Changes in perampanel levels during de‐induction: Simulations following carbamazepine discontinuation

Schuck, Edgar; Ferry, Jim; Gidal, Barry E.; Hussein, Ziad

doi:10.1111/ane.13286

Cited by 4 publications

(6 citation statements)

References 25 publications

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“…Therefore, long-term monitoring of PER concentration is required for treatment management after CBZ discontinuation. There have been reports that PER concentrations reach a new steady state approximately 27 days after the complete discontinuation of CBZ, 18 which is generally consistent with our findings.…”

Section: Discussionsupporting

confidence: 92%

“…Because there was insufficient data during the absorption phase, the absorption rate constant for PER was fixed at 3.37 1/h. 18 A proportional error model was selected to describe the residual variability, and IIV was added to the apparent clearance for PER (CL PER /F PER ). The presence or absence of concomitant use of CBZ was identified as a covariate for CL PER / F PER (DOFV = 244.9).…”

Section: Empirical Ppk Modelmentioning

confidence: 99%

“…The pharmacokinetics of PER and CBZ were described using one-compartment models. Because of the lack of blood samples soon after administration in the current study, absorption rate constant for PER, the absorption rate constant for CBZ, and apparent volume of distribution for CBZ (V CBZ /F CBZ ) were fixed to 3.37 1/h, 0.20 1/h, and 1.91 L/kg, [18][19][20] respectively. The time course of the relative amount of the enzyme was fitted to the turnover model (Equation 3).…”

Section: Semimechanistic Ppk Modelmentioning

confidence: 99%

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Population Pharmacokinetic Analysis of Drug–Drug Interactions Between Perampanel and Carbamazepine Using Enzyme Induction Model in Epileptic Patients

Fujita

Murai

Muraki

et al. 2023

Therapeutic Drug Monitoring

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Background: Perampanel (PER) is an oral antiepileptic drug and its concomitant use with carbamazepine (CBZ) leads to decreased PER concentrations. However, the magnitude of its influence may vary, depending on the dynamics of the enzyme induction properties of CBZ. This study aimed to develop a population pharmacokinetic (PPK) model considering the dynamics of enzyme induction and evaluate the effect of CBZ on PER pharmacokinetics. Methods: We retrospectively collected data on patient background, laboratory tests, and prescribed drugs from electronic medical records. We developed 2 PPK models incorporating the effect of CBZ-mediated enzyme induction to describe time–concentration profiles of PER using the following different approaches: (1) treating the concomitant use of CBZ as a categorical covariate (empirical PPK model) and (2) incorporating the time-course of changes in the amount of enzyme by CBZ-mediated induction (semimechanistic PPK model). The bias and precision of the predictions were investigated by calculating the mean error, mean absolute error, and root mean squared error. Results: A total of 133 PER concentrations from 64 patients were available for PPK modelling. PPK analyses showed that the co-administration of CBZ increased the clearance of PER. Goodness-of-fit plots indicated a favorable description of the observed data and low bias. The mean error, mean absolute error, and root mean square error values based on the semimechanistic model were smaller than those obtained using the empirical PPK model for predicting PER concentrations in patients with CBZ. Conclusions: We developed 2 PPK models to describe PER pharmacokinetics based on different approaches, using electronic medical record data. Our PPK models support the use of PER in clinical practice.

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Section: Discussionsupporting

confidence: 92%

Section: Empirical Ppk Modelmentioning

confidence: 99%

Section: Semimechanistic Ppk Modelmentioning

confidence: 99%

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Population Pharmacokinetic Analysis of Drug–Drug Interactions Between Perampanel and Carbamazepine Using Enzyme Induction Model in Epileptic Patients

Fujita

Murai

Muraki

et al. 2023

Therapeutic Drug Monitoring

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“…Several published studies investigate the pharmacokinetics of carbamazepine using PBPK modeling, (1) to predict the pharmacokinetics of carbamazepine in the pediatric population [ 91 ], (2) to describe gastrointestinal absorption of different carbamazepine formulations [ 92 ], (3) to investigate the DDI with levonorgestrel [ 93 ] and (4) to investigate the DDI performance of victim drug models with carbamazepine as enzyme inducer [ 15 , 16 , 17 , 18 ] using the default Simcyp parent−metabolite PBPK template model of carbamazepine and carbamazepine-10,11-epoxide [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…More than 60% of PBPK models submitted to the FDA investigate DDIs. Several published studies investigate the DDI potential of carbamazepine using a PBPK modeling approach [ 13 , 16 , 17 , 18 , 19 ]. While carbamazepine is typically used as an inducer to investigate the interaction with a substrate, our study aims to provide a comprehensive overview on the pharmacokinetics of carbamazepine and its DDIs, investigating carbamazepine not only as inducer but also as victim drug.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of the CYP3A4 and CYP2B6 Inducer Carbamazepine and Its Drug–Drug Interaction Potential: A Physiologically Based Pharmacokinetic Modeling Approach

et al. 2021

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The anticonvulsant carbamazepine is frequently used in the long-term therapy of epilepsy and is a known substrate and inducer of cytochrome P450 (CYP) 3A4 and CYP2B6. Carbamazepine induces the metabolism of various drugs (including its own); on the other hand, its metabolism can be affected by various CYP inhibitors and inducers. The aim of this work was to develop a physiologically based pharmacokinetic (PBPK) parent−metabolite model of carbamazepine and its metabolite carbamazepine-10,11-epoxide, including carbamazepine autoinduction, to be applied for drug–drug interaction (DDI) prediction. The model was developed in PK-Sim, using a total of 92 plasma concentration−time profiles (dosing range 50–800 mg), as well as fractions excreted unchanged in urine measurements. The carbamazepine model applies metabolism by CYP3A4 and CYP2C8 to produce carbamazepine-10,11-epoxide, metabolism by CYP2B6 and UDP-glucuronosyltransferase (UGT) 2B7 and glomerular filtration. The carbamazepine-10,11-epoxide model applies metabolism by epoxide hydroxylase 1 (EPHX1) and glomerular filtration. Good DDI performance was demonstrated by the prediction of carbamazepine DDIs with alprazolam, bupropion, erythromycin, efavirenz and simvastatin, where 14/15 DDI AUClast ratios and 11/15 DDI Cmax ratios were within the prediction success limits proposed by Guest et al. The thoroughly evaluated model will be freely available in the Open Systems Pharmacology model repository.

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