Inhaled Medicines: Past, Present, and Future.

The purpose of this review is to summarize essential pharmacological, pharmaceutical, and clinical aspects in the field of orally inhaled therapies that may help scientists seeking to develop new products. After general comments on the rationale for inhaled therapies for respiratory disease, the focus is on products approved approximately over the last half a century. The organization of these sections reflects the key pharmacological categories. Products for asthma and chronic obstructive pulmonary disease include ß -2 receptor agonists, muscarinic acetylcholine receptor antagonists, glucocorticosteroids, and cromones as well as their combinations. The antiviral and antibacterial inhaled products to treat respiratory tract infections are then presented. Two "mucoactive" products-dornase α and mannitol, which are both approved for patients with cystic fibrosis-are reviewed. These are followed by sections on inhaled prostacyclins for pulmonary arterial hypertension and the challenging field of aerosol surfactant inhalation delivery, especially for prematurely born infants on ventilation support. The approved products for systemic delivery via the lungs for diseases of the central nervous system and insulin for diabetes are also discussed. New technologies for drug delivery by inhalation are analyzed, with the emphasis on those that would likely yield significant improvements over the technologies in current use or would expand the range of drugs and diseases treatable by this route of administration. SIGNIFICANCE STATEMENT: This review of the key aspects of approved orally inhaled drug products for a variety of respiratory diseases and for systemic administration should be helpful in making judicious decisions about the development of new or improved inhaled drugs. These aspects include the choices of the active ingredients, formulations, delivery systems suitable for the target patient populations, and, to some extent, meaningful safety and efficacy endpoints in clinical trials.

Clinical Bioequivalence of OT329 SOLIS and ADVAIR DISKUS in Adults with Asthma.

RATIONALE: OT329 SOLIS is a generic candidate for the branded asthma treatment, ADVAIR DISKUS (fluticasone propionate/salmeterol xinafoate), and, as such, the manufacturer is required to provide evidence of clinical "bioequivalence" as a condition for regulatory approval. OBJECTIVES: The objective of the current study was to determine if SOLIS and DISKUS provided bioequivalent improvements in lung function at two time points: Day 1 and Week 4. METHODS: This study was a randomized, multiple-dose, placebo-controlled, parallel-group design conducted in the United States (NCT02260492) with a 2-week run-in followed by a 4-week treatment period. Consenting patients were randomized to treatment with OT329 SOLIS 100/50, ADVAIR DISKUS 100/50, or placebo. Lung function was measured predose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours after the first dose to test equivalence of the ß-agonist salmeterol component based on FEV1 area under the curve (0-12 h). After 4 weeks of twice-daily dosing, trough (predose) FEV1 was measured to evaluate equivalence of the fluticasone propionate corticosteroid component. Bioequivalence was concluded if the 90% confidence interval (CI) for the ratio of the products fell within 80-125%. MEASUREMENTS AND MAIN RESULTS: Of the 1,524 screened, 879 patients with asthma were randomized to treatment (n = 418 SOLIS, 419 DISKUS, 42 placebo). OT329 SOLIS and ADVAIR DISKUS were bioequivalent at Day 1, with an FEV1 area under the curve (0-12 h) test/reference ratio of 108% (90% CI = 94-122%). Likewise, the products were bioequivalent at Week 4 with a trough FEV1 test/reference ratio of 105% (90% CI = 90-119). Both active treatments were superior to placebo (P < 0.05) at both time points. CONCLUSIONS: The data support a conclusion of clinical bioequivalence of OT329 SOLIS to ADVAIR DISKUS. Clinical trial registered with www.clinicaltrials.gov (NCT02260492).

Potential trends in Attention Deficit Hyperactivity Disorder (ADHD) drug use on a college campus: wastewater analysis of amphetamine and ritalinic acid.

Attention Deficit Hyperactivity Disorder (ADHD) medication use is on the rise in the United States. The most widely used ADHD medications are the amphetamine-type compounds Adderall (mixed amphetamine salts) and Ritalin (methylphenidate). According to survey data ADHD medications are used as a study drug or "Smart Drug" by students without a prescription on college campuses. Survey data of non-prescribed drug use has limitations with accurate reporting and no empirical data of usage exists in the literature. This study looks for trends in the use of these drugs on a college campus among low-stress and high stress periods. The metabolites of these two drugs, amphetamine and ritalinic acid, are quantified in campus wastewater using solid phase extraction (SPE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Trends show a possible increase in amphetamine levels during periods of high stress such as midterms, the last week of classes and finals week over levels from the baseline low stress weeks such as the first week of classes. Both semesters from the 2011-12 academic year were studied and the highest increase over baseline (760%) occurred during finals week of the second semester. Ritalinic acid levels gradually climbed first semester but had no obvious periodic trend second semester.

Human pharmacokinetics/pharmacodynamics of an interleukin-4 and interleukin-13 dual antagonist in asthma.

Pitrakinra, a 15-kDa recombinant human interleukin-4 mutein, targets allergic Th2 inflammation by competitively binding to interleukin-4 receptor alpha to interfere with interleukin-4 and interleukin-13 action. The authors characterized pitrakinra pharmacokinetics using data from 96 atopic patients, then compared pharmacokinetics with pharmacological response in asthma following subcutaneous versus inhalation dosing. A 1-compartment systemic model with site-specific absorption describes pitrakinra pharmacokinetics following subcutaneous, nebulization, and inhalation powder delivery. Typical CL/F and V/F, referenced to subcutaneous administration, are 15.5 L/h and 67.5 L, yielding a 3.0-hour half-life of plasma decline. Absorption into the blood (half-life

Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies.

BACKGROUND: Increases in T helper (Th) 2 cytokine concentrations have been seen in atopic asthma, with interleukin 4 and interleukin 13 thought to have a role in the physiological response to allergen challenge. Our aim was to assess the therapeutic effect of pitrakinra, an interleukin-4 variant that targets allergic Th2 inflammation by potently inhibiting the binding of interleukin 4 and interleukin 13 to interleukin-4Ralpha receptor complexes. METHODS: In two independent randomised, double-blind, placebo-controlled, parallel group phase 2a clinical trials, patients with atopic asthma were treated with pitrakinra or placebo via two routes. In study 1, patients were randomly assigned to receive either 25 mg pitrakinra (n=12) or placebo (n=12) by subcutaneous injection once daily. In study 2, patients were randomly assigned to receive either 60 mg pitrakinra (n=16) or placebo (n=16) by nebulisation twice daily. Inhaled allergen challenge was done before and after 4 weeks of treatment. The primary endpoint for study 1 was maximum percentage decrease in forced expiratory volume in 1 s (FEV1) over 4-10 h after allergen challenge, whereas that in study 2 was average percentage decrease in FEV(1) over 4-10 h after allergen challenge. All patients except those with baseline data only were included in our analyses. These trials are registered with ClinicalTrials.gov, numbers NCT00535028 and NCT00535031. FINDINGS: No patients dropped out or were lost to follow-up in study 1; in study 2, two patients in the placebo group and one in the pitrakinra group dropped out or were lost to follow-up. These individuals had baseline data only, and were excluded from the analyses. In study 1, there was a 17.1% maximum percentage decrease in FEV1 in the pitrakinra group; by contrast, the maximum decrease was 23.1% in the placebo group (difference 6%, 95% CI -4.37 to 16.32; p=0.243). In study 2, there was a 4.4% average percentage decrease in FEV1 in the pitrakinra group; by contrast, the average percentage decrease was 15.9% in the placebo group (3.7 [95% CI 2.08-6.25] times lower in the pitrakinra group; p=0.0001). There were fewer asthma-related adverse events (p=0.069) and fewer adverse events requiring beta-agonist rescue (p=0.031) after subcutaneous administration of pitrakinra than with placebo. There were too few asthma-related adverse events in study 2 to assess the effect of inhalation of pitrakinra on adverse events. INTERPRETATION: Local treatment, targeted at inhibition of interleukins 4 and 13 in the lung, could substantially diminish the symptoms of asthma.