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A double‐blind, placebo‐controlled, randomised, parallel‐group, dose‐escalating, repeat dose study in healthy volunteers to evaluate the safety, tolerability, pharmacodynamic effects and pharmacokinetics of the once daily rectal application of NRL 001 suppositories for 14 days
Author(s) -
Bell D.,
Duffin A.,
Jacobs A.,
Pediconi C.,
Gruss H. J.
Publication year - 2014
Publication title -
colorectal disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.029
H-Index - 89
eISSN - 1463-1318
pISSN - 1462-8910
DOI - 10.1111/codi.12544
Subject(s) - medicine , tolerability , placebo , pharmacokinetics , adverse effect , pharmacodynamics , dosing , vital signs , anesthesia , population , heart rate , dose ranging study , blood pressure , double blind , alternative medicine , environmental health , pathology
Aims The 1R,2S stereoisomer of methoxamine hydrochloride, NRL 001, is a highly selective α1‐adrenoceptor agonist being developed for the local treatment of non‐structural faecal incontinence caused by weak internal anal sphincter tone. This study investigated the steady state pharmacokinetics ( PK ) and safety of 2 g rectal suppositories containing NRL 001 in different strengths (7.5, 10, 12.5 or 15 mg). Methods Healthy volunteers aged 18–45 years received 14 daily doses of NRL 001 2 g suppositories or matching placebo. In each dose group nine participants received NRL 001 and three received placebo. Blood samples to determine NRL 001 concentrations were taken on Days 1, 7 and 14. Cardiovascular parameters were collected via electrocardiograms, Holter monitoring (three lead Holter monitor) and vital signs. Results Forty‐eight volunteers were enrolled; 43 completed the study and were included in the PK analysis population. AUC and C max broadly increased with increasing dose, T max generally occurred between 4.0 and 5.0 h. Although the data did not appear strongly dose proportional, dose proportionality analysis did not provide evidence against dose proportionality as the log(dose) coefficients were not significantly < 1. NRL 001 did not accumulate over time for any dose. Increasing NRL 001 concentrations were related to changes in vital sign variables, most notably decreased heart rate. The most commonly reported adverse events ( AE s) in the active treatment groups were paraesthesia and piloerection. Conclusions Treatment with NRL 001 was generally well tolerated over 14 days once daily dosing and plasma NRL 001 did not accumulate over time. Treatment was associated with changes in vital sign variables, most notably decreased heart rate. AE s commonly reported with NRL 001 treatment were events indicative of a systemic α‐adrenergic effect.