PROBLEMÁTICA QUE ENFRENTAN EN LA ACTUALIDAD

Cisapride (prior to its withdrawal) and domperidone are both widely accepted for treatment of GORD. Because the pharmacological mechanisms of action of the two compounds differ, their therapeutic activity profiles are bound to be different. Another common pro-kinetic treatment for GORD is metoclopramide but it is not very commonly used in younger children.

4.2.3.1 Introduction to cisapride and domperidone

Cisapride is a HT4-agonist. It stimulates the motility of smooth muscle lining in the oesophagus, stomach, small intestine and colon, therefore reduces colonic transit time.

Cisapride was well tolerated, with adverse effects limited to gastrointestinal tract (Barone, 1994). ESPGAN recommended cisapride as the first line medicine for GORD in children (Vandenplas, 1993). Compared to domperidone, cisapride was found to be more effective in treating GORD with no major or unexpected adverse events (Halter, 1997). Although cisapride was regarded as a safe and effective drug, fatal cardiac arrhythmias and sudden deaths had driven its withdrawal in July 2000 by the Medicines Control Agency (MCA).

Until the end of 2003, cisapride should only be considered after very careful considerations of all known risks and benefits where the child condition would be at a greater threat to life if cisapride were not given than the potential of cardiac sudden death if it were given (RCPCH,

Chapter 4 | 113 2003). Substantial publication bias was reported in a systematic review of the efficacy of cisapride in favour of the studies showing positive effect of cisapride as shown by funnel plot asymmetry; but no evidence of cisapride efficacy was found (Augood, 2003). The evidence of publication bias was also supported by a report of a large unpublished multi-centre trial of children randomised to cisapride and placebo ‘because efficacy results did not reach statistical significance (possibly because inclusion criteria were too broadly defined)’

(Augood, 2003; Levy, 2001).

Domperidone is a peripheral dopamine D2-antagonist with anti-emetic properties. It affects the motility of the upper gastrointestinal tract and effectively improves GORD symptoms.

Some studies (Agorastos, 1981; De Loore, 1979; Haarmann, 1979; Van Outryve, 1979) showed that domperidone has been superior to metoclopramide in treating GORD. In a systematic review of four randomised controlled trials of domperidone use in children one month old to 11 years old with GORD, no robust evidence of efficacy was found in younger children but no adverse reactions were noted. Only the two older trials (Clara, 1979; De Loore, 1979) showed any benefits of domperidone in older children (Pritchard, 2005).

4.2.3.2 Drug dosage bioequivalence

There were oral and rectal formulations of domperidone and cisapride available during our observation period. Because there is a substantial difference between dosage recommended for rectal and oral administration, we rescale the rectal dose to be equivalent to the oral dose.

This is to avoid averaging across different dose “units” as coded on GPRD database.

Domperidone

Different doses for oral vs. rectal formulations were recommended by domperidone manufacturers although they have similar bioavailability. This is because there are other pharmacokinetic differences between oral and rectal formulations which were taken into considerations when choosing dosing. Suppositories (rectal formulations) give a lower peak level, and the level plateaus for longer which mean a higher dose is given but there can be a longer dosing interval.

Chapter 4 | 114 The summary of product characteristics (SPC) for Motilium® 30mg suppositories indicates the pharmacokinetics as:

“After rectal administration of 60mg domperidone suppositories, a plateau is attained with domperidone plasma concentrations of about 20ng/ml lasting from 1 to 5 hours after administration. Although peak plasma levels are only about one third of that of an oral dose, the mean rectal bioavailability of 12.4% is quite similar to that after oral administration.” (eMC, 2010)

Following this, we rescaled rectal doses to a third of that prescribed which gives an equivalent dosing to that of oral doses.

Cisapride

Bioavailability of oral cisapride ranges from 35% to 65%, where it is approximately 50%

under fasting conditions and 65% when taken with a meal. The peak plasma levels (Cmax) are achieved after approximately 1-2 hours.

Bioavailability of rectal cisapride is 40%, but there are other differences in pharmacokinetics which were taken into considerations. Rectal absorption of a 30mg suppository, which also contained hydroxypropyl-beta-cyclodextrine 12%, was slightly slower than after oral administration with a t_max of 3 hours. However, C_max values approximated those seen after an oral 10mg dose administered after fasting. Based on the values of AUC (0-∞), the bioavailability of the rectally administered form was 50% relative to the oral form (McCallum, 1988).

4.2.3.3 Licensing of cisapride and domperidone

Cisapride was licensed in the UK for the treatment of GORD people over 12 years old in 1998. It was never licensed for use in children under 12 years old (RCPCH, 1999).

Domperidone is licensed for use in children but restricted to nausea and vomiting following cytotoxics or radiotherapy, with an indication for use in GORD and gastric stasis (Paediatric Formulary Committee, 2008).

Chapter 4 | 115 4.3 Conclusion

This chapter presented the epidemiology of GOR in children. The often benign nature of the disease can sometimes get worse. In pursuit of the treatment following failure of conservative (lifestyle and non-drug) therapy, pro-kinetics such as cisapride and domperidone were used.

The prescribing of these drugs in children for the treatment of GORD is unlicensed however common it becomes, and the efficacy and safety have been questioned. It is also unknown how long or how many conservative therapies have been tried until they are considered

“failed” before starting a child on pro-kinetics therapy. This might have changed over the years and may also be an important aspect to study but I will not pursue this further in this thesis.

Many different analyses could be carried out to establish the risks and benefits of the drug use. But without good data, any results obtained from such data would be under scrutiny. Past clinical trials on these drugs in children have many problems; and one of them is inconsistency of reporting. Chapter 5 reviews clinical trials of cisapride and domperidone in a non-quantitative manner to appraise the design, conduct and reporting of trials. This reinforces the need for risk-benefit assessment using alternative evidence to justify off-label drug prescribing.

Chapter 4 | 116

Chapter 5 | 117 5. Narrative review on clinical trials of cisapride and domperidone

5.1 Introduction

A narrative¹² review of the inconsistency of evidence reporting from clinical trials of cisapride and domperidone in children is presented here. I summarise and discuss the planning of safety data collection and how they are reported in each trial. This chapter does not appraise the planning and reporting on benefits because they are usually well defined, and not very critical here. They are reviewed in Chapter 7 as part of the quantitative evidence of risks and benefits.

Extensive systematic reviews of the treatment of gastro-oesophageal reflux using cisapride and domperidone in children have already been conducted (Augood, 2003; Pritchard, 2005).

Therefore this chapter simply builds on these systematic reviews.