Excellent post Sherlock. You picked up on the main point which is that target dosing, while potentially affected by patient weight, could be more profoundly influenced by other factors such as disease state.
“As far as receptor occupancy goes, if you have an infection (mild case of flu?) or chronic condition (MASH?), your receptor counts are going to be elevated because your body is fighting back. So the receptor count that needs to be occupied is actually a fluctuating number”
Apologies in advance but due to the number of posts here related to concerns about dosing I want to drive a nail through this point.
For the benefit of other board members I will show this logic reinforced through the lens of pharmacokinetic dosing of aminoglycoside drugs, when physicians either do not know at the outset what micro-organism the patient is infected with (eg: waiting on blood cultures) and thus you need a broad spectrum antimicrobial that punches above its weight, or you need the drug because it has been shown to work for the indications. ALL of these drugs (gentamicin, tobramycin, amikacin) leverage patient weight to determine dose. That said, multiple OTHER FACTORS come into play: what is the kidney function of the patient (as the drug will be cleared by the kidneys). Are they critically ill or not; what am I treating: endocarditis, cystic fibrosis, an open fracture? What is the dosing strategy? As an example, if treating endocarditis with gentamicin for gram positive synergy in a patient with normal kidney function using a conventional dosing strategy, a target drug level of 3-4 mcg/mL is chosen AND TESTED FOR by obtaining blood levels 30 minutes after infusion of the third dose (peak drug level) and 30 minutes prior to 4th dose (drug trough level). Pharmacokinetic calculations are made to ensure you are hitting your target Cmax (maximum concentration), and validating a Cmin (minimum concentration of less than 1 mcg/mL. This math is complex, involving creatinine clearance (kidney function), the volume of distribution of the drug, drug elimination constant etc in an effort to determine maintenance dose going forward. Note this is not simple math, it uses variables that in turn have advanced math involving log and exponential functions. You can get an idea of the actual complexity of it all by taking a peek at the linked Stanford dosing guide document. Jump to page 9 to see the math for maintenance dose calculations.
https://med.stanford.edu/content/dam/sm/bugsa...-Guide.pdf
Here is just the maintenance dose calculation from page 9 (the variables, what they mean and how they are calculated are also on page 9):
MD = [(ke) x (Vd) x (ti) x (Cpeak desired) x (1 – e–K t)] [ (1 – e – K ti) ]
THE KEY TAKEAWAY here: a drug is needed and while weight factors into dosing, a plethora of other factors come into play. The same is true for Leronlimab! If the goal is CCR5 receptor occupancy, while large patients can reasonably be expected to require a higher dose (target in mg/kg), clearly the type of cancer and whether it is small and just detected will be very different than with advanced, widespread metastatic lesions. There is A-LOT yet to be determined about target dosing and pharmacokinetics with Leronlimab. That said, the CRC trial has been reduced down to two dosing arms, simplified to 325 mg SQ or 700mg SQ weekly for patients with advanced disease, and as the tumors brace for impact Cytodyn is getting an indication of seismic activity through circulating tumor DNA levels, imaging, RECIST measurements etc.
I am hoping when the dust settles it will be like that moment in the Bruce Willis movie Armageddon where they successfully drill a hole in the asteroid about to hit earth, blowing it up and saving the planet, returning with hero status. I have some confidence that Leronlimab will have a comparable seismic impact on the solid tumor landscape.
“As far as receptor occupancy goes, if you have an infection (mild case of flu?) or chronic condition (MASH?), your receptor counts are going to be elevated because your body is fighting back. So the receptor count that needs to be occupied is actually a fluctuating number”
Apologies in advance but due to the number of posts here related to concerns about dosing I want to drive a nail through this point.
For the benefit of other board members I will show this logic reinforced through the lens of pharmacokinetic dosing of aminoglycoside drugs, when physicians either do not know at the outset what micro-organism the patient is infected with (eg: waiting on blood cultures) and thus you need a broad spectrum antimicrobial that punches above its weight, or you need the drug because it has been shown to work for the indications. ALL of these drugs (gentamicin, tobramycin, amikacin) leverage patient weight to determine dose. That said, multiple OTHER FACTORS come into play: what is the kidney function of the patient (as the drug will be cleared by the kidneys). Are they critically ill or not; what am I treating: endocarditis, cystic fibrosis, an open fracture? What is the dosing strategy? As an example, if treating endocarditis with gentamicin for gram positive synergy in a patient with normal kidney function using a conventional dosing strategy, a target drug level of 3-4 mcg/mL is chosen AND TESTED FOR by obtaining blood levels 30 minutes after infusion of the third dose (peak drug level) and 30 minutes prior to 4th dose (drug trough level). Pharmacokinetic calculations are made to ensure you are hitting your target Cmax (maximum concentration), and validating a Cmin (minimum concentration of less than 1 mcg/mL. This math is complex, involving creatinine clearance (kidney function), the volume of distribution of the drug, drug elimination constant etc in an effort to determine maintenance dose going forward. Note this is not simple math, it uses variables that in turn have advanced math involving log and exponential functions. You can get an idea of the actual complexity of it all by taking a peek at the linked Stanford dosing guide document. Jump to page 9 to see the math for maintenance dose calculations.
https://med.stanford.edu/content/dam/sm/bugsa...-Guide.pdf
Here is just the maintenance dose calculation from page 9 (the variables, what they mean and how they are calculated are also on page 9):
MD = [(ke) x (Vd) x (ti) x (Cpeak desired) x (1 – e–K t)] [ (1 – e – K ti) ]
THE KEY TAKEAWAY here: a drug is needed and while weight factors into dosing, a plethora of other factors come into play. The same is true for Leronlimab! If the goal is CCR5 receptor occupancy, while large patients can reasonably be expected to require a higher dose (target in mg/kg), clearly the type of cancer and whether it is small and just detected will be very different than with advanced, widespread metastatic lesions. There is A-LOT yet to be determined about target dosing and pharmacokinetics with Leronlimab. That said, the CRC trial has been reduced down to two dosing arms, simplified to 325 mg SQ or 700mg SQ weekly for patients with advanced disease, and as the tumors brace for impact Cytodyn is getting an indication of seismic activity through circulating tumor DNA levels, imaging, RECIST measurements etc.
I am hoping when the dust settles it will be like that moment in the Bruce Willis movie Armageddon where they successfully drill a hole in the asteroid about to hit earth, blowing it up and saving the planet, returning with hero status. I have some confidence that Leronlimab will have a comparable seismic impact on the solid tumor landscape.
10
