ImetelChat

Looking over the abstracts it is pretty clear that the table is being set for CML and AML combo trials next. It was also clear from Dr. S that 24 week data from MF trial holds high hopes. All good. But I noted the doses used in mice was 15mg/kg and 30 mg/kg respective re above lab experiments. Considering the 9.5 mg/kg dose in humans is already associated with (manageable) side effects I wondered if anyone has the knowledge to extrapolate from mice to people. This means you Cheng--, get to work and help us here. Also someone somewhere asked why didn't Imetelstat work in solid tumors? The answer might be in the doses required for effect and the toxicities associated. This could elucidate the problem in transitioning to the clinic from the lab. I continue to think there will be a surprise late breaker re the early MDS data. Have a great weekend all, Janssen's strategy is being telegraphed in code to us, and it are good. Did anyone get the sense from the last call that some of Dr. Boerlacher's (ET) patients might still be on drug? We know Dr. T still has patient(s) still on drug, we just don't know why he won't update. bp

bio, I agree regarding AML and CML. And off course the combos.

Dosing: good question, I was wondering about that myself also. I found the following about the dosing (http://www.naturalhealthresearch.org/ex ... -to-human/):

Extrapolation of Animal Dose to Human
This article shows how to convert from animal data to human data. By Leonid Ber M.D. Posted January 9, 2012.

If only animal experimental data is available for a given compound, it is reasonable to ask what the comparable human dose might be for the same compound. This problem is often faced by researchers when considering a new chemical substance for human trials for the first time. The following is a discussion of how this issue is typically addressed.

The process starts with estimating Maximum Recommended Starting Dose (MRSD) for first-in-human clinical trials. It is based on the No Observable Adverse Effect Level (NOAEL) derived from animal toxicological studies. Once the NOAEL is known, the Human Equivalent Dose (HED) is calculated using the following formula:

Human Equivalent Dose (HED in mg/kg) = Animal Dose (mg/kg) × Animal Km ÷ Human Km , where Km is a correction factor reflecting the relationship between body weight and body surface area.

For a typical adult (body weight 60 kg, body surface area 1.6 m2), Km is 37.

For the most often used laboratory animal species the average Km are as follows:
Mouse 3
Rat 6
Guinea Pig 8
Rabbit 12
Dog 20
Human Adult 37

To calculate the MRSD, the HED derived from NOAEL is further divided by a safety factor (typically 10) to help determine a reasonable safety ceiling and help minimize the risk of toxicity in human clinical trials.

Determination of Human Equivalent of Pharmacologically Active Dose (PAD) is more complicated and depends upon many factors such as pharmacokinetics (i.e. absorption, concentration in the target tissue, metabolism, elimination, etc.) and differs markedly among pharmacological classes of drugs and clinical indications. Although far from ideal, the calculation method described above can be sometimes utilized. However, in the case of Pharmacologically Active Dose (PAD), dividing by safety factor is unnecessary. Below is an example of conversion of a hypothetical PAD from mice to human:

Pharmacologically Active Dose (PAD) in mice 5 mg/kg
Human Equivalent Dose (HED) 5 × 3 ÷ 37 = 0.4 mg/kg

(Sourece: Natural Health Research Institute)

Thank you Fish, that is reassuring. bp