The rofecoxib (Vioxx) story - an interesting case study

The selective COX-2 inhibitor rofecoxib, marketed as Vioxx, tells an interesting story. You can read more about it here at Wikipedia.

Rofecoxib was an initially successful drug that had been used as an anti-inflammatory analgesic for the management of inflammatory joint disease, acute pain and dysmenorrhoea since 1999. The selective inhibition of COX-2 meant that rofecoxib could be used effectively as an anti-inflammatory analgesic but with minimal side effects on the gastric mucosae.

In 2001, rofecoxib was proposed to be used in the prevention of adenomatous polyps in the colon. The 3-year (APPROVe) trial to investigate the prophylactic role of rofecoxib for colorectal polyps was terminated prematurely because rofecoxib was observed to be associated with increased relative risk of thrombotic cardiovascular events beginning after 18 months of treatment. Data in the first 18 months did not reveal any increased risk. In 2004, Merck voluntarily withdrew rofecoxib from the market following the report of this increased risk.

The clinical use of rofecoxib is not without variability issues with respect to its pharmacokinetics. Although it is not substantially metabolized by CYP450 enzymes, it was nevertheless glucuronidated by UGT2B7 and UGT2B15, both of which are genetically polymorphic. It is not clear to what extent these genetic variants are associated with variability in clinical response to rofecoxib.

Although variability in clinical response to NSAIDs are well known, there has not been a major concern about genetic polymorphisms affecting NSAID pharmacokinetics. This has been, I believe, largely related to the the dependence in clinical practice to adjusting dosages and drug choices to the anti-inflammatory clinical drug response. And there is currently a plethora of 'clinical joint scores' that can allow the rheumatologist to adjust for response variability. The toxicities with NSAIDs have also been largely manageable, and with the COX-2 inhibitors, GI toxicity was not perceived to be a significant problem.

The recognition that rofecoxib was associated with cardiovascular toxicity changed all that.

It is interesting that as the use of rofecoxib moved from rheumatology to polyp prevention, the clinical use of rofecoxib also lost its ability to manage any response variability. Rofecoxib use in preventing colorectal polyps was largely based on prophylactic fixed dose regiments. There was an assumption that this was relatively acceptable because rofecoxib was relatively safe.

But this was apparently not so. There was an association with cardiovascular toxicity. Eventually it was the cardiovascular risk that did rofecoxib in, and caused it to be withdrawn. It is not clear to what extent this was due to pharmacokinetic variability. Or individual susceptibilities at the vascular level, but the practical reality was the clinical use of rofecoxib for colorectal polyp prevention did not allow the clinician any means to adjust dosages for any kind of PK or PD variability. Essentially people were flying blind.

It is probably acceptable to fly blind with a drug that had a very high therapeutic index, but not when there is a risk of cardiovascular death for the drug that was being used in a prophylactic setting.