Randomised clinical trial: study of escalating doses of NRL001 given in rectal suppositories of different weights.
OBJECTIVE
The application of α-adrenoceptor agonists can improve faecal incontinence symptoms. The aim of this study was to investigate the pharmacokinetic and systemic effects of NRL001 administered as different strengths in 1 or 2 g suppositories.


METHODS
This randomised, double-blind, placebo controlled study included 48 healthy subjects. Group 1 consisted of two cohorts of 12 subjects administered either four single doses of 1 or 2 g rectal suppository with either 5, 7.5 or 10 mg NRL001, or matching placebo. Group 2 consisted of two cohorts of 12 subjects administered either four single doses of 1 or 2 g rectal suppository with either 10, 12.5 or 15 mg NRL001, or matching placebo. Doses were given in an escalating manner with placebo at a random position within the sequence.


RESULTS
Tmax was at ~4.5 h post-dose for all NRL001 doses. Median AUC0-tz , AUC0-∞ and Cmax increased with increasing dose for both suppository sizes. The estimate of ratios of geometric means comparing 2 g with 1 g suppository, and regression analysis for dose proportionality, was close to 1 for the variables AUC0-tz , AUC0-∞ and Cmax (P > 0.05). For both suppository sizes, 20-min mean pulse rate was significantly decreased compared with placebo with all doses (P < 0.05). Blood pressure decreased overall. There were 144 adverse events (AEs) and no serious AEs reported during the study. All AEs were mild in severity.


CONCLUSIONS
The regression analysis concluded that the doses were dose proportional.
Bio-Kinetic Europe Limited, Belfast, UK.
D
D
Bell
C
C
Pediconi
A
A
Jacobs
D000293:Adolescent; D058646:Adrenergic alpha-1 Receptor Agonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D000328:Adult; D004311:Double-Blind Method; D005242:Fecal Incontinence / Q000188:drug therapy; D005260:Female; D006801:Humans; D008297:Male; D008729:Methoxamine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D008875:Middle Aged; D013488:Suppositories / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology
D058646:Adrenergic alpha-1 Receptor Agonists; D013488:Suppositories; D008729:Methoxamine
Faecal incontinence; adrenergic alpha-agonists; methoxamine hydrochloride; rectal suppositories