Effect of Age-Related Factors on the Pharmacokinetics of Lamotrigine and Potential Implications for Maintenance Dose Optimisation in Future Clinical Trials

Dijkman, Sven C. van; Jager, Nico C. B. de; Rauwé, Willem M.; Danhof, Meindert; Pasqua, Oscar Della

doi:10.1007/s40262-017-0614-5

Cited by 35 publications

(40 citation statements)

References 59 publications

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“…Short-term memory (including working memory) and long-term memory are separate systems. The neural basis of short-term memory and long-term memory are located in the hippocampus and multiple cortical regions, respectively ( Matthews, 2015 ; Hampson et al, 2018 ). In the present study, the neuroprotective effect of optogenetics was limited to the DG and may have been one mechanism underlying the observed improvement in working memory and short-term memory in Aβ-CHR2 mice.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effect of Optogenetics Varies With Distance From Channelrhodopsin-2 Expression in an Amyloid-β-Injected Mouse Model of Alzheimer’s Disease

Cui

Zhang

et al. 2020

Front. Neurosci.

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Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is the most common cause of dementia. Optogenetics uses a combination of genetic engineering and light to activate or inhibit specific neurons in the brain. Objective: The objective of the study was to examine the effect of activation of glutamatergic neurons in the hippocampus of mice injected with Aβ1-42 on memory function and biomarkers of neuroinflammation and neuroprotection in the brain to elucidate the clinical utility of optogenetic neuromodulation in AD. Methods: AAV5–CaMKII–channelrhodopsin-2 (CHR2)–mCherry (Aβ-CHR2 mice) or AAV5—CaMKII–mCherry (Aβ-non-CHR2 mice) was injected into the dentate gyrus (DG) of the bilateral hippocampus of an Aβ1-42-injected mouse model of AD. The novel object recognition test was used to investigate working memory (M1), short-term memory (M2), and long-term memory (M3) after Aβ1-42 injection. Hippocampus tissues were collected for immunohistochemical analysis. Results: Compared to controls, M1 and M2 were significantly higher in Aβ-CHR2 mice, but there was no significant difference in M3; NeuN and synapsin expression were significantly increased in the DG of Aβ-CHR2 mice, but not in CA1, CA3, the subventricular zone (SVZ), or the entorhinal cortex (ENT); GluR2 and IL-10 expressions were significantly increased, and GFAP expression was significantly decreased, in CA1, CA3, the DG, and the SVZ of Aβ-CHR2 mice, but not in the ENT. Conclusion: Activation of glutamatergic neurons by optogenetics in the bilateral DG of an Aβ-injected mouse model of AD improved M1 and M2, but not M3. A single-target optogenetics strategy has spatial limitations; therefore, a multiple targeted optogenetics approach to AD therapy should be explored.

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Section: Discussionmentioning

confidence: 99%

Neuroprotective Effect of Optogenetics Varies With Distance From Channelrhodopsin-2 Expression in an Amyloid-β-Injected Mouse Model of Alzheimer’s Disease

Cui

Zhang

et al. 2020

Front. Neurosci.

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“…Lack of this sigmoidal part of the PMA versus normalized clearance curve produced erratic parameters, which resulted in poor prediction of clearance in children aged ≤ 2 years. van Dijkman et al [26] also recently noted that the prediction of lamotrigine clearance in children aged < 2 years with the sigmoidal maturation model was poor.…”

Section: Discussionmentioning

confidence: 99%

Extrapolation of Drug Clearance in Children ≤ 2 Years of Age from Empirical Models Using Data from Children (> 2 Years) and Adults

Mahmood

2019

Drugs R D

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Background The application of modeling and simulation approaches in clinical pharmacology studies has gained momentum over the last 20 years. Objectives The objective of this study was to develop six empirical models from clearance data obtained from children aged > 2 years and adults to evaluate the suitability of the models to predict drug clearance in children aged ≤ 2 years (preterm, term, and infants). Methods Ten drugs were included in this study and administered intravenously: alfentanil, amikacin, busulfan, cefetamet, meperidine, oxycodone, propofol, sufentanil, theophylline, and tobramycin. These drugs were selected according to the availability of individual subjects' weight, age, and clearance data (concentration-time data for these drugs were not available to the author). The chosen drugs are eliminated by extensive metabolism by either the renal route or both the renal and hepatic routes. The six empirical models were (1) age and body weight-dependent sigmoidal maximum possible effect (E max) maturation model, (2) body weight-dependent sigmoidal E max model, (3) uridine 5′-diphospho [body weight-dependent allometric exponent model (BDE)], (4) age-dependent allometric exponent model (ADE), (5) a semi-physiological model, and (6) an allometric model developed from children aged > 2 years to adults. The model-predicted clearance values were compared with observed clearance values in an individual child. In this analysis, a prediction error of ≤ 50% for mean or individual clearance values was considered acceptable. Results Across all age groups and the ten drugs, data for 282 children were compared between observed and model-predicted clearance values. The validation data consisted of 33 observations (sum of different age groups for ten drugs). Only three of the six models (body weight-dependent sigmoidal E max model, ADE, and semi-physiological model) provided reasonably accurate predictions of clearance (> 80% observation with ≤ 50% prediction error) in children aged ≤ 2 years. In most instances, individual predicted clearance values were erratic (as indicated by % error) and were not in agreement with the observed clearance values. Conclusions The study indicated that simple empirical models can provide more accurate results than complex empirical models.

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“…Fifty-one healthy adult volunteers provided written informed consent to participate in this study and met all inclusion and no exclusion criteria. Specifically, participants were included if they scored as right-handed on the Edinburgh Handedness Inventory (≥+40) ( Oldfield, 1971 ), scored in the normal range (≥26) on the Montreal Cognitive Assessment (MOCA) ( Nasreddine et al, 2005 ), had no history of seizure within 10 years prior to enrollment and were using no medications to prevent seizures, were taking no central nervous system stimulant medications or illicit drugs, had no significant upper extremity injuries, had normal upper extremity strength and sensation on examination, and had no history or presence of neurological diagnosis aside from headaches as assessed by a medical history and physical exam ( Rossetti et al, 2011 ; Nasreddine et al, 2012 ).…”

Section: Methodsmentioning

confidence: 99%

Contraction Phase and Force Differentially Change Motor Evoked Potential Recruitment Slope and Interhemispheric Inhibition in Young Versus Old

Ermer

Harcum

Lush

et al. 2020

Front. Hum. Neurosci.

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Interhemispheric interactions are important for arm coordination and hemispheric specialization. Unilateral voluntary static contraction is known to increase bilateral corticospinal motor evoked potential (MEP) amplitude. It is unknown how increasing and decreasing contraction affect the opposite limb. Since dynamic muscle contraction is more ecologically relevant to daily activities, we studied MEP recruitment using a novel method and short interval interhemispheric inhibition (IHI) from active to resting hemisphere at 4 phases of contralateral ECR contraction: Rest, Ramp Up [increasing at 25% of maximum voluntary contraction (MVC)], Execution (tonic at 50% MVC), and Ramp Down (relaxation at 25% MVC) in 42 healthy adults. We analyzed the linear portion of resting extensor carpi radialis (ECR) MEP recruitment by stimulating at multiple intensities and comparing slopes, expressed as mV per TMS stimulation level, via linear mixed modeling. In younger participants (age ≤ 30), resting ECR MEP recruitment slopes were significantly and equally larger both at Ramp Up (slope increase = 0.047, p < 0.001) and Ramp Down (slope increase = 0.031, p < 0.001) compared to rest, despite opposite directions of force change. In contrast, Active ECR MEP recruitment slopes were larger in Ramp Down than all other phases (Rest:0.184, p < 0.001; Ramp Up:0.128, p = 0.001; Execution: p = 0.003). Older (age ≥ 60) participants’ resting MEP recruitment slope was higher than younger participants across all phases. IHI did not reduce MEP recruitment slope equally in old compared to young. In conclusion, our data indicate that MEP recruitment slope in the resting limb is affected by the homologous active limb contraction force, irrespective of the direction of force change. The active arm MEP recruitment slope, in contrast, remains relatively unaffected. Older participants had steeper MEP recruitment slopes and less interhemispheric inhibition compared to younger participants.

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Effect of Age-Related Factors on the Pharmacokinetics of Lamotrigine and Potential Implications for Maintenance Dose Optimisation in Future Clinical Trials

Cited by 35 publications

References 59 publications

Neuroprotective Effect of Optogenetics Varies With Distance From Channelrhodopsin-2 Expression in an Amyloid-β-Injected Mouse Model of Alzheimer’s Disease

Neuroprotective Effect of Optogenetics Varies With Distance From Channelrhodopsin-2 Expression in an Amyloid-β-Injected Mouse Model of Alzheimer’s Disease

Extrapolation of Drug Clearance in Children ≤ 2 Years of Age from Empirical Models Using Data from Children (> 2 Years) and Adults

Contraction Phase and Force Differentially Change Motor Evoked Potential Recruitment Slope and Interhemispheric Inhibition in Young Versus Old

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