E single entity products DISCUSSION These PK studies were part of the clinical development program of M , a novel AZE and FP containing nasal spray product. Neither study showed any evidence of pharmacokinetic-based drug-drug interactions between the activeponents. The very low systemic FP bioavailability from nasal FP spray was attributed to poor aqueous solubility and high first-pass metabolism of the swallowed fraction of dose . Previous bioavailability studies of FP nasal spray products were  fesoterodine hampered by limitations in bioanalytical assay sensitivi which required repeated administrations of supra-therapeutic doses . Administration with high doses of up to μg required larger dose volumes that could exceed amounts readily retained by the nasal mucosa and escape nasal absorption .

Therefo these historical studies with large doses may not accurately reflect the true nasal deposition and absorption that would be associated with the use of therapeutic doses. For the quantification of we employed a highly sensitive LC-MS-MS with a LLOQ of pg/ml that was approximately 0-fold more sensitive than bioanalytical assays used previously . Hen  MK-4827 the studies could be conducted with doses reflecting the approved maximum single doses for AZE and FP and at the same time the intended maximum daily dose of M . The assay was sensitive to quantify systemic FP concentrations through 4 hours in all but one study subjects and the sensitivity met current bioequivalence guideline requirements . Interesting the FP serum concentration time profiles displayed discrete double-peak phenomen possibly reflecting a biphasic nature of nasal FP absorption from the suspensio . a rapid absorption of the fraction of dose dissolved in the formulation and more sustained absorption from slowly dissolving suspended particles.

Plasma AZE profiles from the three treatments were nearly identical and the calculated  naratriptan 121679-13-8 primary PK-parameters confirm that all products display similar in vivo performance in terms of AZE bioavailability . Results indicate that the FPponent in M does not affect the rate or extent of AZE absorption and does not appear to alter the subsequent in vivo disposition of AZE. In additi the data confirm that the excipients included in the M formulation do not impair AZE bioavailabilitypared to the marketed Astelin nasal spray formulation. Taken togeth neither formulation effects nor the presence of FP changed the overall AZE bioavailability and systemic exposure from M aspared to the marketed product . Serum FP profiles following M and the M-based FP single entity products confirm that both products displayparable in vivo performanc indicating negligible effect of AZE on FP bioavailability and disposition in M based formulations. Howev both M  buy Ofloxacin based formulations showed a higher peak and total exposurepared to the FP marketedparator product . Howev it should be noted that the systemic exposure of FP with M nasal spray is still very low with mean peak concentrations of only pg/ml or less.

Estimates of absolute bioavailability based on an early intravenous FP study with a μg intravenous dose are consistent with low systemic FP bioavailabilities from the nasal  bacteria spray products of only for M and for FP-BI. It is unlikely that the difference in FP systemic exposure.