Metabolism and <i>in vitro</i> drug–drug interaction assessment of viloxazine

Yu, Chung-Ping

doi:10.1080/00498254.2020.1767319

Cited by 19 publications

(31 citation statements)

References 14 publications

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“…Viloxazine ER is primarily metabolized to 5-hydroxyviloxazine by the cytochrome P450 (CYP) system isoenzyme CYP2D6 as a first step before its glucuronidation, with minor involvement of several other CYP isoenzymes. Subsequent glucuronidation to 5-HVLX-gluc is mediated by uridine 5′-diphospho-glucuronosyltransferase (UGT) 1A9 and UGT2B15 [32]. Viloxazine ER also functions as a reversible inhibitor of CYP1A2 (half maximal inhibitory concentration [IC 50 ] 0.269 µM) [32].…”

Section: Discussionmentioning

confidence: 99%

“…Subsequent glucuronidation to 5-HVLX-gluc is mediated by uridine 5′-diphospho-glucuronosyltransferase (UGT) 1A9 and UGT2B15 [32]. Viloxazine ER also functions as a reversible inhibitor of CYP1A2 (half maximal inhibitory concentration [IC 50 ] 0.269 µM) [32]. Conversely, methylphenidate is metabolized primarily by carboxylesterase 1 via de-esterification into ritalinic acid, which has little, if any, pharmacologic activity [30,33].…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics of Coadministered Viloxazine Extended-Release (SPN-812) and Methylphenidate in Healthy Adults

et al. 2020

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Background and Objectives Viloxazine extended-release (viloxazine ER, SPN-812) is a novel non-stimulant with activity at serotonin receptors and the norepinephrine transporter, which is under investigation as a potential treatment for attention-deficit/hyperactivity disorder. Given the potential for viloxazine ER to be coadministered with other pharmacotherapies, this trial investigated the pharmacokinetics and safety of combination viloxazine ER + methylphenidate versus viloxazine ER or methylphenidate alone. Methods In this single-center, crossover, open-label trial, healthy adult participants received oral administration of 700 mg viloxazine ER alone, 36 mg methylphenidate alone, and combination viloxazine ER (700 mg) + methylphenidate (36 mg), with blood samples collected over 4 days post-administration. The active drug in viloxazine ER (viloxazine) and methylphenidate was measured using chromatographic tandem mass spectrometry. Safety assessments included adverse events (AEs), vital signs, echocardiograms, and clinical laboratory evaluations. Results Of 36 healthy adults who were enrolled, 34 completed the trial. The geometric least squares mean ratios are reported as [combination/single drug (90% confidence intervals)]. For viloxazine ER, maximum measured plasma concentration ( C max ) = 100.98% (96.21–105.99), area under the concentration–time curve from time zero to the last measurable time (AUC t ) = 98.62% (96.21–101.08), and area under the concentration–time curve from time zero to infinity (AUC ∞ ) = 98.96% (96.55–101.44). For methylphenidate, C max = 103.55% (97.42–110.07), AUC t = 106.67% (101.01–112.64), and AUC ∞ = 106.61% (100.99–112.54). All reported AEs were mild in severity. Conclusions Coadministration of viloxazine ER and methylphenidate did not impact the pharmacokinetics of viloxazine or methylphenidate relative to administration of either drug alone. The combination appeared to be safe and well tolerated.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Coadministered Viloxazine Extended-Release (SPN-812) and Methylphenidate in Healthy Adults

et al. 2020

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“…10 Viloxazine forms a unique N-carbamoyl glucuronide in humans, the chemical reactivity characteristics of which are similar to stable glucuronide conjugates and dissimilar from acyl glucuronides; therefore, it is a stable Phase II conjugate. 10 Viloxazine is rapidly metabolized and excreted in the urine, with no known active metabolites. 10 In vitro drug-drug interaction testing has shown that viloxazine is not a significant inhibitor or inducer of CYP isoenzymes, with the exception of being a strong inhibitor of CYP1A2.…”

Section: Introductionmentioning

confidence: 99%

“…10 Viloxazine is rapidly metabolized and excreted in the urine, with no known active metabolites. 10 In vitro drug-drug interaction testing has shown that viloxazine is not a significant inhibitor or inducer of CYP isoenzymes, with the exception of being a strong inhibitor of CYP1A2. 10 Viloxazine metabolism is not thought to rely solely on CYP2D6, alternatively, metabolism switching using multiple alternative CYP enzymes pathways may be activated if the major pathway is inhibited or not fully active.…”

Section: Introductionmentioning

confidence: 99%

Population Pharmacokinetics of Viloxazine Extended‐Release Capsules in Pediatric Subjects With Attention Deficit/Hyperactivity Disorder

Nasser

Goméni²,

Wang

et al. 2021

The Journal of Clinical Pharma

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Viloxazine extended-release capsules (viloxazine ER, Qelbree™) is a novel non-stimulant, recently approved by the U.S. FDA for the treatment of ADHD in pediatrics. Here, we characterize the pharmacokinetics (PK) of viloxazine and its major metabolite 5-HVLX-gluc using a population PK model, and evaluate the impact of 1-4 days of missed viloxazine ER doses on viloxazine PK. Data from four phase 3 trials in pediatric subjects treated with viloxazine ER were used to establish the PK model. Covariate analysis was conducted on the final base model. The impact of 1-4 days of missed doses on steady-state viloxazine PK was evaluated using Monte Carlo simulations. A onecompartmental linear model with first-order absorption and elimination of the parent drug, and first-order metabolite formation and elimination, properly described the population PK of viloxazine and 5-HVLX-gluc. Body weight impacted the systemic exposure of viloxazine and 5-HVLX-gluc. Predicted PK parameters at steady-state in children receiving viloxazine ER were: C max (µg/mL ± standard deviation) at 100 mg = 1.

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“…It is, therefore, not feasible to assess the ECG effects of SPN-812 at C max above approximately 10-11 μg/mL. Based on these data as well as the findings from a SPN-812 metabolism assessment study, which showed that renal clearance was a major elimination route for SPN-812 (approximately 90% cleared within 24 hours of the dose, 100% within 96 hours), 19 the supratherapeutic dose of SPN-812 1,800 mg was selected and positive control (moxifloxacin) 17 was used.…”

Section: Dose Selectionmentioning

confidence: 99%

Evaluation of the Effect of SPN-812 (Viloxazine Extended-Release) on QTc Interval in Healthy Adults

Nasser¹,

Faison²,

Liranso³

et al. 2020

J. Clin. Psychiatry

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Objective: To assess the effects of a supratherapeutic dose of SPN-812, a drug currently under investigation as a treatment for attention-deficit/hyperactivity disorder, on cardiac repolarization (QTc) in healthy adults. Methods: The study was conducted from June 27, 2018, to July 10, 2018. It had a double-blind, randomized, crossover design in which subjects received a 3-treatment sequence-placebo, 400 mg moxifloxacin, and 1,800 mg SPN-812 for 2 consecutive days (separated by at least a 3-day washout). The primary endpoint was the correlation between the change from baseline (CFB) in individual heart rate corrected QT interval (QTcI) (ΔQTcI) and viloxazine and 5-hydroxyviloxazine glucuronide (5-OH-VLXgluc) plasma concentrations (Cps). The secondary endpoint was the time point placebo-adjusted CFB in QTcI (ΔΔQTcI) for viloxazine. For assay sensitivity, the correlations between moxifloxacin Cp and the ΔQTcI, and moxifloxacin and time point ΔΔQTcI were evaluated. Additional evaluations included Fridericia's formula QT correction, heart rate, and the PR and QRS intervals. Changes in electrocardiogram (ECG) morphology along with other safety parameters were also analyzed and reported. Results: The correlation between ΔQTcI and viloxazine Cp demonstrated a statistically significant negative slope (P = .0012). 5-OH-VLX-gluc Cp and ΔQTcI also demonstrated a statistically significant negative slope (P = .0007). Secondary time point analyses showed no effect of SPN-812 on QTcI. Assay sensitivity with moxifloxacin was confirmed. Safety parameters were acceptable. Conclusions: This study demonstrated that SPN-812 had no effect on cardiac repolarization or other ECG parameters in healthy adults, suggesting that it is not associated with a risk for cardiac arrhythmias or other electrocardiographic parameters.

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Metabolism and in vitro drug–drug interaction assessment of viloxazine

Cited by 19 publications

References 14 publications

Pharmacokinetics of Coadministered Viloxazine Extended-Release (SPN-812) and Methylphenidate in Healthy Adults

Pharmacokinetics of Coadministered Viloxazine Extended-Release (SPN-812) and Methylphenidate in Healthy Adults

Population Pharmacokinetics of Viloxazine Extended‐Release Capsules in Pediatric Subjects With Attention Deficit/Hyperactivity Disorder

Evaluation of the Effect of SPN-812 (Viloxazine Extended-Release) on QTc Interval in Healthy Adults

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