Impact of a High-Fat Meal and Sprinkled Administration on the Bioavailability and Pharmacokinetics of Viloxazine Extended-Release Capsules (QelbreeTM) in Healthy Adult Subjects.

BACKGROUND AND OBJECTIVES: Viloxazine extended-release (viloxazine ER) capsules (QelbreeTM) is a novel nonstimulant recently approved as a treatment for attention-deficit/hyperactivity disorder in children and adolescents. Here, we determined whether the pharmacokinetics of viloxazine are impacted by consuming the capsule contents sprinkled on applesauce rather than an intact capsule, and the effect of a high-fat meal on the pharmacokinetics of viloxazine ER. METHODS: This was a randomized, open-label, crossover, three-treatment, three-period study in healthy adults using orally administered single-dose viloxazine ER 200 mg capsules. Subjects consumed: (1) an intact capsule after a 10-h fast (control condition); (2) the capsule contents sprinkled on one tablespoon of applesauce; and (3) an intact capsule with a standard high-fat meal. Blood samples were collected for 48 h post-dosing. Relative bioavailability analyses were performed to assess the impact of each test condition against the control condition (intact capsule, fasting). The absence of an impact was indicated if the 90% confidence interval (CI) for the least-squares geometric mean ratio (LSGMR) of maximal concentration (Cmax), the area under the concentration-time curve from time 0 to the last measurable concentration time (AUClast), and the area under the concentration-time curve from time 0 to infinity (AUCinf) were within the predetermined no-difference limits of 80-125%. RESULTS: Out of 27 enrolled subjects, 25 were included in the pharmacokinetic analysis. The LSGMR (90% CI) for viloxazine ER sprinkled vs. intact were 90.10% (83.35-97.40) for Cmax, 93.71% (89.09-98.57) for AUClast, and 95.37% (89.80-101.28) for AUCinf. The LSGMR (90% CI) for viloxazine ER consumed in the fed state vs. fasting state were 90.86% (84.05-98.21) for Cmax, 89.68% (85.26-94.33) for AUClast, and 92.35% (86.96-98.07) for AUCinf. The 90% CIs of the LSGMRs were within the predetermined no-difference limits of 80-125%. Viloxazine ER was well tolerated, with most adverse events reported as mild. CONCLUSIONS: These data suggest that viloxazine ER can be consumed sprinkled on applesauce or as intact capsules with or without meals without significantly changing its pharmacokinetics.

Effects of administration route on pharmacokinetics of viloxazine in the rabbit.

The absorption of viloxazine chlorhydrate was investigated in ten rabbits. Each animal received the drug (15 mg/kg) by three routes: intravenous, gastric and duodenal. Viloxazine plasma concentrations were low when administered by gastric and duodenal routes compared to those after intravenous injection. Concentrations to peak were 1-2 times higher after duodenal than gastric administration. Times to peak were 23.0 +/- 4.7 min after gastric administration and 9.5 +/- 5.4 min after duodenal administration. A better absorption of viloxazine after administration occurred in the duodenum than in the stomach; these results agree with viloxazine pKa = 8.13. The other pharmacokinetic parameters such as half-life, clearance and volume of distribution where the same irregardless of the administration route.

Viloxazine in depressed women: clinical response and cardiovascular effects.

The antidepressant effect of viloxazine (300 and 500 mg/day) was investigated for 4 weeks in 26 depressed women. The decrease in the Hamilton Depression Rating Scale score indicated a prompt overall clinical improvement, the depressed mood and suicide items showing the highest percent diminution. The highest plasma level of viloxazine was reached at day 7 and decreased during treatment only with the 500 mg dosage. Blood pressure and pulse rate responses to orthostatic stress were slightly affected and showed few untoward cardiovascular reactions to drug treatment. The decrease of noradrenaline plasma levels in both postural positions might indicate a lower sympathetic nervous system tone.

Age, therapeutic "milieu" and clinical outcome in depressive patients treated with viloxazine: a study with plasma levels.

Authors studied 42 depressed patients of both sexes suffering from Major Depression and Dysthimic Disorder, treated with viloxazine for 4 weeks. All patients were divided into two groups on the basis of their age (Group 1 mean age 45 +/- 2.2 and Group 2 mean age 68.3 +/- 1.12). Viloxazine was effective in different depressive situations, regardless of the age of the patient or the therapeutic context, even if in Group 2 the out-patients did significantly better (p less than 0.01) than the hospitalized ones. Mean steady-state plasma levels and level/dose ratios were significantly higher (p less than 0.05) in elderly patients than in younger ones. No correlation between viloxazine plasma levels-clinical efficacy and side-effects was found even though patients suffering from Major Depression showed a trend to a better response with plasma levels below 5 gamma/ml. The satisfactory antidepressant activity and the good tolerability of viloxazine in elderly depressed patients make this drug particularly suitable for using in ambulant geriatric depressed patients.

Pharmacokinetics of the antidepressant drug viloxazine in normal subjects and in epileptic patients receiving chronic anticonvulsant treatment.

In order to evaluate the influence of chronic antiepileptic drug treatment on the kinetics of the antidepressant viloxazine (VLX), six drug-free control subjects and six epileptic patients treated with one or two anticonvulsants (phenobarbital, carbamazepine or phenytoin) were given a single oral dose of VLX (200 mg). On a separate occasion, the patients were also given 200 mg VLX by IV infusion. Plasma VLX levels were determined by GLC. Following oral dosing, VLX was rapidly absorbed from the gastrointestinal tract (peak levels at 0.5-4 h); plasma level profiles showed a considerable interindividual variability but did not differ significantly between patients and controls. Terminal half-lives were 4.3 +/- 1.5 h in the patients and 4.3 +/- 1.8 h in the controls. Clearance and volume of distribution calculated after IV dosing in the patients were 124 +/- 11 ml h-1 kg-1 and 0.73 +/- 0.28 l/kg, respectively. The absolute oral availability was 85 +/- 14%. At variance with findings reported for other antidepressants, VLX kinetics do not appear to be significantly altered by concurrent treatment with enzyme-inducing antiepileptic drugs.

A clinical and pharmacological study of the antidepressant activity of viloxazine in adult and elderly patients.

This work deals with the results of a clinical experience with viloxazine (VLZ) carried out on 43 depressed subjects of the female sex categorized with D.S.M. III criteria. Clinical ratings were made by means of the Hamilton Scale for depression and the Taylor self rating scale for anxiety. The results prove the efficacy of the drug in all the examined patients, along with the rapidity of effects in comparison with the tricyclic antidepressants. The elderly patients improved better than the adult subjects, especially when the depression was of the inhibited type.

A sensitive gas chromatographic assay for the determination of serum viloxazine concentration using a nitrogen-phosphorus-selective detector.

A gas-liquid chromatographic procedure for measuring the serum levels of the antidepressant viloxazine is described. The drug and the internal standard [imipramine (IMI)] are extracted from 1 ml serum. The method involves a three-step extraction, derivatization of viloxazine with acetic anhydride, and injection into a gas chromatograph equipped with a nitrogen-phosphorus-selective detector. The retention times for IMI and viloxazine were 4.7 and 6.1 min, respectively. The standard curves were linear over the 100- to 2,000-ng/ml range. The recovery averaged 64.5% and the lowest detection limit was 80 ng/ml. The within-run and day-to-day coefficients of variations were 11.9 and 12.5%, respectively, at 250 ng/ml, and 8.9 and 9.2%, respectively, at 1,500 ng/ml. The method is adequate both for single-dose pharmacokinetic studies and for monitoring serum viloxazine levels in chronically treated patients.

Pharmacokinetics of viloxazine hydrochloride in man.

The pharmacokinetic characteristics of a new antidepressant, viloxazine hydrochloride, were investigated in five males and five females to study sex differences. Plasma levels were determined over a period of 9 h after a single dose of viloxazine of 100 mg (expressed as base). The half life of the drug was in the range of 2.19 - 4.21 for females and 2.61 - 4.31 h for males. The maximum plasma levels occurred in 29 - 171 min of the oral dose for females and 54 - 155 min for males. They reached 1382 - 1769 ng/ml-l for females and 1108 - 2932 ng/ml for males. Pharmacokinetic data were not statistically different between males and females.

Anticonvulsant and proconvulsant properties of viloxazine hydrochloride: pharmacological and pharmacokinetic studies in rodents and the epileptic baboon.

Viloxazine HCl is evaluated as an anticonvulsant in a wide range of rodent seizure models and in the epileptic baboon (Papio papio). In the maximal electroshock test, the oral ED50 for abolition of tonic extension was 9 mg/kg-1 after 30-min pretreatment (mouse) rising to 30 mg/kg-1 after 60 min (mouse and rat). Comparable ED50 values were also found for protection against tonic extension in the mouse induced by the administration of the chemical convulsants metrazole or 3-mercaptopropionic acid. In DBA/2 mice the ED50 for abolition of tonic extension during sound-induced seizures was 6.8 mg/kg-1 IP (30-min pretreatment). Pharmacokinetic studies in the mouse showed peak plasma levels to occur 30 min following oral doses, with a mean half-life of 58 min. The anticonvulsant plasma concentration was within 0.5 -- 1 microgram/ml-1. In the baboon, significant protection against photomyoclonic responses is observed 1 -- 2h after viloxazine (2.6 mg/kg-1 IV), during which period the plasma concentration was again 0.5-1 microgram/ml-1. After administration of approximately ten-times this latter dose level, i.e. 24 mg/kg-1 IV, a syndrome characterised by an abnormal EEG and, in some instances, seizure activity was observed.

Clinical pharmacology of viloxazine hydrochloride.

Plasma concentrations of viloxazine were determined in twenty depressed inpatients during 4 weeks of treatment with progressively increasing dosage. Viloxazine plasma levels varied markedly during the day, due to the short half-life of the drug. Plasma levels rose to peak values after 7-10 days of treatment and then decreased, perhaps due to enzymatic induction by viloxazine. A negative linear correlation was found between the plasma concentration of viloxazine and its clinical effect, with the best clinical improvement in patients whose plasma concentration was 20-500 ng/ml at 7 a.m. Performance in psychomotor tests (visual reaction time and ring of Pierron was improved in many patients after treatment and was correlated with the plasma viloxazine level and the Hamilton Rating score. Assessment of viloxazine effects of electroencephalogram showed a decrease in EEG amplitude in the eight clinically improved patients.

High-pressure liquid chromatographic determination of viloxazine in human plasma and urine.

A rapid, specific, high-pressure liquid chromatographic method is presented for the determination of viloxazine in plasma and urine. This method employs the high sensitivity of fluorescence detection with selective extraction and reversed-phase chromatography to measure concentrations as low as 25 ng/ml of plasma and 1.0 microgram/ml of urine. Known metabolites of viloxazine do not interfere with the analysis, and experience with several hundred samples in a bioavailability study demonstrated the applicability and reliability of the method.

Viloxazine plasma concentrations and clinical response.

Eleven patients suffering from primary depressive illness were treated with 300 mg/d of viloxazine for 29 days. Blood samples were collected at weekly intervals and severity of depression assessed using the Hamilton depression rating scale. Mean plasma viloxazine level for all patients during the trial was 1.20 micrograms/ml and ranged from 0.40 to 2.70 micrograms/ml. No simple relationship between plasma concentration and amelioration score was observed at day (rs = -0.02), day 22 (rs = -0.29) or day 29 (rs = 0.09). No significant difference in plasma concentrations between responders and non-responders was observed at day 29. Side effects were not correlated with plasma concentrations.

Relationship between blood and cerebrospinal levels of the antidepressant agent viloxazine.

Viloxazine levels in blood and CSF have been measured following acute and chronic dosing in depressed patients. Blood profiles confirm previous findings that viloxazine is rapidly absorbed and eliminated with a half-life of 4.5 h. Viloxazine crosses the blood-brain barrier and concentrations in CSF remain virtually unchanged over a ten hour period post administration. Viloxazine does not accumulate in CSF on chronic administration. The fact that CSF levels do not reflect concentrations in blood has significant implications on any attempt to correlate the clinical efficacy and the pharmacokinetic behaviour of an antidepressant agent.

Determination of viloxazine in plasma by GLC.

1 A gas chromatographic procedure for the determination of viloxazine in therapeutic concentrations in human plasma, with use of a flame ionization detector, is described. 2 The drug is extracted at pH 12 into hexane, back extracted into HCl, re-extracted into hexane after alkalinization of the HCl and derivatized with acetic anhydride. 3 An imipramine-butriptyline mixture is used as an internal standard. The coefficients of variation for a concentration of 0.75 microgram/ml are 9.4% and 13.1% for within day and day to day precision respectively. For a 1.75 micrograms/ml solution the within day precision was 5.7%. 4 The method has been applied to a patient receiving 300 mg/day viloxazine treatment.

Clinical profile and serum concentration of viloxazine as compared to amitriptyline.

The antidepressive effect of viloxazine (300 mg/d) was investigated during three weeks in 41 patients with depressive syndromes requiring drug-treatment against amitriptyline (150 mg/d), using a controlled double-blind design. Viloxazine differs from amitriptyline by selective inhibition of norepinephrine re-uptake, whereas amitriptyline acts also on serotonin re-uptake. Psychopathological changes were documented by means of the Hamilton Depression Rating Scale, the Bf-S (v. Zerssen), the AMDP-System, and videotaped recordings. Besides routine clinical-chemical tests, the serum concentrations of viloxazine and partly of amitriptyline were determined. Repeated EEG-recordings were evaluated by spectral analysis. The number of global responders and non-responders -- defined according to the final HDRS-scores -- was equally distributed between the two drug-groups. The AMDP-evaluation suggests that viloxazin has a somewhat more marked and more rapid effect on symptoms of retardation, whereas amitriptyline acts predominantly on depressive mood, disturbances of sleep and vital feelings. The EEG-profile of both drugs was similar to the spectral changes seen under tricyclic antidepressants, through only the viloxazine-induced changes reached statistical significance on the 10th and 20th day, the variability of the EEG-recordings being greater in the amitriptyline group. The viloxazine blood levels showed a remarkably low inter- and intraindividual variance. Steady state was reached at day 5 at the latest. Amitriptyline serum concentrations still increased between the 10th and the 21st day. The average blood concentration of viloxazine was higher in the responder- than in the non-responder-group.

Blood level studies with viloxazine hydrochloride in man.

1 The pharmacokinetic characteristics of a new antidepressant, viloxazine hydrochloride, (ICI 58,834, Vivalan), have been investigated in four separate studies. 2 In Study 1, blood levels were measured over a period of 24 h after single doses of viloxazine hydrochloride from 10-100 mg (expressed as base). In Study 2, blood levels were measured over 24 h, during which three single doses of viloxazine hydrochloride (80 mg, expressed as base) were given 4 h apart. In Study 3, blood samples and urine and faeces were collected for 96 h after doses of 40 and 100 mg of [14C] viloxazine hydrochloride (40 muCi). In Study 4, 1 h blood levels were measured at weekly intervals during a comparative clinical trial in which viloxazine was given at a dose of 100 mg four times a day. 3 The half-life of the drug is in the range 2-5 h with maximum blood levels occurring in 1-4 h of the oral dose. Maximum blood levels are proportional to the oral dose given over the range studied (0.76(mug/ml)/(mg/kg)). The drug is very well absorbed orally, only 2% being found in faeces. Repeated dosing at 4 hourly intervals leads to slightly higher blood levels after the second, but not subsequent, doses. No accumulation was seen from week to week in depressed patients. No regular sex difference was seen in the pharmacokinetic characteristics of viloxazine hydrochloride but two females in one study did show a markedly higher maximum blood level and apparently longer half-life than the males. 4 It is concluded that viloxazine is rapidly and almost totally absorbed after an oral dose, and has a shorter half-life than the tricyclic antidepressants; therapy with it should be easily controllable.