and fat compartment, while a two-compartment mammillary model explained further disposition. Dexmedetomidine-induced reductions in plasma norepinephrine concentrations were accurately described by an indirect response model. For blood pressure models, the net effect was specified as hyper-and hypotensive effects of dexmedetomidine due to vasoconstriction on peripheral arteries and sympatholysis mediated via the central nervous system, respectively. A heart rate model combined the dexmedetomidine-induced sympatholytic effect, and input from the central nervous system, predicted from arterial blood pressure levels. Internal evaluation confirmed the predictive performance of the final models, as well as the accuracy of the parameter estimates with narrow confidence intervals. Conclusions Our final model precisely describes dexmedetomidine pharmacokinetics and accurately predicts dexmedetomidine-induced sympatholysis and other pharmacodynamic effects. After subcutaneous dosing, dexmedetomidine is taken up into subcutaneous fat tissue, but our simulations indicate that accumulation of dexmedetomidine in this compartment is insignificant.

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Semimechanistic Population Pharmacokinetic Model to Predict the Drug–Drug Interaction Between S‐ketamine and Ticlopidine in Healthy Human Volunteers

Cited by 15 publications

References 43 publications

Pharmacokinetic and pharmacodynamic considerations for NMDA-receptor antagonist ketamine in the treatment of chronic neuropathic pain: an update of the most recent literature

Pharmacokinetic and pharmacodynamic considerations for NMDA-receptor antagonist ketamine in the treatment of chronic neuropathic pain: an update of the most recent literature

Esketamine: new hope for the treatment of treatment-resistant depression? A narrative review

Population Modelling of Dexmedetomidine Pharmacokinetics and Haemodynamic Effects After Intravenous and Subcutaneous Administration

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