Population Pharmacokinetic Study of Memantine: Effects of Clinical and Genetic Factors

Noetzli, Muriel; Guidi, Monia; Ebbing, Karsten; Eyer, Stephan; Wilhelm, Laurence; Michon, Agnès; Thomazic, Valérie; Alnawaqil, Abdel-Messieh; Maurer, Sophie; Zumbach, Serge; Giannakopoulos, Pantéleimon; Gunten, Armin von; Csajka, Chantal; Eap, Chin B.

doi:10.1007/s40262-013-0032-2

Cited by 40 publications

(21 citation statements)

References 42 publications

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“…In contrast, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2E1, and CYP3A4 are weakly inhibited [55,120,164,165]. Studies in human liver microsomes show that memantine inhibits CYP2B6 and CYP2D6; decreases CYP2A6 and CYP2C19; and has no effect on CYP1A2, CYP2E1, CYP2C9, or CYP3A4 [166]. The coadministration of CYP2B6 substrates decreases memantine metabolism by 65%.…”

Section: Memantinementioning

confidence: 99%

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Cacabelos

2020

IJMS

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Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6–10 drugs/day with the consequent risk for drug–drug interactions and adverse drug reactions (ADRs >80%) which accelerate cognitive decline. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms. CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-normal metabolizers are the best responders and CYP2D6-poor metabolizers are the worst responders. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.

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Section: Memantinementioning

confidence: 99%

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Cacabelos

2020

IJMS

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“…However, (1) lack of published modulators for evaluation of the sensitivity and specificity of this probe, (2) low inter-individual variability observed in this study, and (3) recent findings on the influence of the glomerular filtration rate and gender as well as NR1I2 (c.1663T[C, rs1523130) polymorphism on memantine clearance (Noetzli et al 2013) preclude meaningful use of this probe in the future. Memantine will therefore not be included in upgraded versions of the CIME combination.…”

Section: Discussionmentioning

confidence: 89%

Safety and pharmacokinetics of the CIME combination of drugs and their metabolites after a single oral dosing in healthy volunteers

Lenuzza

Duval

Nicolas

et al. 2014

Eur J Drug Metab Pharmacokinet

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This phase I, pilot clinical study was designed to evaluate the safety and the pharmacokinetic (PK) profiles of the CIME (Metabolic Identity Card) combination of ten drugs, with a view to its use as a phenotyping cocktail. Ten healthy Caucasian subjects were orally dosed with the CIME combination (caffeine-CYP1A2, repaglinide-CYP2C8, tolbutamide-CYP2C9, omeprazole-CYP2C19, dextromethorphan-CYP2D6, midazolam-CYP3A, acetaminophen-UGT1A1, 6&9 and 2B15, digoxin-P-gp, rosuvastatin-OATP1B1&3 and memantine-active renal transport). Blood was collected over 3 days and on day 7. CIME probes and relevant metabolites were assayed by LC-MS/MS and PK parameters were calculated. Main results were: (1) good safety with reversible mild or moderate adverse effects, (2) an analytical method able to quantify simultaneously the 10 probes and the major metabolites, (3) calculation of PK parameters for all probes in general agreed with published values, and (4) identification of the low CYP2D6 metabolizer. This pilot study showed that the CIME combination was well tolerated and that its pharmacokinetics could be accurately measured in healthy volunteers. This combination can now confidently be checked for sensitivity and specificity and for lack of interaction to be validated as a phenotyping cocktail.

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“…NR1I2 genotyping In the literature the NR1I2 rs1523130 SNP was found to be significantly associated with memantine clearance with carriers of the NR1I2 rs1523130 CT/TT genotypes presenting 16% slower memantine excretion than the CC genotype carriers 24. Genotyping was performed by Taq Man ® Drug Metabolism Genotyping Assays.…”

Section: Methodsmentioning

confidence: 99%

“…Dextromethorphan alleviates NP in diabetes21,22 and trauma4,5 but has no beneficial effect on NP in other clinical trials 8,23. Genetic polymorphism has been identified as a variability factor of dextromethorphan ( CYP2D6, CYP3A4 and ABCB1 ) and memantine ( NR1I2 ) metabolism, and may be involved in the modulation of their analgesic effect 4,5,24…”

Section: Introductionmentioning

confidence: 99%

<p>Dextromethorphan and memantine after ketamine analgesia: a randomized control trial</p>

Martin¹,

Sorel²,

Morel³

et al. 2019

DDDT

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Purpose Intravenous ketamine is often prescribed in severe neuropathic pain. Oral N -methyl-D-aspartate receptor (NMDAR) antagonists might prolong pain relief, reducing the frequency of ketamine infusions and hospital admissions. This clinical trial aimed at assessing whether oral dextromethorphan or memantine might prolong pain relief after intravenous ketamine. Patients and methods A multicenter randomized controlled clinical trial included 60 patients after ketamine infusion for refractory neuropathic pain. Dextromethorphan (90 mg/day), memantine (20 mg/day) or placebo was given for 12 weeks (n=20 each) after ketamine infusion. The primary endpoint was pain intensity at one month. Secondary endpoints included pain, sleep, anxiety, depression, cognitive function and quality of life evaluations up to 12 weeks. Results At 1 month, dextromethorphan maintained ketamine pain relief (Numeric Pain Scale: 4.01±1.87 to 4.05±2.61, p =0.53) and diminished pain paroxysms ( p =0.03) while pain intensity increased significantly with memantine and placebo ( p =0.04). At 3 months, pain remained lower than at inclusion ( p =0.001) and was not significantly different in the three groups. Significant benefits were observed on cognitive-affective domains and quality of life for dextromethorphan and memantine ( p <0.05). Conclusions Oral dextromethorphan given after ketamine infusion extends pain relief during one month and could help patients to better cope with pain. Future studies should include larger populations stratified on pharmacogenetics screening. Optimization of an oral drug that could extend ketamine antihyperalgesia, with fewer hospital admissions, remains a prime challenge in refractory neuropathic pain.

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Population Pharmacokinetic Study of Memantine: Effects of Clinical and Genetic Factors

Abstract: The better understanding of inter-individual variability of memantine disposition might be beneficial in the context of individual dose optimization.

Cited by 40 publications

References 42 publications

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Safety and pharmacokinetics of the CIME combination of drugs and their metabolites after a single oral dosing in healthy volunteers

<p>Dextromethorphan and memantine after ketamine analgesia: a randomized control trial</p>

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