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But then, in 1986, while designing an ad for a new allergy medication called Seldane, Davis hit on a way around the fine print. He checked with the Food and Drug Administration to see if it would be OK."We didn't give the drug's name, Seldane," he says. "All we said was: 'Your doctor now has treatment which won't make you drowsy. See your doctor.' "
This was one of the very first national direct-to-consumer television ad campaigns. The results were nothing short of astounding. Before the ads, Davis says, Seldane made about $34 million in sales a year, which at the time was considered pretty good.
"Our goal was maybe to get this drug up to $100 million in sales. But we went through $100 million," Davis says. "And we said, 'Holy smokes.' And then it went through $300 million. Then $400 million. Then $500 million. $600 [million]! It was unbelievable. We were flabbergasted. And eventually it went to $800 million."
1 comment:
Seldane (terfenadine) was removed from the market due to lethal toxicities secondary to drug interactions.
90% of drugs removed from the market have drug metabolism issues. Typically it is due to a build up of a toxic metabolite, either through increased formation or decreased elimination of one metabolic pathway resulting in an increase in exposure to the parent and with other metabolic pathways picking up the slack (shunting) resulting in increased formation of toxic metabolites by that pathway. Although in the case of terfenadine it appears to be due to accumulation of the parent drug secondary to decreased elimination of the parent through both primary pathways.
This is well known science since the 1980's and the regulatory standard for drug development since that time is to completely define the metabolic scheme and proportions going to each pathway and subpathway and to see what effects them and the consequences.
Asenapine an antipsychotic drug that was recently approved by the FDA did not meet this standard and this is well documented in the reviews. In addition it's clear that the developer (Organon/Pfizer) designed the mass balance studies and the drug interaction studies to avoid obtaining any useful information. For example according to the reviews 99% of circulating radioactivity in humans from radiolabeled drug hasn't been identified. Part of the reasons is that they used a 0.3 mg radioactive dose on top of a 10 mg cold unlabeled dose. Consequently there was insufficient radioactivity to analyze after several hours. Instead the sponsor could have safely given the entire 10.3 mg dose as radiolabeled drug and combined samples from 10 or more subjects to obtain sufficient quantities to separate and identify.
Based on structure and similar drugs such as Zyprexa it's obvious that one of the most abundant metabolites is likely to be 10 or 11 hydroxy-asenapine and would be formed by CYPs 1A2 and 3A4.
So this metabolite was really never reported or tested for effects on the 5HT2B or other receptors. In stead it was reported peaks with a mixture of conjugates of this (of course the conjugates could have been enzymatically cleaved).
Most importantly when you look at the drug interaction studies they are clearly designed to look around this most important pathway.
So the effects of inducing CYP1A2 by smoking was studied by giving 1 cig to chronic smokers. Of course there won't be any decrease in parent asenapine. The metabolism is already revved up. And many other drug interaction studies look at changes in other metabolites so you can infer what is happening but in the AC meeting and the labeling there are claims of no effects on asenapine itself with no mention of significant changes in exposures to metabolites.
Since the approval of asenapine was held up for over a year and it's clear from the reviews that the clinical pharmacologist stated that this information was required for approval for concerns regarding receptor activity. This raises questions why weren't at least screening experiments performed which could have answered the reviewer's primary concern in a few days instead of holding off approval for over a year and the loss of potentially over $1 B US and maybe more long term.
See Shearlings got Plowed for more information.
Salmon
PS someone who worked on the terfenadine approval told me that similar work was requested at the time and was denied by Bob Temple.
It's also very interesting that with terfenadine FDA hired a 'drug metabolism expert' from industry. Yet we are still having problems and published guidances have been slow in coming and have been misleading and protective of the industry when they do come out.
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