Exploratory clinical development of ropivacaine, a local anaesthetic, in ulcerative colitis

Abstract: The aims of this thesis were to explore the clinical pharmacology of ropivacaine gel as a potential new rectal therapy for ulcerative colitis (UC). The studies included pharmacokinetics, tolerability, preliminary efficacy in patients, formulation factors and drug-drug interactions. These results paved the way for the start of a larger scale dose finding study in patients. UC is an idiopathic inflammation involving part of or the entire colon, and characterised by early onset and often a chronic intermittent or continuous course. UC is described as the result of a disturbed intestinal immune response. Ropivacaine is a long-acting local anaesthetic of the amidetype, and pre-clinical investigations in vitro and in vivo show that ropivacaine has an antiinflammatory activity, which, in addition to the local anaesthetic activity, makes the compound interesting as a treatment of UC. The single dose pharmacokinetics of rectally administered ropivacaine were characterised by dose proportionality. The mean bioavailability was 60% with a range from 30% to 70%, as determined after simultaneous administration of rectal ropivacaine and intravenous (iv) deuteriumlabelled drug. The metabolic pattern was similar after single dose iv and single dose rectal administration in healthy subjects and patients. However, after multiple dose rectal administration the levels of the active metabolite 2,6-pipecoloxylidide (PPX) increased during the first days due to the long half-life causing a longer time to steady state. The levels of unbound ropivacaine concentrations remained stable during multiple dose administration in patients with UC whereas the total concentrations fluctuated in parallel with the alpha-1 -acid glycoprotein levels. These findings illustrate the importance of monitoring concentrations of metabolites and unbound concentrations of drug, especially if the therapeutic window is narrow. Ropivacaine was absorbed to a higher extent from colon in patients with UC in comparison to healthy subjects, a finding that could be related to the characteristics of the inflamed mucosa. The local and systemic tolerability of ropivacaine was good. The first open study in patients with distal UC showed promising results. Mucosal inflammation assessed endoscopically at the most severely affected site decreased after two weeks of treatment. There was also a trend towards histological improvement. Clinical symptoms, including total number of stools, blood in stools, diarrhoea and tenesmus decreased after only a few days treatment. These results resembled those in the second patient study when a prompt decrease in inflammation and symptoms was also recorded in some patients. The main objective of this second patient study was to evaluate anorectal manometry recordings of rectal sensitivity and reactivity as a biomarker for the pharmacological effect of rectal ropivacaine treatment in UC. The clinical effects did not parallel the manometric findings, which may be explained by different kinetics of rectal sensitivity and mucosal inflammation. Fluvoxamine (a CYP1A2 inhibitor), but not ketoconazole (a CYP3A4 inhibitor), significantly affected the clearance of ropivacaine after single iv administration. This study confirms the in vitro findings indicating CYP1A2 as the most important enzyme in ropivacaine metabolism. Consequently, CYP1A2 inhibitors may cause clinically relevant interactions with ropivacaine. The colonic spread of 20 ml to 80 ml rectal ropivacaine gel was studied to guide the eligibility of patients for the clinical studies in later phases of development. To achieve a local effect it is believed that the formulation should spread over the inflamed part of colon. The spread of ropivacaine gel was limited to the descending colon and there was no or minor differences between the studied volumes. The limited spread could be related to the higher viscosity of the present formulation in comparison to commercially available formulations for treatment of UC. These studies represent an example of the early phase in the development of a previously registered drug on a new indication. This is an important pathway of drug development, of interest both for the patient and the pharmaceutical industry.