A randomized, double-blind, placebo-controlled study of breath powered nasal delivery of sumatriptan powder (AVP-825) in the treatment of acute migraine (The TARGET Study)

摘要: Triptans are first-line treatments for moderate-to-severe migraine headaches, and sumatriptan (a 5-HT1B/1D receptor agonist) is the most commonly prescribed drug in this class.1 The efficacy safety profiles of various routes delivery, including subcutaneous, intranasal, transdermal, oral, rectal, have been extensively characterized clinical trials, multiple formulations widespread use.1 Although oral administration common route used triptans, variability gastric emptying during resulting delay absorption may contribute to inconsistent effectiveness, delayed onset reduced magnitude relief.2 In an effort overcome limitations delivery while maintaining a similar level convenience, intranasal (in form nasal sprays) aims at improving speed consistency avoiding issues associated with self-administering injection (eg, pain aversion).3–5 Currently available employ standard single-dose nasal-spray pumps that characteristically deposit substantial fraction liquid dose along floor cavity, proximal valve.6,7 A portion delivered through sprays either drips out nose wiped away, or accumulates sniffed toward pharynx swallowed.8 Active sniffing actuation further narrows slit-like valve results additional being sucked cavity oropharynx swallowed. swallowed then subject same challenges variable intestinal delivery. This “dual route” from shown pharmacokinetic (PK) studies sumatriptan.9–12 small peak plasma concentration observed ∼20 minutes post-dose (nasal absorption), followed by ∼90 (intestinal absorption). AVP-825 (formerly “OptiNose Sumatriptan”) investigational drug–device combination containing powder developed Avanir Pharmaceuticals, Inc., acute treatment without aura. It employs novel closed-palate, Breath Powered drug-delivery system (OptiNose US, Yardley, PA, USA) designed take advantage specific features anatomy physiology order deficiencies conventional sprays. Closure soft palate opening AVP-825 allows targeted deposition deep into throughout helping avoid lungs.12,13 device includes mouthpiece exhalation, connected body, nosepiece, seal improve extent reproducibility dosing.7,11,14 Exhalation causes air flow resistance positive pressure naturally elevates palate, separating cavities. shaped, sealing nosepiece redirects exhaled creating obstructive compression tissues, balance across gently expand narrow, passages, valve. Under balanced pressure, pathway located behind septum remains open between two nostrils. With these dynamic circumstances, powdered particles emitted airflow enter via one nostril deposited deeply before delivering exits other (Bi-Directional delivery).6,7 Drug humans using radiolabeled lactose demonstrated significantly greater deeper regions beyond valve, compared spray-pump (Fig. 1).6,7 Greater initial more superior posterior following consistent decreased anterior drip-out less drug.6,10 Fig 1 Gamma camera image 2 after solution 99mTcO4 saline spray (A) 99mTc-labeled (B). ... The advantages method phase 1 bioavailability crossover study 20 healthy participants where (delivered 16 mg) produced earlier higher systemic exposure within first 30 than 20 mg sumatriptan) lower Imitrex (100 mg) subcutaneous (6 mg) (Imitrex Nasal Spray Tablet, GlaxoSmithKline, Research Triangle Park, NC, USA).10,12 benefits were placebo-controlled 117 patients migraine, high sustained relief, relief migraine-associated symptoms, no reported triptan-related adverse events (AEs).13 Taken together, randomized comparative PK showed address unmet needs sufferers efficiently low which provide fast potential AEs. This 3 (the TARGET study, NCT01462812) was data larger patient cohort comparing placebo-containing (placebo device) adults headache