Meet The Professors: Pancreatic Cancer Edition, 2016 - Video 5Efficacy, pharmacokinetics and toxicity of nal-IRI
2:50 minutes.
TRANSCRIPTION:
DR BEKAII-SAAB: So the way you think about the nanoliposomal irinotecan, the nanoliposomal, essentially, it’s packed with a much larger dose of irinotecan. The concept itself is that you could actually deliver a bigger punch with the irinotecan to the tumor. So as the nanoliposomal circulates around in the bloodstream, every time it hits close to the tumor, it releases the irinotecan. So the concept of nanoliposomal agents and irinotecan in this case is that you actually increase the cancer kill but you don’t change much in terms of the toxicity profile. So you use a much higher dose of the agent, theoretically, but not change the toxicity profile while improving the activity. And some clinical trials, Phase I trials, have suggested looking at the pharmacokinetic profile of irinotecan and SN-38 that indeed there’s very little leakage rate into the circulation, as expected, less than 3% of the irinotecan. And then most of it seems to actually concentrate itself intratumorally. DR LOVE: So with that kind of target and mechanism, I’m not sure this question’s even relevant. But what about the half-life compared to IV irinotecan? DR BEKAII-SAAB: So really, the half-life is the half-life of irinotecan, not the liposome itself. So technically, it’s a little longer with the liposomal agent. But ultimately, it’s really what happens at the level of the tumor, so the internal pharmacokinetic within the tumor, irinotecan and SN-38 and its activity in the tumor. So not much difference in that standpoint. There are certain differences in the peaks, essentially, and the AUC. But overall, the half time of the irinotecan and SN-38 are about the same. DR LOVE: How would you expect and what do we know clinically about how this whole strategy and delivery mechanism affects toxicity? DR BEKAII-SAAB: Toxicity is historically the same as what you would expect for irinotecan agents. So you see the exact same levels of toxicities and at the same rate. DR LOVE: I thought the trials showed that it was the same, that it didn’t add to the toxicity of 5-FU/leucovorin. DR BEKAII-SAAB: Yes. So the trick with what was, if you look at the dosages, the dosage of the MM-398 was higher when you used it without 5-FU. And, therefore, you see, actually, more toxicities related to the irinotecan with a higher dose of MM-398. When combined with 5-FU the dose was lower and, therefore, the toxicities actually I think were a little bit more favorable because of the lower dose of the MM-398. |