Rectal ropivacaine is absorbed proportionally to the dose, with low intraindividual variability

Abstract

Aims This study investigated the absorption characteristics and the tolerability of rectally administered ropivacaine, a local anaesthetic, intended as a new local therapy for ulcerative colitis. Methods Thirty-two healthy volunteers participated in a randomized, placebocontrolled study. In study phase 1 ( n = 16, double-blind, crossover) single rectal doses of ropivacaine corresponding to 50, 100 and 200 mg base were given as 20-ml gel enemas. Eight of these subjects also received an i.v. infusion corresponding to 20 mg ( 2 H 3 )ropivacaine base given with the last rectal dose. In study phase 2 ( n = 16, singleblind, crossover) the same rectal doses were given but formulated in 20, 40 and 80 ml gel, respectively. Peripheral venous plasma samples and urine were collected over 12 h after dosing and analysed for ropivacaine base by gas chromatography and ( 2 H 3 )ropivacaine by gas chromatography-mass spectrometry. Ropivacaine and metabolites were analysed in urine by reversed phase liquid chromatography.Results AUC was proportional to the dose with a point estimate [95% confidence interval (CI)] for the increase, after doubling the dose, of 1.91 (1.66-2.20) and 1.95 (1.78-2.13) in study phases 1 and 2, respectively. The increase in C max was also proportional to the dose with corresponding results of 1.76 (1.52-2.04) and 1.84 (1.70-1.99). The volume of the rectal formulation had no influence on either the extent or the time course of absorption. The mean (s.d.) absolute bioavailability (% F ) was 56 (18)%. AUC and C max showed a two-to three-fold lower intra-than interindividual variability. Zero-order kinetics dominated the first 4 h of the absorption phase. Thereafter first-order kinetics were observed. The terminal half-lives were similar between the rectal doses and were longer than that after the i.v. administration, indicating an absorption-dependent half-life. The main urinary metabolite was 3-hydroxyropivacaine corresponding to about 23% of the dose. The subjects had no difficulties in retaining the doses and rectal administration of ropivacaine was well tolerated, both locally and systemically. Conclusions Plasma drug concentrations were proportional to the dose after rectally administered doses corresponding to 50-200 mg ropivacaine base in a gel formulation. The drug was well-tolerated. Mean bioavailability was about 60% and not influenced by variations in the enema volume. Initial absorption seemed to follow zero-order kinetics and then first-order kinetics after about 4 h. C max and AUC showed considerably less intra-compared with inter-individual variability, resulting in more consistent plasma concentrations within subjects.

Within‐ and between‐ subject variability in methadone pharmacokinetics and pharmacodynamics in methadone maintenance subjects

“…Intuitively one might predict that the between‐individual variability in drug disposition is greater than the within‐individual variability. Examples include: alcohol [42], gabapentin [43], talinolol [44], ropivacaine [45], hydroxychloroquine [46] and etoposide [47]. It is noteworthy that there are no common features determining the disposition mechanisms for these examples.…”

No volume effect on retrograde colonic spread of rectally‐administered ropivacaine gel

“…We did not find a strong relationship between the extent of spread and the plasma concentration of ropivacaine, but rather an individual variability in absorption independent of volume and spread. A previous pharmacokinetic study with rectally administered ropivacaine in the same gel formulation showed dose proportionality with low intra‐individual variability for doses of 60, 120 and 240 mg ropivacaine in gel volumes of 20, 40 and 80 mL, respectively 24 . Thus, this study agrees with our present finding that there are no or only minor differences in plasma concentrations between volumes of 20 and 80 mL with the present formulation, a finding that seems to be in agreement with the conclusion that there are no or only minor differences in the colonic spread of the studied volumes.…”

Exploring Anorectal Manometry as a Method to Study the Effect of Locally Administered Ropivacaine in Patients with Ulcerative Colitis

“…A long-acting local anaesthetic, ropivacaine, has been explored as a potential therapy for UC [12]. An open clinical study of patients with active distal CU treated with 200 mg rectal ropivacaine gel twice daily indicated a prompt symptomatic relief including a decrease in the number of stools and tenesmi [13].…”