4.1 Overview
This study assessed the ability of viloxazine ER to meaningfully affect CYP1A2, 2D6, and 3A4 enzyme function in healthy adults. Based on US FDA guidelines [
7] for defining the strength of a drug’s capacity for CYP inhibition, our results show viloxazine ER to be a strong inhibitor of CYP1A2 and a weak inhibitor of CYP2D6 and 3A4. Specifically, viloxazine ER increased exposure (AUC) of the CYP1A2 index substrate caffeine by 4.4- to 5.8-fold (Fig.
2), the CYP2D6 substrate dextromethorphan by 1.9-fold (~90%) [Fig.
3], and the CYP3A4 substrate midazolam 1.7-fold (~70%) relative to MCC alone (Fig.
4). Despite these increases in exposure, viloxazine ER did not increase the maximal measured concentration (
Cmax) of single-dose caffeine or midazolam and produced only a modest increase in
Cmax (~50%) of dextromethorphan.
These data are consistent with a published in vitro study showing viloxazine to be a strong, reversible inhibitor of CYP1A2 and a weak inhibitor of CYP2B6, 2D6, and 3A4/5 [
19]. The in vitro study also showed viloxazine produced no meaningful inhibition at CYP2C8, 2C9, or 2C19 and no impact on CYP induction at clinically relevant doses [
6]. Building on the in vitro work, the present study provides a clinical context for understanding potential sources of variability in concomitant medication exposure when using viloxazine ER in a clinical setting and how this variability might impact treatment outcomes. Specifically, the results suggest potential for clinically relevant drug interactions with viloxazine ER and drugs that are primarily metabolized by CYP1A2, and, to a lesser extent, drugs that are metabolized by CYP2D6 or 3A4. Observations of an increase in AEs of insomnia and a decrease in AEs of somnolence when viloxazine ER was coadministered with MCC, likely resulting from inhibition of caffeine metabolism, would appear to support this conclusion. Notably, the use of viloxazine ER in combination with MCC in this study appeared generally safe and well tolerated, with no reported severe or serious AEs and no discontinuations resulting from AEs, even despite the 900-mg/day viloxazine ER dosage, which is higher than the currently recommended maximum dosage for treatment of ADHD in adults (600 mg/day) [
3]. However, we note that the study was a single-dose design, and therefore, the results presented do not evaluate the accumulation of index substrates (particularly caffeine) with repeated dosing and potential consequent effects on tolerability or AEs. Additionally, simulations were not done to estimate drug accumulation over multiple doses.
4.2 Influence of CYP2D6 Polymorphisms on Systemic Viloxazine Exposure
A secondary objective of the present study was to assess the impact of CYP2D6 genetic polymorphisms on the pharmacokinetic profile of viloxazine. Our results suggest a low likelihood for CYP2D6 polymorphisms to meaningfully impact viloxazine exposure, as CYP2D6 PMs had increases in viloxazine
Cmax,
Cmin, and AUC
24 values that were 21%, 33%, and 26% higher than EMs, respectively, with upper-bound 90% CIs falling only slightly above the predetermined no-difference limit of 80.00–125.00% (Fig.
5). The increase in peak and total exposures for CYP2D6 PMs generally fell within the pharmacokinetic variability of CYP2D6 EMs, and the differences observed in PMs are not considered to be clinically relevant.
Whether or not changes in CYP enzyme function will result in clinically meaningful changes in drug efficacy or safety is influenced by many factors, such as the fraction of drug metabolized by a given pathway; genetic variation in enzyme function; the ability to shift metabolism to compensatory pathways; the drug’s therapeutic index; the dose of medication administered; and the potential influence of concomitantly administered food, drug, or herbal preparations on primary and alternative elimination pathways.
Viloxazine is hepatically metabolized to 5-hydroxyviloxazine with subsequent glucuronidation to its primary metabolite 5-hydroxyviloxazine-glucuronide; approximately 22% of the dose is excreted unchanged [
6]. Like it is for many psychiatric medications, CYP2D6 is a primary pathway for viloxazine hydroxylation; however, in the case of viloxazine, CYP1A2, 2B6, 2C9, 2C19, and 3A4 also play a minor role, and in total, 5-hydoxyviloxazine metabolites account for only about 50% of the metabolized fraction of the drug [
6]. Previous research has shown that the overall fraction of a drug metabolized by CYP2D6 can predict whether genetic polymorphisms for this enzyme will result in substantial variability in drug exposure [
20]. For drugs with < 60% CYP2D6-mediated metabolism in vivo (such as viloxazine), the difference in AUCs between CYP2D6 PMs and EMs was modest (< 2.5 fold), whereas for major 2D6 substrates (> 60% 2D6 involvement), the exposure differences were between 3.5- and 53-fold larger [
20].
Consistent with this research, CYP2D6 PMs in the present study demonstrated a < 1.5-fold increase in viloxazine exposure relative to EMs. Conversely, the nonstimulant ADHD drug atomoxetine, which relies more heavily on CYP2D6 for metabolism, is more heavily influenced by CYP2D6 genetic polymorphisms [
21,
22] and shows ~ 8- to 10-fold higher atomoxetine exposure in CYP2D6 PMs compared with EMs [
23]. Lower reliance on CYP2D6 for drug metabolism may also make viloxazine less susceptible to drug interaction when administered with CYP2D6 inhibitors. Overall, our study data suggest that reduction in CYP2D6 enzyme function or availability by itself is unlikely to result in clinically significant variability in viloxazine exposure. Therefore, no dose reduction or routine testing for CYP2D6 genetic polymorphism is recommended when viloxazine ER is used. Additionally, there is no need to genotype patients who are naïve to viloxazine.
4.3 Clinical Relevance
Individuals with ADHD may be treated with combination therapy, either to better control ADHD symptoms or to treat psychiatric comorbidities [
24‐
29]. Because viloxazine is a weak inhibitor of CYP2D6 and CYP3A4, it is not anticipated to impact the pharmacokinetics of drugs metabolized by these pathways to a clinically meaningful extent under most circumstances. Exemplifying this, a pharmacokinetic study in healthy adults showed no evidence of clinically relevant drug interaction when viloxazine ER was coadministered with lisdexamfetamine [
17]. While lisdexamfetamine is not itself metabolized by any CYP enzymes, its primary metabolite,
d-amphetamine, is metabolized, at least in part, by CYP2D6 [
30]. Administration of clinically relevant single doses of lisdexamfetamine (50 mg) alone and in combination with viloxazine ER (700 mg) showed no relevant increase in
d-amphetamine, with
Cmax, AUC
t, and AUC
∞ all within the predetermined no-difference limits of 80.00–125.00% [
17]. The lack of impact on
d-amphetamine, versus the modest impact on dextromethorphan pharmacokinetics seen in the present study, may be accounted for by the fraction of each drug metabolized by CYP2D6 (while
d-amphetamine is presumed to be metabolized via multiple routes, dextromethorphan elimination uses the CYP2D6 pathway almost exclusively) as well as the larger dose of viloxazine ER used in this study (900 mg/day × 4 days vs. a single 700-mg dose in the lisdexamfetamine study) [
17]. Similarly, a drug-drug interaction study between viloxazine ER and methylphenidate (another stimulant used in ADHD treatment) also showed no significant drug interactions [
18].
When viloxazine is coadministered with paroxetine, a selective serotonin reuptake inhibitor and a strong CYP2D6 inhibitor, only modest changes to viloxazine pharmacokinetics were observed (increase in AUC < 35% and no changes in
Cmax) that are unlikely to have a clinically relevant impact on efficacy or safety [
19]. Viloxazine ER effects on CYP3A4 were below the range established by the FDA that would require additional drug-drug interaction studies, such as those with oral contraceptives.
Conversely, because viloxazine is a strong inhibitor of CYP1A2, clinically meaningful interactions with drugs primarily metabolized by this enzyme are likely, particularly for drugs with narrow therapeutic indices and without compensatory elimination pathways. Indeed, the few potentially serious drug interactions involving viloxazine that have been reported during its otherwise long track record of safe use since the 1970s have involved drugs with narrow therapeutic indices that predominantly use singular metabolic pathways. For instance, in a 1986 case report, theophylline, a bronchodilator predominantly metabolized by CYP1A2, showed significantly decreased clearance, with a doubling of serum concentrations and signs of toxicity three days following viloxazine treatment initiation. These effects were quickly reversed upon cessation of viloxazine treatment [
31]. A subsequent drug interaction study in eight healthy volunteers found viloxazine (300 mg/day) significantly increased theophylline plasma concentrations and decreased apparent clearance, likely resulting from viloxazine’s strong inhibition of CYP1A2 [
32]. Theophylline is known to have a narrow therapeutic window with saturable metabolism, and as a result, its use requires careful monitoring, particularly when administered in tandem with drugs affecting CYP1A2 [
33,
34].
Similarly, a drug interaction study by Pisani et al. showed the potential for carbamazepine intoxication with viloxazine coadministration [
35]. Carbamazepine is an anticonvulsant medication that also has a narrow therapeutic index [
34,
36]. At the time the drug interaction study with carbamazepine was conducted (pre-1994), viloxazine was among the few available antidepressants considered to be non-epileptogenic [
37,
38] and was therefore evaluated in seven adults with epilepsy and depression to characterize the potential for drug interactions between the two products. Individuals receiving stable treatment with carbamazepine were administered viloxazine at doses totaling 300 mg/day for three weeks. Viloxazine coadministration increased carbamazepine concentrations, although symptoms of carbamazepine intoxication quickly normalized following viloxazine discontinuation [
35]. Although carbamazepine is said to be metabolized primarily by CYP3A4 [
39], its metabolism is also affected by polymorphisms in CYP1A2, and it is known to interact with ciprofloxacin, which, like viloxazine, is a strong inhibitor of CYP1A2 yet a weak inhibitor of CYP3A4. Although clinical monitoring for drug interactions in the context of polypharmacy is generally prudent, such monitoring is particularly important for sensitive CYP1A2 substrates and CYP1A2 substrates with a narrow therapeutic range.
While viloxazine ER is a relatively new viloxazine formulation, the original, immediate-release version has a long history of use in Europe dating from the 1970s and was typically administered in one to four divided doses totaling 100–600 mg/day without any major safety concerns [
37,
40,
41]. Contemporarily, no major safety concerns have been reported in drug interaction studies after single doses of viloxazine ER in healthy adults (dosing 700 mg/day) either alone or in combination with methylphenidate [
18], lisdexamfetamine [
17], or paroxetine [
19], nor after chronic dosing in children (100–400 mg/day) [
42‐
44], adolescents (200–600 mg/day) [
45,
46], or adults (200–600 mg/day) [
47] in well-controlled studies, leading to viloxazine ER approval for the treatment of ADHD in these populations [
43‐
47].
Although doses above 600 mg/day have not been examined in pediatric populations, in healthy adults, the maximum tolerated doses of viloxazine ER in phase I testing were 2100 mg/day after a single dose and 1800 mg/day after multiple doses [
48]. Additionally, a recently published study using single doses of viloxazine ER 1800 mg for two consecutive days found no demonstrable increase in the risk of cardiac arrhythmias, altered ECG parameters, or major safety concerns [
49]. These data offer preliminary evidence suggesting viloxazine ER has a wide therapeutic index and would be unlikely to result in serious toxicity following modest elevations in plasma concentration.
Although viloxazine ER significantly increased systemic caffeine exposure in the present study, caffeine is known to have a wide therapeutic index and rarely causes serious toxicity [
50]. Because most individuals self-regulate their caffeine intake based on subjective and physiological effects, caffeine intoxication is rare [
51]. Given the numerous intrinsic and extrinsic sources of variability in caffeine exposure, at typical levels of caffeine consumption, individuals are likely to be able to safely regulate their intake while also receiving treatment with viloxazine ER [
51,
52]. Notably, caffeine use was allowed in the phase III pediatric and adult ADHD treatment studies, where the majority (over 85%) of adult subjects treated with viloxazine ER also used caffeine [
47]. However, clinicians should be aware of the possibility that viloxazine interactions with CYP1A2 could lead to caffeine-related AEs.