PMID- 33368026 OWN - NLM STAT- MEDLINE DCOM- 20210322 LR - 20220531 IS - 1179-1918 (Electronic) IS - 1173-2563 (Print) IS - 1173-2563 (Linking) VI - 41 IP - 2 DP - 2021 Feb TI - Pharmacokinetics of Coadministered Viloxazine Extended-Release (SPN-812) and Methylphenidate in Healthy Adults. PG - 149-159 LID - 10.1007/s40261-020-00992-6 [doi] AB - 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(infinity)) = 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(infinity) = 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. FAU - Faison, Shamia L AU - Faison SL AD - Supernus Pharmaceuticals, Inc., 9715 Key West Avenue, Rockville, MD, 20850, USA. FAU - Fry, Nicholas AU - Fry N AD - Supernus Pharmaceuticals, Inc., 9715 Key West Avenue, Rockville, MD, 20850, USA. FAU - Adewole, Toyin AU - Adewole T AD - Supernus Pharmaceuticals, Inc., 9715 Key West Avenue, Rockville, MD, 20850, USA. FAU - Odebo, Oyinkansola AU - Odebo O AD - Supernus Pharmaceuticals, Inc., 9715 Key West Avenue, Rockville, MD, 20850, USA. FAU - Schwabe, Stefan AU - Schwabe S AD - Supernus Pharmaceuticals, Inc., 9715 Key West Avenue, Rockville, MD, 20850, USA. FAU - Wang, Zhao AU - Wang Z AD - Supernus Pharmaceuticals, Inc., 9715 Key West Avenue, Rockville, MD, 20850, USA. FAU - Maletic, Vladimir AU - Maletic V AD - Department of Psychiatry/Behavioral Science, University of South Carolina School of Medicine, Greenville, SC, USA. FAU - Nasser, Azmi AU - Nasser A AD - Supernus Pharmaceuticals, Inc., 9715 Key West Avenue, Rockville, MD, 20850, USA. anasser@supernus.com. LA - eng PT - Journal Article PT - Randomized Controlled Trial DEP - 20201223 PL - New Zealand TA - Clin Drug Investig JT - Clinical drug investigation JID - 9504817 RN - 0 (Central Nervous System Stimulants) RN - 0 (Delayed-Action Preparations) RN - 0 (Norepinephrine Plasma Membrane Transport Proteins) RN - 0 (SLC6A2 protein, human) RN - 207ZZ9QZ49 (Methylphenidate) RN - 5I5Y2789ZF (Viloxazine) SB - IM MH - Administration, Oral MH - Adult MH - Attention Deficit Disorder with Hyperactivity/drug therapy MH - Central Nervous System Stimulants/*administration & dosage MH - Cross-Over Studies MH - Delayed-Action Preparations MH - Female MH - Humans MH - Male MH - Methylphenidate/*administration & dosage/pharmacokinetics MH - Middle Aged MH - Norepinephrine Plasma Membrane Transport Proteins/metabolism MH - Viloxazine/*administration & dosage/pharmacokinetics MH - Young Adult PMC - PMC7886742 COIS- Nicholas Fry, Toyin Adewole, Oyinkansola Odebo, Stefan Schwabe, Zhao Wang, Azmi Nasser are employees of Supernus Pharmaceuticals, Inc. Shamia L. Faison was an employee of Supernus Pharmaceuticals, Inc. at the time of this work, but is now an employee of Certara Strategic Consulting. Vladimir Maletic is an employee of the University of South Carolina School of Medicine, and is a consultant for ACADIA Pharmaceuticals Inc.; Alfasigma USA, Inc.; Alkermes, Inc.; Allergan; Eisai-Purdue; Intra-Cellular Therapies; Janssen; H. Lundbeck A/S; Otsuka America Pharmaceutical, Inc.; Sage Pharmaceuticals; Sunovion Pharmaceuticals Inc.; Supernus Pharmaceuticals, Inc.; and Takeda Pharmaceutical Company Ltd. He also serves on the speakers bureau of ACADIA Pharmaceuticals Inc.; Alkermes, Inc.; Allergan; Ironshore; Intra-Cellular Therapies; Janssen; H. Lundbeck A/S; Otsuka America Pharmaceutical, Inc.; Sunovion Pharmaceuticals Inc.; and Takeda Pharmaceutical Company Ltd; and his spouse serves on the speakers bureau of Otsuka America Pharmaceutical, Inc. EDAT- 2020/12/29 06:00 MHDA- 2021/03/23 06:00 PMCR- 2020/12/23 CRDT- 2020/12/28 12:21 PHST- 2020/11/28 00:00 [accepted] PHST- 2020/12/29 06:00 [pubmed] PHST- 2021/03/23 06:00 [medline] PHST- 2020/12/28 12:21 [entrez] PHST- 2020/12/23 00:00 [pmc-release] AID - 10.1007/s40261-020-00992-6 [pii] AID - 992 [pii] AID - 10.1007/s40261-020-00992-6 [doi] PST - ppublish SO - Clin Drug Investig. 2021 Feb;41(2):149-159. doi: 10.1007/s40261-020-00992-6. Epub 2020 Dec 23.