Clinical Assessment of Drug Drug Interactions of Tasimelteon, a Novel Dual Melatonin Receptor Agonist

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1 Drug Interactions Clinical Assessment of Drug Drug Interactions of Tasimelteon, a Novel Dual Melatonin Receptor Agonist The Journal of Clinical Pharmacology 2015, 55(9) The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology DOI: /jcph.507 Brian W. Ogilvie, PhD 1, Rosarelis Torres, PhD 2, Marlene A. Dressman, PhD 2, William G. Kramer, PhD 3, and Paolo Baroldi, MD, PhD 2 Abstract Tasimelteon ([1R-trans]-N-[(2-[2,3-dihydro-4-benzofuranyl] cyclopropyl) methyl] propanamide), a novel dual melatonin receptor agonist that demonstrates specificity and high affinity for melatonin receptor types 1 and 2 (MT 1 and MT 2 receptors), is the first treatment approved by the US Food and Drug Administration for Non-24-Hour Sleep-Wake Disorder. Tasimelteon is rapidly absorbed, with a mean absolute bioavailability of approximately 38%, and is extensively metabolized primarily by oxidation at multiple sites, mainly by cytochrome P450 (CYP) 1A2 and CYP3A4/5, as initially demonstrated by in vitro studies and confirmed by the results of clinical drug drug interactions presented here. The effects of strong inhibitors and moderate or strong inducers of CYP1A2 and CYP3A4/5 on the pharmacokinetics of tasimelteon were evaluated in humans. Coadministration with fluvoxamine resulted in an approximately 6.5-fold increase in tasimelteon s area under the curve (AUC), whereas cigarette smoking decreased tasimelteon s exposure by approximately 40%. Coadministration with ketoconazole resulted in an approximately 54% increase in tasimelteon s AUC, whereas rifampin pretreatment resulted in a decrease in tasimelteon s exposure of approximately 89%. Keywords tasimelteon, dual melatonin receptor agonists, Non-24-Hour Sleep-Wake Disorder, Non-24, cytochrome P450, pharmacokinetics, drug drug interactions Tasimelteon ([1R-trans]-N-[(2-[2,3-dihydro-4-benzofuranyl] cyclopropyl) methyl] propanamide), a novel dual melatonin receptor agonist that demonstrates specificity and high affinity for melatonin receptor types 1 and 2 (MT 1 and MT 2 receptors), was approved by the US Food and Drug Administration (FDA) in January 2014 for the treatment of Non-24-Hour Sleep-Wake Disorder (Non- 24). The most abundant metabolites of tasimelteon (M9, M11, M12, M13, and M14) also bind to the MT 1 and MT 2 receptors but have less than one-tenth the binding affinity of the parent. Although Non-24 occurs in both sighted and totally blind individuals, it is rare in sighted individuals but highly prevalent among people who are totally blind. The estimated prevalence in people who are totally blind is 50% 70%. The link between blindness and circadian rhythm disruption was first reported by Remler in 1948 and confirmed in numerous subsequent studies. 1 6 Although circadian rhythm disruption affects multiple systems including those of cardiovascular, metabolic, and immune regulation a common patient complaint is sleep-wake cycle disruption, including insomnia, excessive daytime sleepiness, or both In regulatory pivotal clinical studies, tasimelteon showed efficacy in restoring and maintaining biological synchronization (entrainment) and the sleep-wake patterns of totally blind individuals with Non-24 (ClinicalTrials.gov identifiers: NCT and NCT ). 11 Tasimelteon (1 300 mg) was safe and well tolerated in all clinical studies. The most common adverse events in these studies included headache, increased alanine aminotransferase levels, nightmares/ abnormal dreams, and urinary and upper respiratory tract infections (Lockley SW, Dressman MA, Xiao C, et al, unpublished data, 2013; Torres R, Lockley SW, Dressman MA, et al, unpublished data, 2014). Tasimelteon is rapidly absorbed, with a total absorption of approximately 80%, an absolute bioavailability of approximately 38%, 12 and a median time to maximum 1 XenoTech, LLC, Lenexa, KS, USA 2 Vanda Pharmaceuticals, Inc., Washington, DC, USA 3 Kramer Consulting LLC, North Potomac, MD, USA This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Corresponding Author: Paolo Baroldi, MD, PhD, 2200 Pennsylvania Avenue NW, Suite 300-E, Washington, DC 20037, USA paolo.baroldi@vandapharma.com

2 Ogilvie et al 1005 concentration of 30 minutes for the parent (range, 0.5 to 3 hours) and minutes for the most abundant metabolites. The pharmacokinetics of tasimelteon are linear from 3 to 300 mg (ie, 0.15 to 15 times the approved daily dose of 20 mg), and repeated once-daily dosing of 20 mg for 16 consecutive days did not result in changes in pharmacokinetics or accumulation of tasimelteon or its metabolites. 13 Tasimelteon is extensively metabolized through oxidation at multiple sites, with an elimination half-life (t 1/2 ) ranging from 0.6 to 3.0 hours and a mean of 1.3 hours. Tasimelteon is extensively metabolized. Early in vitro studies suggested that cytochrome P450 (CYP) 1A1, CYP1A2, CYP2C9, and CYP2D6 were the major CYP enzymes involved in the metabolism of tasimelteon, with some contribution by CYP2C Additional in vitro studies suggested that CYP1A2 and CYP3A4/5 are the major CYP enzymes involved in the metabolism of tasimelteon, with minor involvement of CYP2C9, CYP2C19, and CYP2D6 in the formation of the most abundant metabolites, including M9, M11, M12, M13, and M14 (Figure 1). 13 These conclusions from the in vitro data were made based on the formation of metabolites by recombinant human CYPs, combined with the CYP1A2- selective inhibitor furafylline inhibiting the formation of most metabolites of tasimelteon in human liver microsomes by 40% 70% and the selective CYP3A4/5 inhibitor ketoconazole inhibiting M12 and M14 formation by 74% 99% (data on file). The major route of elimination of the metabolites is through urinary excretion, with a small biliary contribution. Unchanged parent compound in the urine accounts for less than 1% of the dose, with approximately 4% excreted in feces. 15 Several clinical drug drug interaction studies were performed during the development of tasimelteon to further elucidate the CYPs responsible for its metabolism and to evaluate the potential for clinically relevant drugdrug interactions. Because CYP1A2 and CYP3A4/5 appeared to be prominently involved in the metabolism of tasimelteon, clinical studies were conducted to examine the effects of strong inhibition (fluvoxamine) and moderate induction (cigarette smoking) of CYP1A2 and strong inhibition (ketoconazole) and induction (rifampin) of CYP3A4/5. These studies were conducted as openlabel, single-sequence, or parallel-group studies to define what would likely be the extremes of induction-related and inhibitory drug drug interactions with tasimelteon encountered during clinical practice. Methods Ethics These studies were conducted according to standards of Good Clinical Practice. The protocols and all modifications and appropriate consent procedures were approved Figure 1. In vitro metabolic pathways of tasimelteon. Major metabolic pathways of tasimelteon are shown as determined from reaction phenotyping data. CYP, cytochrome P450.

3 1006 The Journal of Clinical Pharmacology / Vol 55 No 9 (2015) by the Bio-Kinetic Clinical Applications Institutional Review Board, which is constituted and operates in accordance with the principles and requirements described in the US Code of Federal Regulations (21 CFR Part 56). All study participants provided written informed consent prior to enrollment in the study. Fluvoxamine Study (ClinicalTrials.gov identifier: NCT ) This study was an open-label, single-sequence study. The primary objective of this study was to evaluate the singledose pharmacokinetics of tasimelteon 5 mg, alone and in combination with fluvoxamine, with the latter at steady state. Fluvoxamine tablets (United States Pharmacopeia; USP) (50 mg) were provided by Sandoz (Princeton, New Jersey). A total of 24 healthy male or female subjects aged years (inclusive) were enrolled in the study; these subjects were nonsmokers and had a body mass index (BMI) 18 and 35 kg/m 2. Subjects were treated with a single oral dose of 5 mg tasimelteon on day 1, followed by 6 single oral doses of 50 mg fluvoxamine on days 2 7 and then coadministration of single oral doses of 5 mg tasimelteon and 50 mg fluvoxamine on day 8. Blood samples for the measurement of plasma concentrations of tasimelteon and its metabolites were collected for 24 hours after dosing on days 1 and 8. Fluvoxamine plasma concentrations were measured on day 8 to confirm exposure. Smoking Study (ClinicalTrials.gov identifier: NCT ) This study was an open-label, parallel-group study. One of the primary objectives of this study was to assess the plasma concentrations and pharmacokinetics of tasimelteon and its metabolites in subjects who smoked compared with those for subjects who did not smoke. Forty-eight male and female subjects between ages 18 and 55 years, inclusive, were enrolled in the study in 1 of 2 cohorts: current smokers (cohort 1, n ¼ 24) and nonsmokers (cohort 2, n ¼ 24). Within each cohort, subjects were further stratified by BMI (8 subjects per BMI stratum). Each subject received a single 20-mg dose of tasimelteon (Hetlioz 1 : Vanda Pharmaceuticals, Inc., Washington, DC), and blood samples for the measurement of plasma concentrations of tasimelteon and its metabolites were collected for 24 hours after dosing. Ketoconazole and Rifampin Study (ClinicalTrials.gov identifier: NCT ) This was an open-label, single-sequence study. Forty-eight healthy, nonsmoking male or female subjects between 18 and 55 years of age, inclusive, with a BMI 18 and 35 kg/m 2 were enrolled into 1 of 2 cohorts. The objective of the study was to evaluate the potential effect of administration of a potent CYP3A4/5 inhibitor or inducer on tasimelteon s pharmacokinetics. Rifampin capsules USP (300 mg) were provided by Lannett Company, Inc. (Philadelphia, Pennsylvania), and ketoconazole tablets USP (200 mg) were provided by Taro Pharmaceutical Industries Ltd. (Hawthorne, New York). Subjects in cohort 1 received a single oral dose of 20 mg tasimelteon on day 1, followed by 4 single oral 400- mg doses of ketoconazole on days 2 5, and then coadministration of single oral doses of 20 mg tasimelteon and 400 mg ketoconazole on day 6. Subjects in cohort 2 received a single oral dose of 20 mg tasimelteon on day 1, followed by 10 single oral 600-mg doses of rifampin on days 2 11, and then administration of single oral doses of 20 mg tasimelteon alone on day 12. The second dose of tasimelteon was administered 1 day after the last dose of rifampin on day 11 to minimize any possible transporter inhibition by rifampin. Bioanalysis A validated assay for the simultaneous determination of tasimelteon and metabolites M9, M11, M12, M13, and M14 in plasma was developed. 12 This method was found to be reliable and consistent for the routine analysis of these compounds in human plasma (Table S1). 12 Statistical Analyses An absence of a drug drug interaction was concluded if the 90% confidence intervals (CIs) for the ratios of the geometric means for tasimelteon and metabolites with and without the concomitant treatment were within the equivalence limits of 80% 125% for area under the curve (AUC) from time zero to infinity (AUC 0 inf ), and maximum plasma concentration (C max ). Analysis of Tasimelteon s Potential Interaction With Fluvoxamine, Ketoconazole, and Rifampin. Comparison of the pharmacokinetic parameters C max, AUC 0 inf, and oral clearance (CL/F) of tasimelteon between tasimelteon alone and tasimelteon plus concomitant drug, as well as between smoking and nonsmoking young subjects, was performed using an analysis of variance model with subject and day as the classification variable, using the natural logarithms of the data. CIs (90%) were constructed for the ratios of tasimelteon plus concomitant drug to tasimelteon alone or smoking to nonsmoking young subjects for all applicable parameters using the logtransformed data and the 2 one-sided t tests procedure. The point estimates and CIs were exponentiated back to the original scale. Results Impact of Fluvoxamine (50 mg) on the Pharmacokinetics of Tasimelteon (5 mg) A 5-mg dose of tasimelteon was assessed in this study, rather than the approved 20-mg dose, because of the

4 Ogilvie et al 1007 potential for greatly increased exposure to tasimelteon due to fluvoxamine s known strong inhibition of CYP1A2 and CYP2C19 and weak inhibition of CYP2C8, CYP2C9, and CYP3A4/5 16 and in vitro data suggesting that CYP1A2, CYP2C9, CYP2C19, and CYP3A4/5 were involved in the metabolism of tasimelteon. 13,14 As illustrated in Figure 2A, the mean plasma concentrations of tasimelteon were higher after coadministration with fluvoxamine, as were the mean values for C max and AUC (Table 1). Concomitant administration of fluvoxamine and tasimelteon resulted in an approximate 85% decrease in tasimelteon CL/F, which led to an approximate 6.5-fold increase in AUC 0 inf and an approximately 2.3-fold increase in C max (Table 2). The M14 AUC 0 inf and C max increased approximately 9.5- and 2.6-fold, respectively; the M12 AUC 0 inf increased 2.7-fold (with little change in C max ), and there were relatively small changes in exposures of M9, M11, and M13 (ie, a 26% increase in AUC 0 inf ); see Table S2. The day 7 pharmacokinetic data for fluvoxamine are summarized in Table S3. These data demonstrate that subjects in this study have been exposed to fluvoxamine, and that exposure achieved in this study is consistent with the known pharmacokinetics of fluvoxamine. In addition, the data show that steady state has been reached, as the mean concentrations prior to and 24 hours after the dose on day 7 were essentially the same and ng/ml (data not shown). Effects of CYP1A2 Induction (ie, Cigarette Smoking) on the Pharmacokinetics of Tasimelteon Consistent with moderate induction of CYP1A2 by cigarette smoking, smoking increased the CL/F of tasimelteon by approximately 70% (Table 2), decreasing plasma concentrations (Figure 2B). The tasimelteon AUC 0 inf decreased by approximately 40% in smokers compared with nonsmokers (Table 2). The C max also decreased to approximately the same extent as AUC inf (Table 2). There were minimal changes in the exposure to M12 and M13 in smokers compared with nonsmokers (Table S2). There was an 25% decrease in exposure to M9 in smokers compared with nonsmokers. There was an 20% decrease in exposure to M11 in smokers compared with nonsmokers. There was an 60% decrease in Figure 2. Mean plasma concentrations of tasimelteon (A) after oral administration of 5 mg of tasimelteon alone and after dosing with fluvoxamine 50 mg once daily for 7 days to healthy subjects, (B) after oral administration of single 20-mg doses of tasimelteon to young smokers and young nonsmokers, (C) after oral administration of 20 mg of tasimelteon alone and after dosing with ketoconazole 400 mg once daily for 5 days, and (D) after oral administration of 20 mg of tasimelteon alone and after dosing with rifampin 600 mg.

5 1008 The Journal of Clinical Pharmacology / Vol 55 No 9 (2015) Table 1. Summary of Pharmacokinetic Parameters for Tasimelteon After Oral Administration of Single Doses of Tasimelteon Alone and After Dosing With a CYP Inducer or Inhibitor Parameter a Tasimelteon 5 mg Treatment Tasimelteon 5 mg þ Fluvoxamine 50 mg C max (ng/ml) (24) (24) AUC 0 inf (ng hr/ml) (24) (24) t 1/2 (h) (24) (24) CL/F (ml/min) (24) (24) Young Nonsmokers Young Smokers C max (ng/ml) (24) (24) AUC (0 inf) (ng hr/ml) (24) (24) t 1/2 (h) (24) (24) CL/F (ml/min) (24) (24) Tasimelteon 20 mg Tasimelteon 20 mg þ Ketoconazole 400 mg C max (ng/ml) (24) (24) AUC 0 inf (ng hr/ml) (24) (21) t 1/2 (h) (24) (21) CL/F (ml/min) (24) (21) Tasimelteon 20 mg Tasimelteon 20 mg þ Rifampin 600 mg C max (ng/ml) (24) (24) AUC 0 inf (ng hr/ml) (24) (23) t 1/2 (h) (24) (23) CL/F (ml/min) (24) (23) a Arithmetic mean standard deviation (n). AUC 0 inf, area under the curve from time zero to infinity; CL/F, oral clearance; C max, maximum plasma concentration; CYP, cytochrome P450. exposure to M14 in smokers compared with nonsmokers (Table S2). Effects of a Strong CYP3A4/5 Inhibitor (Ketoconazole) or Strong CYP3A4/5 Inducer (Rifampin) on the Pharmacokinetics of Tasimelteon (20 mg) The mean plasma concentrations of tasimelteon were higher or lower after coadministration with ketoconazole or rifampin, respectively, as were the mean values for C max and AUC (Table 1). Table 2 shows the statistical comparison of the pharmacokinetic parameters for tasimelteon and on oral administration alone and after coadministration of either ketoconazole (cohort 1, 400 mg once daily for 5 days) or rifampin (cohort 2, 600 mg once daily for 11 days). Figure 2C,D shows the effects of ketoconazole or rifampin, respectively, on the mean plasma concentration versus time profiles for tasimelteon. Ketoconazole caused an approximately 35% decrease in tasimelteon CL/F, which led to a 54% increase in AUC 0 inf and a 33% increase in C max (Table 2). In addition, there were approximately 45% and 67% Table 2. Statistical Comparison of Pharmacokinetic Parameters for Tasimelteon After Oral Administration of Single Doses of Tasimelteon Alone and After Dosing With CYP Inducer or Inhibitor Parameter a Estimate Geometric Mean Ratio (%) a 90% Confidence Interval b 5 mg of Tasimelteon Alone and After Dosing With Fluvoxamine 50 mg C max AUC 0 inf CL/F Single 20-mg Doses of Tasimelteon to Young Smokers and Young Nonsmokers C max AUC 0 inf CL/F mg of Tasimelteon Alone and After Dosing With Ketoconazole 400 mg C max AUC 0 inf CL/F mg Tasimelteon Alone and After Dosing With Rifampin 600 mg C max AUC 0 inf CL/F a Based on analysis of natural log-transformed parameters. b A confidence interval of 80.0% 125.0% for AUC 0 inf indicates no effect. AUC 0 inf, area under the curve from time zero to infinity; CL/F, oral clearance; C max, maximum plasma concentration; CYP, cytochrome P450. decreases in M14 AUC 0 inf and C max, respectively (Table S4). In contrast to M14, there was a 61% increase in the M12 AUC 0 inf (with little change in C max ) and very little change in the exposures to M9, M11, and M13 (Table S4). Changes in laboratory values (hematology, chemistry, and urinalysis) from baseline with all treatments were generally small and not clinically significant. The mean standard error plasma concentrations for ketoconazole prior to and 24 hours after the dose on day 6 were essentially the same and ng/ml (data not shown) indicating that steady state had been reached. The pharmacokinetic parameters for ketoconazole on day 6 are summarized in Table S3. This demonstrates that subjects have been exposed to ketoconazole, that exposure is consistent with the known pharmacokinetics of ketoconazole, and that steady state has been reached. Rifampin caused an approximately 9.4-fold increase in tasimelteon CL/F, which led to an 89% decrease in AUC 0 inf and an 83% decrease in C max (Table 2). In addition, there were approximately 15% and 170% increases in the M14 AUC 0 inf and C max, respectively (Table S4). Changes in the pharmacokinetics of M12 after pretreatment with rifampin contrasted with these changes observed with M14, with 83% and 47% decreases in the M12 AUC 0 inf and C max, respectively (Table S4). In addition, there were approximately 48% and 20%

6 Ogilvie et al 1009 decreases in the M11 AUC 0 inf and C max, respectively. For M13, there was an approximately 30% decrease in the AUC 0 inf, but an 18% increase in C max. Very little change in exposure to M9 was found, whereas the C max increased approximately 60% (Table S4). The mean standard error whole-blood rifampin concentrations prior to dosing on days 11 and 12 were essentially the same and ng/ml (data not shown) indicating that steady state had been reached. This demonstrates that subjects have been exposed to rifampin and that steady state has been reached. Discussion Tasimelteon is a novel DMRA that demonstrates specific and high affinity for MT 1 and MT 2 receptors. It is believed that tasimelteon resets the circadian pacemaker, located in the suprachiasmatic nuclei of the hypothalamus, by binding to both melatonin MT 1 and MT 2 receptors. Tasimelteon is the first FDA-approved treatment for Non- 24. The most abundant metabolites of tasimelteon (M9, M11, M12, M13, and M14) have 13-fold or less activity at melatonin receptors compared with tasimelteon 15 and are formed mainly by CYP1A2 and CYP3A4/5. Taken together with the in vitro studies, 13,14 the clinical drug drug interaction studies presented here strongly suggest that CYP1A2 is the major CYP450 enzyme involved in the metabolism of tasimelteon, followed by CYP3A4/5. For instance, cigarette smoking (a moderate CYP1A2 inducer) decreases exposure to tasimelteon by >40%, and fluvoxamine (a strong CYP1A2 inhibitor) increases exposure to tasimelteon by 6.5-fold. It should be noted that fluvoxamine also inhibits CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/ Therefore, although the relatively high fold-increase in exposure may be partly due to inhibition of multiple pathways of metabolism by fluvoxamine, 22 given the effect of moderate induction of CYP1A2 alone, it appears that CYP1A2 is more important to the overall metabolism of tasimelteon at clinically relevant concentrations than CYP2C9, CYP2C19, and CYP2D6, despite some in vitro data that implicated these enzymes. The in vitro studies were conducted with tasimelteon at concentrations that were at least 10-fold higher than the plasma C max observed at the recommended dose of 20 mg. In fact, the only evidence for the contribution of CYP2C19 to the metabolism of tasimelteon comes from an in vitro study conducted at approximately 100-fold higher than its clinical C max. 13 It is quite noteworthy that an in vitro study conducted at only 10-fold tasimelteon s clinical C max indicated that recombinant CYP2C19 could not metabolize tasimelteon. 14 After CYP1A2, CYP3A4/5 is the next most clinically important enzyme in the overall metabolism of tasimelteon, as suggested by the results of the clinical drug drug interaction study with rifampin and ketoconazole (strong CYP3A4/5 inducers and inhibitors, respectively). 16 When a single tasimelteon 20-mg dose was administered after 11 days of rifampin (600 mg once daily), the mean tasimelteon exposure was reduced by approximately 89%. Additional clinical evidence for the importance of CYP3A4/5 in the metabolism of tasimelteon comes from the 2.7-fold increase in the C max of M14 (ie, the tasimelteon metabolite, which is formed solely by CYP3A4/5 in vitro) after pretreatment with rifampin (Table S4). Finally, ketoconazole, a strong CYP3A4/5 inhibitor, causes a 54% increase in exposure to tasimelteon (Table 2). Tasimelteon has a small residual clearance (ie, <1% unchanged drug in urine and 4% in feces), and as such, the contribution of CYP1A2 and CYP3A4/5 to overall metabolism can be approximated if it is assumed that the strong CYP1A2 inhibitor fluvoxamine and the strong CYP3A4/5 inhibitor ketoconazole caused nearly complete inhibition of these enzymes under the clinical conditions employed in the drug drug interaction studies. Under such assumptions, the fraction metabolized through a given pathway, f m, can be estimated by: f m (CYP) ¼ 1 AUC ui AUC i, where AUC ui is the average AUC in the absence of an inhibitor and AUC i is the average AUC in the presence of the inhibitor. 22 Therefore, f m ðcyp1a2þ ¼1 AUC ui 1 AUC i ¼ 0:9; and 102 h ng ml 701 h ng ml f m ðcyp3a4=5þ ¼1 AUC ui ; which is AUC i ng 457 h ml h ng ¼ 0:3 ml The f m (CYP1A2) value is very likely an overprediction, in part because of multiple CYPs implicated in tasimelteon metabolism being inhibited by fluvoxamine. In addition, this simplified analysis ignores the F g term for CYP3A4/5 metabolism of tasimelteon in the small intestine (ie, the fraction of tasimelteon that escapes gut metabolism, which was not determined). The sum of the estimated contribution of CYP1A2 and CYP3A4/5 is 1.2, greater than 1.0, which provides additional support for the conclusion that the contribution of these 2 enzymes accounts for the majority of the CYP-mediated metabolism of tasimelteon in vivo. Of particular interest for consideration of likely maximum exposure when 2 or more parallel pathways of clearance are lost or diminished 22 is that in vitro reaction phenotyping studies also implicated the polymorphic CYPs, namely, CYP2C19, CYP2C9, and CYP2D6, as being somewhat important in the metabolism of tasimelteon. 13,14 The hypothetical concern raised by these data would be that that a poor metabolizer of one of

7 1010 The Journal of Clinical Pharmacology / Vol 55 No 9 (2015) these polymorphic enzymes (ie, those who completely lack 1 or more of these enzymes) might also be coadministered with fluvoxamine or another strong inhibitor of CYP1A2 or CYP3A4/5 while on tasimelteon therapy and, therefore, attain very high exposures to tasimelteon. However, the in vitro studies were conducted at tasimelteon concentrations that were at least 10 times higher than the clinically relevant C max. The in vitro studies also were not conducted in such a way to allow for prediction of the quantitative in vivo involvement of these enzymes in the metabolism of tasimelteon. In addition, genotyping data for CYP2D6 from 4 clinical studies with tasimelteon actually showed a negative correlation between tasimelteon exposure and CYP2D6 poor metabolizer status. 13 Therefore, compared with the clinical contribution of CYP1A2 and CYP3A4/5 observed when these enzymes are inhibited and induced (as highlighted above), the additional enzymes are likely to be of minor, if any, importance, except in very unlikely scenarios, such as when patients who are poor metabolizers of more than 1 of these enzymes also are concomitantly administered both strong CYP1A2 and CYP3A4/5 inhibitors. Based on the foregoing, and that fluvoxamine is both a strong CYP1A2 and CYP2C19 inhibitor and also a weak inhibitor of CYP2C8, CYP2C9, and CYP3A4/5, the fluvoxamine-tasimelteon drug drug interaction is likely to be one of the most dramatic caused by a single drug, in terms of an increase in exposure to tasimelteon (ie, a 6.5- fold increase in AUC 0 inf ). Even when tasimelteon exposure is increased by this amount, clinical data show that the drug is well tolerated and safe. For instance, the AUC from a 20-mg dose of tasimelteon coadministered with fluvoxamine would be approximately 2800 ng hr/ml (ie, 701 ng hr/ml 4), which is less than the observed mean AUC with 300 mg tasimelteon (ie, AUC, 3230 ng hr/ml), a dose that was well tolerated in clinical studies. 23 When tasimelteon 300 mg was administered (ie, 15 times the clinically used 20-mg dose), the primary treatment-emergent adverse event was sleepiness. Mild constipation and postural hypotension were also reported, but there were no serious adverse events or discontinuations. 23 Additional safety information for the observed increased exposure with fluvoxamine (that is, less than or similar to 300 mg tasimelteon) can be surmised from no potential to affect cardiac repolarization being observed at either 20 or 300 mg tasimelteon in a thorough QT study. 23 In conclusion, these studies show that CYP1A2 and CYP3A4 are clinically the most important CYPs in the metabolism of tasimelteon, consistent with in vitro data. Moreover, the study identifies what are likely 2 of the most dramatic drug drug interactions caused by single drugs in terms of inhibitory and induction-related clinical drug drug interactions with tasimelteon (ie, fluvoxamine and rifampin, respectively). Tasimelteon should not be used in combination with fluvoxamine because of a potentially large increase in tasimelteon exposure and greater risk of adverse reactions. 15 Similarly, use of tasimelteon should be avoided in combination with rifampin or other CYP3A4/5 strong inducers, because there is potential for a large decrease in exposure of tasimelteon, which, in turn, can potentially lead to reduced efficacy. The results presented in this article provide additional context around tasimelteon s labeling recommendations for clinicians seeking to treat Non-24 patients with tasimelteon. Acknowledgments The study team is grateful to the individuals who participated in these studies. The authors thank David Buckley, PhD, for insightful comments on the article. We are also grateful to Callie Heaton, MS, for her work on helping to implement these studies. In addition, the authors would like to acknowledge Synchrony Medical Communications, LLC, West Chester, Pennsylvania, for providing editorial assistance. Funding for this assistance was provided by Vanda Pharmaceuticals, Inc., Washington, DC. Declaration of Conflicting Interests The studies described here were funded by Vanda Pharmaceuticals, Inc., Washington, DC. Dr. Ogilvie is an employee of XenoTech, LLC. Drs. Torres, Dressman, and Baroldi are employees of Vanda Pharmaceuticals, Inc. Dr. Kramer is a paid consultant to Vanda Pharmaceuticals, Inc. References 1. Remler O. [Article in undetermined language.] Klin Monbl Augenheilkd Augenarztl Fortbild. 1948;113: Lewy AJ, Newsome DA. Different types of melatonin circadian secretory rhythms in some blind subjects. J Clin Endocrinol Metab. 1983;56: Sack RL, Lewy AJ, Blood ML, Keith LD, Nakagawa H. Circadian rhythm abnormalities in totally blind people: incidence and clinical significance. 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