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

Viloxazine extended-release capsules (viloxazine ER; Qelbree) is a novel nonstimulant, recently approved by the US Food and Drug Administration 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 4 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 1-compartmental 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 (mean ± standard deviation) in children receiving viloxazine ER were determined. Cmax was 1.60 ± 0.70 µg/mL at 100 mg, 2.83 ± 1.31 µg/mL at 200 mg, and 5.61 ± 2.48 µg/mL at 400 mg. AUC0-t was 19.29 ± 8.88 µg·h/mL at 100 mg, 34.72 ± 16.53 µg·h/mL at 200 mg, and 68.00 ± 28.51 µg·h/mL at 400 mg. PK parameters for adolescents receiving viloxazine ER were also determined. Cmax was 2.06 ± 0.90 µg/mL at 200 mg, 4.08 ± 1.67 µg/mL at 400 mg, and 6.49 ± 2.87 µg/mL at 600 mg. AUC0-t was 25.78 ± 11.55 µg·h/mL at 200 mg, 50.80 ± 19.76 µg·h/mL at 400 mg, and 79.97 ± 36.91 µg·h/mL at 600 mg. Simulations revealed that, regardless of the duration of the dosing interruption, viloxazine concentration returned to steady-state levels after approximately 2 days of once-daily dosing of viloxazine ER.

The lowest effective plasma concentration of atomoxetine in pediatric patients with attention deficit/hyperactivity disorder: A non-randomized prospective interventional study.

BACKGROUND: Atomoxetine (ATX) is used as a first-line, non-stimulant treatment for attention-deficit/hyperactivity disorder (ADHD), although no studies have systematically examined the relationship between plasma concentration and clinical efficacy. We conducted this non-randomized prospective interventional study to examine the relationship between plasma concentration of ATX and clinical efficacy. METHODS: Forty-three ADHD pediatric patients received ATX, and the steady-state through plasma concentration of the last daily dose that was maintained for at least 4 weeks were determined by high-performance liquid chromatography. RESULTS: The receiver operating characteristic curve suggested that when plasma concentration exceeded 64.60 ng/mL, scores on the ADHD-Rating Scale improved by 50% or more (P = .14). Although 6 of the 8 final responders were unresponsive at the initial dose (.72 ±â€Š.04 mg/kg [mean ±â€Šstandard deviation]), they responded after increasing the ATX dose to the final dose (1.52 ±â€Š.31 mg/kg). Excluding 7 outlier participants, the concentration was 83.3 ±â€Š32.3 ng/mL in 7 responders and was significantly higher than 29.5 ±â€Š23.9 ng/mL (P < .01) for the 29 non-responders. CONCLUSIONS: These results suggest that a minimum effective plasma concentration of ATX is required to achieve sufficient clinical efficacy. We hypothesized a mechanism that results in the realization of a clinical effect when the plasma concentration exceeds a certain threshold in the potential response group, whereas will not improve even if the plasma concentration is increased in the unqualified non-responder group.

Impact of Paroxetine, a Strong CYP2D6 Inhibitor, on SPN-812 (Viloxazine Extended-Release) Pharmacokinetics in Healthy Adults.

SPN-812 (viloxazine extended-release) is a novel nonstimulant recently approved as a treatment for attention-deficit/hyperactivity disorder in children and adolescents. Given that SPN-812 is metabolized by CYP2D6 and may be coadministered with CYP2D6 inhibitors, this trial investigated the pharmacokinetics and safety of SPN-812 coadministered with the potent CYP2D6 inhibitor paroxetine. In this single-sequence, 3-treatment period study in healthy volunteers, subjects received a single oral dose of 700 mg SPN-812 alone (period 1), 20 mg daily paroxetine (10 days, period 2), followed by concurrent administration of SPN-812 and paroxetine (period 3). Blood samples were collected for 72 hours post-SPN-812 dosing and analyzed for viloxazine and its primary metabolite, 5-HVLX-gluc. Twenty-two healthy adults were enrolled; all completed the trial. The potential for drug interaction between SPN-812 and paroxetine was assessed using analysis of variance on the log-transformed pharmacokinetic parameters Cmax , AUC0-t , and AUCinf . The least-squares geometric mean ratios for viloxazine were (reported as the ratio of combination/SPN-812 alone) Cmax , 116.04%; 90%CI, 109.49%-122.99%; AUC0-t , 134.65%; 90%CI, 127.65-142.03; and AUCinf , 134.80%; 90%CI, 127.94%-142.03%. CYP2D6 inhibition resulted in a modest change (<35%) on viloxazine AUCs with no change in Cmax . All adverse events were mild in severity.

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

BACKGROUND: Viloxazine extended-release is a novel nonstimulant under investigation as a potential treatment for attention-deficit/hyperactivity disorder (ADHD). Given the potential for viloxazine extended-release to be co-administered with stimulant ADHD pharmacotherapies, this trial investigated the pharmacokinetics and safety of combination viloxazine extended-release + lisdexamfetamine dimesylate (lisdexamfetamine) versus viloxazine extended-release and lisdexamfetamine alone. METHODS: In this single-center, cross-over, open-label trial, healthy, non-ADHD adults received single oral doses of 700 mg viloxazine extended-release alone, 50 mg lisdexamfetamine alone, and a combination of viloxazine extended-release (700 mg) + lisdexamfetamine (50 mg), with blood samples collected over 4 days postadministration. The active drug in viloxazine extended-release (viloxazine) and primary metabolite of lisdexamfetamine (d-amphetamine) were measured using chromatographic tandem mass spectrometry. Safety assessments included adverse events, vital signs, echocardiograms, and clinical laboratory evaluations. RESULTS: Thirty-six adults were enrolled, and 34 completed the trial. The least squares geometric mean ratios are reported as [combination / single drug (90% confidence intervals)]. Viloxazine extended-release: Cmax = 95.96% (91.33-100.82), area under the concentration-time curve from 0 to the last measurable time (AUC0-t) = 99.19% (96.53-101.91), and area under the concentration-time curve from 0 to infinity (AUCinf) = 99.23% (96.61-101.93). Lisdexamfetamine: Cmax = 112.78% (109.93-115.71), AUC0-t = 109.64% (105.25-114.22), and AUCinf = 109.52% (105.19-114.03). All reported adverse events, except 1 (moderate vomiting), were mild in severity. CONCLUSIONS: Co-administration of viloxazine extended-release and lisdexamfetamine did not impact the pharmacokinetics of viloxazine or d-amphetamine relative to administration of either drug alone. After single dose administration, the combination appeared to be safe and well tolerated.

A Randomized, Double-Blind, Placebo- and Positive-Controlled, 4-Period Crossover Study of the Effects of Solriamfetol on QTcF Intervals in Healthy Participants.

Solriamfetol, a dopamine and norepinephrine reuptake inhibitor, is approved (United States and European Union; Sunosi) to treat excessive daytime sleepiness associated with narcolepsy (75-150 mg/day) or obstructive sleep apnea (37.5-150 mg/day). A thorough QT/QTc study assessed solriamfetol effects on QT interval (Fridericia correction for heart rate; QTcF). This randomized, double-blind, placebo- and positive-controlled, 4-period crossover study compared single doses of 300 and 900 mg solriamfetol, 400 mg moxifloxacin, and placebo in healthy adults. Placebo- and predose-adjusted mean differences in QTcF (ddQTcF; primary end point) were analyzed, and solriamfetol pharmacokinetics were characterized. Fifty-five participants completed all periods. Upper bounds of 2-sided 90% confidence intervals (CIs) for ddQTcF for both solriamfetol doses were <10 milliseconds at all postdose time points. Assay sensitivity was demonstrated with moxifloxacin; lower bounds of 2-sided 90%CIs for ddQTcF > 5 milliseconds at 1, 2, and 3 hours postdose. There were no QTcF increases > 60 milliseconds or QTcF values > 480 milliseconds at either solriamfetol dose. Solriamfetol median tmax was 2-3 hours; exposure was dose-proportional. More participants experienced adverse events (AEs) after solriamfetol 900 versus 300 mg (70% vs 29%); none were serious (all mild/moderate), and there were no deaths. Common AEs were nausea, dizziness, and palpitations. Neither solriamfetol dose resulted in QTcF prolongation > 10 milliseconds.

Pharmacokinetics of Deutetrabenazine and Tetrabenazine: Dose Proportionality and Food Effect.

Deutetrabenazine (Austedo, Teva), an approved treatment of chorea in Huntington's disease and tardive dyskinesia in adult patients, is a rationally designed deuterated form of tetrabenazine. Two studies assessed the pharmacokinetics and safety of deutetrabenazine compared with tetrabenazine, and the effects of food on absorption of the deuterated active metabolites, α-dihydrotetrabenazine (α-HTBZ) and ß-dihydrotetrabenazine (ß-HTBZ). One study was an open-label 2-part study in healthy volunteers; the first part included a crossover single dose of two 15 mg candidate deutetrabenazine formulations in fed and fasted states compared with tetrabenazine 25 mg in the fasted state, and the second part included single and repeated dosing of the commercial formulation of deutetrabenazine (7.5, 15, and 22.5 mg) compared with tetrabenazine 25 mg. The second study was an open-label 5-way crossover study in healthy volunteers (n = 32) to evaluate relative bioavailability of 4 dose levels of the commercial formulation of deutetrabenazine (6, 12, 18, and 24 mg) with a standard meal and 18 mg with a high-fat meal. Both studies confirmed longer half-lives for active metabolites and lower peak-to-trough fluctuations for the sum of the metabolites (total [α+ß]-HTBZ) following deutetrabenazine compared with tetrabenazine (3- to 4-fold and 11-fold, respectively) in steady-state conditions. Deutetrabenazine doses estimated to provide total (α+ß)-HTBZ exposure comparable to tetrabenazine 25 mg were 11.4-13.2 mg. Food had no effect on exposure to total (α+ß)-HTBZ, as measured by AUC. Although the total (α+ß)-HTBZ Cmax of deutetrabenazine was increased by ≈50% in the presence of food, it remained lower than that of tetrabenazine.

Safety and Pharmacokinetics of High-Dose TAS-303 in Healthy Japanese Volunteers: A Single-Center, Single-Blind, Randomized, Placebo-Controlled, Parallel-Group, Multiple-Ascending-Dose Study.

Preclinical data of TAS-303 (4-piperidinyl 2,2-diphenyl-2-[propoxy-1,1,2,2,3,3,3-d7 ] acetate hydrochloride), a noradrenaline reuptake inhibitor, show that it increases urethral contraction in rats and may therefore benefit stress urinary incontinence patients. In this single-blind, randomized, placebo-controlled, parallel-group, multiple-ascending-dose phase 1 study, we evaluated the safety and tolerability of once-daily TAS-303 8, 10, 12, 15, or 18 mg administered for 16 days in healthy subjects. In addition, we investigated the pharmacokinetics and inhibitory effect of TAS-303 on hepatic cytochrome P450 (CYP) 3A activity. Rates of adverse events, adverse drug reactions, and pharmacokinetic parameters of TAS-303 were evaluated. Fifty subjects were randomized: 7 subjects each were assigned to receive TAS-303 8-18 mg, and 3 subjects each were assigned to receive placebo at each dose. The overall incidences of adverse events and adverse drug reactions in all subjects administered TAS-303 (n = 35) was 25.7% and 2.9%, respectively, and those for the placebo groups (n = 15) were 46.7% and 0%, respectively. No deaths or serious adverse events occurred. TAS-303 displayed a dose-proportional pharmacokinetic profile across doses of 8-18 mg over the 16-day multiple administration period, and TAS-303 might inhibit hepatic CYP3A activity within this dose range. TAS-303 at a dose of 8-18 mg was confirmed to be safe and tolerable.

Pharmacokinetic and Metabolic Profile of Deutetrabenazine (TEV-50717) Compared With Tetrabenazine in Healthy Volunteers.

Deutetrabenazine (Austedo, Teva Pharmaceuticals) is a deuterated form of tetrabenazine. It is the first deuterated drug to receive US regulatory approval and is approved for treatment of chorea in Huntington's disease and tardive dyskinesia. Two oral single dose studies comparing deutetrabenazine (25 mg) with tetrabenazine (25 mg) in healthy volunteers evaluated the impact of deuteration on pharmacokinetics of the active metabolites, alpha-dihydrotetrabenazine (α-HTBZ) and beta-dihydrotetrabenazine (ß-HTBZ), metabolite profile, safety, and tolerability. In the two-way, cross-over study, the mean elimination half-life of deuterated total (α + ß)-HTBZ was doubled compared with nondeuterated total (α + ß)-HTBZ, with a twofold increase in overall mean exposure (area under the concentration-time curve from zero to infinity (AUC0-inf )) and a marginal increase in mean peak plasma concentration (Cmax ). In the mass balance and metabolite profiling study, there were no novel plasma or urinary metabolites of [14 C]-deutetrabenazine relative to [14 C]-tetrabenazine. Specific deuteration in deutetrabenazine resulted in a superior pharmacokinetic profile and an increased ratio of active-to-inactive metabolites, attributes considered to provide significant benefits to patients.

A Drug-Drug Interaction Study to Evaluate the Effect of TAS-303 on CYP3A Activity in the Small Intestine and Liver.

TAS-303 (4-piperidinyl 2,2-diphenyl-2-[propoxy-1,1,2,2,3,3,3-d7 ] acetate hydrochloride) is a novel selective noradrenaline reuptake inhibitor being developed for the treatment of stress urinary incontinence. An in vitro study and a physiologically based pharmacokinetic model simulation showed that TAS-303 had inhibitory potential against cytochrome P450 (CYP) 3A. This open-label, single-group study investigated the effect of TAS-303 on CYP3A activity by evaluating the pharmacokinetics (PK) of single-dose oral simvastatin 5 mg or intravenous midazolam 1 mg after repeated oral administration of TAS-303 3 mg in 12 healthy participants. TAS-303 plus simvastatin resulted in a 1.326-fold and a 1.420-fold increase of simvastatin in peak plasma concentration and area under the plasma concentration-time curve from time zero to time t, where t is the final time of detection (AUC0-t ), respectively. The addition of midazolam resulted in a 1.090-fold increase in the midazolam AUC0-t . TAS-303 had a weak PK interaction with simvastatin but no apparent interaction with midazolam. TAS-303 at 3 mg/day is a weak inhibitor of intestinal but not hepatic CYP3A activity. No clinically important safety concerns related to TAS-303 were raised.

Clinical Pharmacogenetics Implementation Consortium Guideline for Cytochrome P450 (CYP)2D6 Genotype and Atomoxetine Therapy.

Atomoxetine is a nonstimulant medication used to treat attention-deficit/hyperactivity disorder (ADHD). Cytochrome P450 (CYP)2D6 polymorphisms influence the metabolism of atomoxetine thereby affecting drug efficacy and safety. We summarize evidence from the published literature supporting these associations and provide therapeutic recommendations for atomoxetine based on CYP2D6 genotype (updates at www.cpicpgx.org).

Oral reserpine administration in horses results in low plasma concentrations that alter platelet biology.

BACKGROUND: Reserpine is a popular drug in the equine industry for long-term tranquilisation. Clinical observations revealed that blood from horses receiving oral reserpine was hypercoagulable. No studies have documented the pharmacokinetics of orally administered reserpine nor the effects of reserpine on platelets in horses. OBJECTIVES: To evaluate the pharmacokinetics of oral reserpine in horses and the effects of clinically relevant concentrations of reserpine on platelet functionality in vitro. STUDY DESIGN: Experimental controlled study. METHODS: The pharmacokinetics of oral reserpine (2.5 mg/horse, once) were determined in six healthy adult horses. Plasma samples were collected and concentrations of reserpine were determined by UPLC-MS/MS. Using this data, the in vitro effects of reserpine on platelets were examined. Aggregation, adhesion and releasate assays for serotonin and thromboxane B2 were performed on platelets exposed to varying concentrations of reserpine (0.01-10 ng/mL), aspirin (negative control) and saline (unexposed control). RESULTS: Oral reserpine administration demonstrated low plasma concentrations with a Cmax of 0.2 ± 0.06 ng/mL and a prolonged half-life of 23.6 ± 6.24 h. Simulations over a dose range of 2-8 µg/kg predicted Cmax at steady state between 0.06-0.9 ng/mL. Platelets exposed to these reserpine concentrations in vitro displayed increased aggregation and adhesion compared to unexposed or aspirin-exposed platelets as well as compared to higher concentrations of reserpine. These functional changes correlated with lower concentrations of serotonin and higher concentrations of thromboxane B2 in the platelet suspension supernatant. MAIN LIMITATIONS: This study used a small number of horses and only in vitro platelet experiments. CONCLUSIONS: Oral reserpine demonstrates low plasma concentrations and a prolonged half-life in horses. At these concentrations, reserpine causes significant changes in platelet function, most likely due to serotonin release and re-uptake which primes platelets for activation and thromboxane B2 release. These findings suggest that clinicians should harvest blood for biological processing prior to the onset of reserpine administration.

Management of Attention-Deficit Disorder and Attention-Deficit/Hyperactivity Disorder Drug Intoxication in Dogs and Cats: An Update.

Amphetamines and the nonamphetamine atomoxetine are commonly used in the treatment of attention-deficit disorder/attention-deficit/hyperactivity disorder in humans. Because these medications are often found in homes, dog and cat exposure to these medications is a common intoxication. Amphetamine intoxication can cause life-threatening central nervous system and cardiovascular stimulation, even when small amounts are ingested.

Comparing pharmacologic mechanism of action for the vesicular monoamine transporter 2 (VMAT2) inhibitors valbenazine and deutetrabenazine in treating tardive dyskinesia: does one have advantages over the other?

The two approved treatments for tardive dyskinesia both inhibit the vesicular monoamine transporter type 2 (VMAT2) yet have pharmacologic properties that distinguish one from the other. Knowing these differences may help optimize which treatment to select for individual patients.

Deutetrabenazine for the treatment of Huntington's chorea.

INTRODUCTION: Huntington's disease (HD) is an inherited neurodegenerative disorder for which no disease-modifying treatment is currently available. Only symptomatic treatment can be offered. Chorea is the most common motor manifestation of HD and may interfere with daily activities, reduce quality of life, and cause injury. Areas covered: Deutetrabenazine is the first deuterated drug and second drug after tetrabenazine, the classic vesicular monoamine transporter type 2 (VMAT2) inhibitor, to receive approval for the treatment of chorea associated with HD. This review, based largely on a detailed PubMed search, will summarize the pharmacological properties, clinical evidence of efficacy and tolerability of deutetrabenazine in the treatment of HD chorea. Expert commentary: Due to differences in pharmacology and pharmacokinetics, deutetrabenazine has shown promise that it is at least as effective as tetrabenazine in the treatment of HD chorea but has a lower risk of adverse effects. The role of VMAT2 inhibitors in the treatment of hyperkinetic movement disorders is expanding due to their efficacy and favorable tolerability profiles.

Review of deutetrabenazine: a novel treatment for chorea associated with Huntington's disease.

Deutetrabenazine was recently approved for the treatment of chorea in Huntington's disease (HD) and is the first deuterated medication that has been US Food and Drug Administration (FDA)-approved for therapeutic use. In this article, we review deutetrabenazine's drug design, pharmacokinetics, drug interactions, efficacy, adverse events, comparison with tetrabenazine, dosage, and administration. Deutetrabenazine is a deuterated form of tetrabenazine and is a vesicular monoamine transporter 2 (VMAT2) inhibitor. The substitution of deuterium for hydrogen at key positions in the tetrabenazine molecule allows a longer drug half-life and less frequent daily dosing. Deutetrabenazine is administered twice daily up to a maximum daily dose of 48 mg, which corresponds to a similar daily dose of 100 mg of tetrabenazine. In a Phase III clinical trial (First-HD), there was a statistically significant improvement of chorea in HD subjects, as well as improvements in global impression of change as assessed by both patients and clinicians. This improvement was seen without significant adverse effects as the overall tolerability profile of deutetrabenazine was similar to placebo. Somnolence was the most commonly reported symptom in the deutetrabenazine group. In a study where subjects converted from tetrabenazine to deutetrabenazine in an open-label fashion (ARC-HD) and indirect comparison studies between tetrabenazine and deutetrabenazine, there is a suggestion that while efficacy for chorea is similar, the data may slightly favor tetrabenazine, but adverse effects and tolerability strongly favor deutetrabenazine. These data have not been replicated in true head-to-head studies. Current evidence supports that deutetrabenazine is an effective therapeutic treatment option for chorea in HD and may provide a more favorable adverse effect profile than tetrabenazine. However, more data are needed, particularly in the form of head-to-head studies between deutetrabenazine and other treatment options as well as longer term clinical experience with deutetrabenazine.

Reference tissue models in the assessment of 11 C-DTBZ binding to the VMAT2 in rat striatum: A test-retest reproducibility study.

Dopaminergic PET imaging is a useful tool to assess the dopaminergic integrity and to follow-up longitudinal studies. The aim of this study was to evaluate the reliability and reproducibility of different reference tissue-based methods to determine the non-displaceable binding potential (BPND ) as a quantitative measure of 11 C-DTBZ binding to the VMAT2 in rat striatum using cerebellum as reference region. Eight healthy Wistar rats underwent two microPET scans at the age of 12 (test) and 20 weeks (retest). BPND was determined using the simplified reference tissue model, Logan reference tissue model, and multilinear reference tissue models (MRTMo and MRTM2). Additionally, a striatal-to-cerebellar-ratio (SCR) analysis was performed. The reproducibility between the two scans was assessed using the interclass correlation coefficients (ICC) and the variability index. Repeatability indices showed acceptable ICC = 0.66 (SCR) to excellent ICC = 0.98 (MRTM2) reliability for this study and a variability ranging from 12.26% (SCR) to 3.28% (MRTM2). To the best of our knowledge, this is the first report on longitudinal studies for 11 C-DTBZ in rats using reference tissue methods. Excellent intersubject and intrasubject reproducibility was obtained with the multilinear reference MRTM2, suggesting this as the best method to compare longitudinal studies, whereas the SCR method had poor reliability. Logan method, however, is a method simple to compute that shows accurate reproducibility with a reasonable level of inter- and intra-subject variability allowing crossover studies to follow-up the uptake of 11 C-DTBZ in rat striatum.

Differences in Dihydrotetrabenazine Isomer Concentrations Following Administration of Tetrabenazine and Valbenazine.

BACKGROUND: Tetrabenazine (TBZ) activity is thought to result from four isomeric dihydrotetrabenazine (HTBZ) metabolites ([+]-α-HTBZ, [-]-α-HTBZ, [+]-ß-HTBZ, [-]-ß-HTBZ). Each isomer has a unique profile of vesicular monoamine transporter 2 (VMAT2) inhibition and off-target binding. Previously published data only report total isomer (α) and (ß) concentrations. We developed a method to quantify the individual HTBZ isomers in samples from patients with Huntington's disease receiving TBZ. For comparison, concentrations of [+]-α-HTBZ, the single active metabolite shared by valbenazine (VBZ) and TBZ, were determined in samples from patients with tardive dyskinesia receiving VBZ. METHODS: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for quantitation of the four individual HTBZ isomers. Concentrations were determined in serum from patients with Huntington's disease administered TBZ and plasma from patients with tardive dyskinesia administered VBZ once daily. RESULTS: In patients administered TBZ, [-]-α-HTBZ and [+]-ß-HTBZ were the most abundant HTBZ isomers while [-]-ß-HTBZ and [+]-α-HTBZ were present as minor metabolites. Only [+]-α-HTBZ was observed in patients administered VBZ. CONCLUSIONS: Based on relative abundance and potency, [+]-ß-HTBZ appears to be the primary contributor to VMAT2 inhibition by TBZ, a finding in contrast with the generally held assertion that [+]-α-HTBZ is the major contributor. [-]-α-HTBZ, the other abundant TBZ metabolite, has much lower VMAT2 inhibitory potency than [+]-ß-HTBZ, but increased affinity for other CNS targets, which may contribute to off-target effects of TBZ. In contrast, pharmacological activity for VBZ is derived primarily from [+]-α-HTBZ. Individual HTBZ isomer concentrations provide a more clinically relevant endpoint for assessing on- and off-target effects of TBZ than total isomer concentrations.

Single Dose and Repeat Once-Daily Dose Safety, Tolerability and Pharmacokinetics of Valbenazine in Healthy Male Subjects.

Valbenazine (VBZ) is a vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of tardive dyskinesia. The safety, tolerability and pharmacokinetics of VBZ following single and repeat once-daily (QD) dosing were evaluated in 2 randomized, single-center, double-blind studies in healthy male subjects. In the first study, 2 cohorts of 8 subjects were administered single doses (SD) of placebo (PBO; N = 2/period) or VBZ (N = 6/period; 1, 2, 5, or 12.5 mg for Cohort 1 and 12.5, 25, 50, or 75 mg for Cohort 2) using a sequential escalation scheme. The second study consisted of 2 phases. In the initial phase, subjects were administered SD PBO (N = 2/period) or VBZ (N = 6/period; 75, 100, 125 or 150 mg) with sequential escalation. In the second phase, subjects received PBO, or 50 or 100 mg VBZ (N = 4:8:8) QD for 8 days (Cohort 1) or PBO or 50 mg VBZ (N = 6:6) QD for 8 days (Cohort 2). For both studies, plasma concentrations of VBZ and its active metabolite, NBI-98782, were determined. Safety was assessed throughout the studies. PK parameters were determined using noncompartmental methods. In both studies, VBZ was rapidly absorbed with peak concentrations typically observed within 1.5 hours. Peak NBI-98782 concentrations were typically observed at 4.0 to 9.0 hours. Terminal elimination half-life for both VBZ and NBI-98782 was ~20 hours. Across the 1 to 150 mg SD range evaluated across the studies, VBZ and NBI-98782 Cmax and AUC increased dose-proportionally from 50 to 150 mg and more than dose-proportionally from 1 to 50 mg. QD VBZ and NBI-98782 Cmax and AUC parameters were also dose-proportional between the 50 and 100 mg doses. Steady-state for both analytes appeared to be achieved by Day 8. The accumulation index was ~1.5 for VBZ and ~2.5 for NBI-98782. Peak to trough fluctuation was approximately 250% for VBZ and 70% for NBI-98782. Across both studies, NBI-98782 exposure was approximately 20%-30% that of VBZ based on molar ratios. In the first study, the maximum-tolerated dose was not achieved; headache (2 events) was the only treatment-emergent adverse event (TEAE) reported by more than one subject. In the second study, fatigue (4 events) was the only TEAE reported by more than one subject following SD VBZ. Following QD VBZ, the TEAEs of fatigue, insomnia, disturbance in attention, and nervousness were dose-dependent; the latter three TEAEs were considered dose-limiting. Subject withdrawals due to TEAEs were 1 each for PBO and 50 mg VBZ QD, and 3 for 100 mg VBZ QD. Clinically relevant effects on laboratory parameters, vital signs or ECGs were limited to increased CPK (SD: 1 each for 5 mg VBZ and PBO), ALT (QD: 1 each for 50 and 100 mg VBZ and PBO), and triglycerides (QD: 1 each for 50 mg VBZ and PBO). VBZ has an acceptable safety profile and predictable pharmacokinetics that result in stable concentrations of active compounds with low peak-to-trough fluctuation following once-daily dosing.

Deutetrabenazine: Treatment of hyperkinetic aspects of Huntington's disease, tardive dyskinesia and Tourette syndrome.

Deutetrabenazine is a derivative of tetrabenazine in which two trideuteromethoxy groups substitute two methoxy groups. The active metabolites of deutetrabenazine have a longer half-life than those of tetrabenazine, together with a greater overall absorption. However, the peak plasma concentrations are lower. Because of these pharmacokinetic differences, deutetrabenazine can be given twice daily, thus improving compliance. The lower peak concentrations may account for a lower incidence of some unwanted adverse effects. Unlike tetrabenazine, deutetrabenazine has no effect on the QT interval. Treatment with deutetrabenazine significantly improved chorea in Huntington's disease, the hyperkinetic features of tardive dyskinesia, and tics in Tourette syndrome. In all three conditions, deutetrabenazine produced an acceptable level of overall adverse effects without causing any severe adverse effects.