Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing

Fanta, Samuel; Kinnunen, Mari; Backman, Janne T.; Kalso, Eija

doi:10.1007/s00228-015-1826-y

Cited by 79 publications

(85 citation statements)

References 36 publications

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“…A three‐compartment mammillary model (∆OFV = −598) with a central and two peripheral compartments was observed to be superior to a two‐compartmental model (∆OFV = −578). This was consistent with a recent study,31 developing a population model for S ‐ketamine and norketamine after oral and i.v. dosing.…”

Section: Resultssupporting

confidence: 93%

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

Ashraf

Peltoniemi

Olkkola

et al. 2018

CPT Pharmacom & Syst Pharma

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Low‐dose oral S‐ketamine is increasingly used in chronic pain therapy, but extensive cytochrome P450 (CYP) mediated metabolism makes it prone to pharmacokinetic drug‐drug interactions (DDIs). In our study, concentration‐time data from five studies were used to develop a semimechanistic model that describes the ticlopidine‐mediated inhibition of S‐ketamine biotransformation. A mechanistic model was implemented to account for reversible and time‐dependent hepatic CYP2B6 inactivation by ticlopidine, which causes elevated S‐ketamine exposure in vivo. A pharmacokinetic model was developed with gut wall and hepatic clearances for S‐ketamine, its primary metabolite norketamine, and ticlopidine. Nonlinear mixed effects modeling approach was used (NONMEM version 7.3.0), and the final model was evaluated with visual predictive checks and the sampling‐importance‐resampling procedure. Our final model produces biologically plausible output and demonstrates that ticlopidine is a strong inhibitor of CYP2B6 mediated S‐ketamine metabolism. Simulations from our model may be used to evaluate chronic pain therapy with S‐ketamine.

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Section: Resultssupporting

confidence: 93%

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

Ashraf

Peltoniemi

Olkkola

et al. 2018

CPT Pharmacom & Syst Pharma

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“…Further, it has been suggested that ketamine's analgesic properties may be partially mediated by its active metabolite, norketamine. Norketamine has a longer half-life than ketamine itself, is yielded in higher concentrations than ketamine following biotransformation, and is proposed to significantly contribute to ketamine's analgesic effects [181][182][183]. Nonetheless, ketamine's use in clinical practice for pain is limited, despite promise in studies of chronic pain [184], as well as clinically applied and experimental pain models of OIH (Table 3), in part due to its cardiovascular and psychotropic side effects [172,185].…”

Section: Ketaminementioning

confidence: 99%

Targeting Opioid-Induced Hyperalgesia in Clinical Treatment: Neurobiological Considerations

et al. 2015

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Opioid analgesics have become a cornerstone in the treatment of moderate to severe pain, resulting in a steady rise of opioid prescriptions. Subsequently, there has been a striking increase in the number of opioid-dependent individuals, opioid-related overdoses, and fatalities. Clinical use of opioids is further complicated by an increasingly deleterious profile of side effects beyond addiction, including tolerance and opioid-induced hyperalgesia (OIH), where OIH is defined as an increased sensitivity to already painful stimuli. This paradoxical state of increased nociception results from acute and long-term exposure to opioids, and appears to develop in a substantial subset of patients using opioids. Recently, there has been considerable interest in developing an efficacious treatment regimen for acute and chronic pain. However, there are currently no well-established treatments for OIH. Several substrates have emerged as potential modulators of OIH, including the N-methyl-D-aspartate and γ-aminobutyric acid receptors, and most notably, the innate neuroimmune system. This review summarizes the neurobiology of OIH in the context of clinical treatment; specifically, we review evidence for several pathways that show promise for the treatment of pain going forward, as prospective adjuvants to opioid analgesics. Overall, we suggest that this paradoxical state be considered an additional target of clinical treatment for chronic pain.

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“…Compared to iv, the im route is associated with longer recovery time and www.nature.com/aps Gao M et al Acta Pharmacologica Sinica npg a higher rate of vomiting [13] . The oral bioavailability of ketamine is low [14] , but with small doses per os (po) S-ketamine can be assumed to be a feasible alternative to repeated intravenous injections, especially in the setting of chronic pain [15] . Intranasal (in) administration is also an option.…”

Section: Modes Of Administrationmentioning

confidence: 99%

Ketamine use in current clinical practice

2016

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After nearly half a century on the market, ketamine still occupies a unique corner in the medical armamentarium of anesthesiologists or clinicians treating pain. Over the last two decades, much research has been conducted highlighting the drug's mechanisms of action, specifically those of its enantiomers. Nowadays, ketamine is also being utilized for pediatric pain control in emergency department, with its anti-hyperalgesic and anti-inflammatory effects being revealed in acute and chronic pain management. Recently, new insights have been gained on ketamine's potential anti-depressive and antisuicidal effects. This article provides an overview of the drug's pharmacokinetics and pharmacodynamics while also discussing the potential benefits and risks of ketamine administration in various clinical settings.

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Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing

Abstract: Given that the analgesic effect of S-ketamine is due to both S-ketamine and norketamine, relatively small oral doses of S-ketamine can be assumed to be a feasible alternative to repeated intravenous dosing, for example in the setting of chronic pain.

Cited by 79 publications

References 36 publications

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

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

Targeting Opioid-Induced Hyperalgesia in Clinical Treatment: Neurobiological Considerations

Ketamine use in current clinical practice

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