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Biotech / Medical : Cell Therapeutics (CTIC) -- Ignore unavailable to you. Want to Upgrade?

To: former_pgs who wrote (464)	2/24/2005 8:33:39 PM
From: Ian@SI	Read Replies (1) \| Respond to of 946

In Message 20932102 , MJ says, "My memory on 2103 PK is going back to 2000/2001. It was one report-note (I found it online), but now I can not find even print copy ... Never saw complete PK data (urine content). ...". He also provides links to PH 1 study abstracts which seem to disagree with his memory. In the first abstract posted is the statement, "Peak concentrations of unconjugated paclitaxel in plasma varied from 0.06 to 2.48µM, but were less than the threshold concentration for toxicity of 0.1µM 24 hours after CT-2103 administration at doses up to 480mg/m2. The patient at 720mg/m2 who experienced Grade 4 toxicity had prolonged elevated plasma concentrations of paclitaxel (0.53µM at 24 hr) and remained above 0.1µM for over 48 hours.". Is this inconsistent with the drug being active in tumours?

To: former_pgs who wrote (464)	2/24/2005 8:42:00 PM
From: zeta1961	Respond to of 946

no message

To: former_pgs who wrote (464)	2/24/2005 8:50:37 PM
From: zeta1961	Respond to of 946

the fact that an inactive prodrug is largely excreted as an inactive prodrug simply suggests that this excreted fraction can not contribute to a therapeutic effect. In fact, this fully embraces the premise and theory behind conjugated drugs... :-) The above is a statement of the obvious..It seems to me that the more productive discussion would not be about Miljenko's past statements about Xyotax since he's not posting in response but to look at the recently published paper to see if it increases our knowledge about the PK/PD and and if it helps us understand the clinical data when it is reported or better yet to 'guesstimate' the data based on what we know now about the progress of the trials... No?? Zeta

To: former_pgs who wrote (464)	2/24/2005 9:08:23 PM
From: CrazyPete	Read Replies (1) \| Respond to of 946

> That leaves the remaining 10-20% of the dose to do the heavy lifting That seems clear. > the rates of metabolism are not relevant I disagree. I think that would be a serious oversimplification of a complicated pharmacokinetic question. I think that for nearly all drugs, most of the drug ends up never reaching the target tissue, so the disposition of the 80-90% excreted in this case doesn't seem particularly worrying. I think in most cases, you would be lucky if one percent of a chemotherapeutic agent in the general circulation ended up in a tumor. And what happens to that small fraction of the drug is very dependent on relative rates of metabolism in the tumor, versus clearance. Say that 100% of the drug was excreted as the active form. Would that be better? Not clear. The argument is that the conjugated form is delivered more efficiently to the tumor, where it is converted to the active form; so if it is rapidly converted to the active form by other tissues, that could result in delivery of less drug to the tumor. The change in excretion at least tells us that the conjugation made a difference.

To: former_pgs who wrote (464)	2/24/2005 9:10:53 PM
From: Clarksterh	Respond to of 946

If I'm correctly reading Miljenko's original comment (valuation thread #15165), 80-90% of the xyotax administered is recovered in the urine, intact. If the glutamate chains were not severed from the active ingredient, then logically that conjugated form could not have had a therapeutic effect in the patient. From the article: <<In rats, the major route of elimination of [14C]paclitaxel poliglumex was by hepatic clearance and biliary excretion; urinary excretion was a minor route of elimination (Baker, unpublished observations). >> A contradiction. (unless you believe rats and humans metabolize Xyotax very differently) Clark

To: former_pgs who wrote (464)	2/25/2005 3:32:57 AM
From: tuck	Respond to of 946

First, let me say thanks to everyone for contributing. I pretty much got what I wanted: some enlightened discourse on an issue that was bugging me. "THANKS!" I am reassured. The thread consensus is pretty much what I came up with on my own, but other biofreaks have much better background than I, so I was looking for confirmation. Miljenko's contention seemed to contradict everything I could find in the literature, as well as the implications of the sheer length of the STELLAR 3 trial. But again, Miljenko knows his stuff, has saved me from a bad decision on a cancer drug at least once, etc. . . . I wanted some second opinons. One possibility that seems pretty unlikely is that the length of the trial is extended because the the comparator drug is working way better than XYOTAX, as well as way better than it historically has (rather than XYOTAX working better). Unless the enrollment criteria were just completely flouted at the majority of sites, I don't see any sensible reason for that, but it's the only way I can see for Miljenko's assertions to hold up. I'm going to assume Miljenko was operating on some combination of old data, flawed memory, and missing notes, and hold on to my remaining shares. Thanks again, everybody! You, too, Erik, for bringing this one back to our attention at a good time. Cheers, Tuck