Jake: I think we have something to learn yet on wh
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Posted On: 10/01/2025 1:15:59 PM
Jake: I think we have something to learn yet on what dose represents “inadequate.” I would have been far more comfortable with 700 mg dosing but we need to reflect on the reality this is a phase 2 study, not a definitive phase 3. Teasing out dose response and safety profile are usually in the mix along with efficacy in a phase 2.
My sense from what little pharmacokinetic data are published is that while 700 mg is more effective for receptor occupancy 350 mg is no slouch either:
https://pmc.ncbi.nlm.nih.gov/articles/PMC2944...he%20arrow.
That said, the kinetics in the link pertain to HIV and I can’t honestly comment on CCR5 expression density for an oncologic condition on macrophages and T-cells etc and suspect it likely varies across patients and within a patient based on the trajectory of other treatments being engaged (what is the tumor mass burden triggering all this).
Undoubtedly we will learn something with the results due to the inherent clinical fluidity within and across patients. In the future, post approval the clinician will be empowered to use some level of clinical judgement, reacting to what is happening. On commercial jets with engine fire detected a halon fire suppression bottle can be released while cutting off fuel flow. One may work but if it doesn’t a second bottle can be deployed…the pilots are reacting to the result from the first bottle. It’s not a clinical trial where you have to abide by a protocol, but it is also life and death and so judgement and response matters to outcome.
Route also matters to kinetics…it was the right idea to move to an IV infusion in the Brazil study…immediately ramp up receptor occupancy and smother the inflammatory response to the virus with critical COVID19 whereas mild to moderate SQ and different dosing can calm things down. To expand a little I think we are in the early stages of dose discovery…maybe not a fair comparison but I think in terms of all the variables that come into play dosing a drug like gentamicin: calculated renal function, intended maximum peak blood level/concentration based on clinical indication (eg endocarditis), calculation of peak and trough levels, elimination constants, body weight and volume of distribution of drug etc.
We are starting where we are and will find where it leads based on clinical trials and real world use. I am just glad we are starting and hope we get to where it leads as quickly as possible because lives are at stake.
My sense from what little pharmacokinetic data are published is that while 700 mg is more effective for receptor occupancy 350 mg is no slouch either:
https://pmc.ncbi.nlm.nih.gov/articles/PMC2944...he%20arrow.
That said, the kinetics in the link pertain to HIV and I can’t honestly comment on CCR5 expression density for an oncologic condition on macrophages and T-cells etc and suspect it likely varies across patients and within a patient based on the trajectory of other treatments being engaged (what is the tumor mass burden triggering all this).
Undoubtedly we will learn something with the results due to the inherent clinical fluidity within and across patients. In the future, post approval the clinician will be empowered to use some level of clinical judgement, reacting to what is happening. On commercial jets with engine fire detected a halon fire suppression bottle can be released while cutting off fuel flow. One may work but if it doesn’t a second bottle can be deployed…the pilots are reacting to the result from the first bottle. It’s not a clinical trial where you have to abide by a protocol, but it is also life and death and so judgement and response matters to outcome.
Route also matters to kinetics…it was the right idea to move to an IV infusion in the Brazil study…immediately ramp up receptor occupancy and smother the inflammatory response to the virus with critical COVID19 whereas mild to moderate SQ and different dosing can calm things down. To expand a little I think we are in the early stages of dose discovery…maybe not a fair comparison but I think in terms of all the variables that come into play dosing a drug like gentamicin: calculated renal function, intended maximum peak blood level/concentration based on clinical indication (eg endocarditis), calculation of peak and trough levels, elimination constants, body weight and volume of distribution of drug etc.
We are starting where we are and will find where it leads based on clinical trials and real world use. I am just glad we are starting and hope we get to where it leads as quickly as possible because lives are at stake.
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