Regarding below update to the protocol:These are pharmacokinetic parameters (pk), essentially a dissection of the dynamics of drug distribution, peak concentration, duration and trough. Kinetics are not done with all drugs, dosage may be well understood and prescribed simply accordingly, eg motrin 200 mg QID for pain. There is a class of broad spectrum antimicrobial drugs for which kinetics calculations are routinely performed: aminoglycosides (gentamicin, amikacin and tobramycin…also vancomycin). Dosing strategy is driven by indication and the dosing strategy will target peak drug concentration levels. For example bacterial endocarditis has a dual synergy treatment approach involving the combination of gentamicin and another antibiotic. The strategy aims to kill the microbe with drugs involving two different mechanisms of action where the goal is to ensure a peak target drug level of gentamicin. This is Cmax or maximum concentration. Tmax is the time to maximum concentration. t1/2 is the half life of the drug. For aminoglycosides kidney function is an important variable as these drug concentrations are modulated by kidney clearance so the math behind kinetics factors in renal clearance, the volume of distribution of the drug in the body etc. AUC refers to area under the curve and relates to bioavailability of the drug over time. τ Refers to “tau” or dosing interval. Leronlimab aside physicians and pharmacists use kinetics to optimize patient dosing, leveraging peak and trough drug levels and the time deltas for these along with complex math involving log and exponential functions in making decisions on drug dose, drug interval to hit indication based target peak and trough drug levels.
That said I recall Jay saying we know little about dose optimization with Leronlimab and I see inclusion of this information in the protocol as paving the way for future guidance on dosing. Historically we are used to taking a stab at weekly SQ dosing with 325mg, 525mg or 700mg Leronlimab. There was flirtation with IV route dosing for covid19 in Brazil. Route can matter also in trimming down the time to Tmax. We are used to thinking of receptor occupancy with Leronlimab and I believe macaque studies that demonstrated duration. This is Jay saying we could use additional data on kinetics to help physicians with dosing. Any approval should include administration standards for drug dosing. I am personally of the opinion for critical Covid19 the patient should get a loading dose via IV to quell the cytokine storm as quickly as possible. Maybe SQ would be ok subsequently but kinetic studies would provide more confidence. Oncology is a different indication so stay tuned for the data to come in.
Sorry for the long post but many on this board may have no clue what that protocol addition was for and I’m just trying to add some color knowing pharmacokinetics for aminoglycosides in great detail.
“Assessment of PK parameters of leronlimab during the 12-month treatment period.
PK parameters will be calculated following multiple dosing during the Treatment Period (12 months) and will include the following:
Cmax, Tmax, AUC0-168, AUC0-last, and AUC0-τ, trough concentrations
AUC0-inf, t1/2, CL/F, and Vz/F.
From enrollment through end of treatment at 12 months.”
That said I recall Jay saying we know little about dose optimization with Leronlimab and I see inclusion of this information in the protocol as paving the way for future guidance on dosing. Historically we are used to taking a stab at weekly SQ dosing with 325mg, 525mg or 700mg Leronlimab. There was flirtation with IV route dosing for covid19 in Brazil. Route can matter also in trimming down the time to Tmax. We are used to thinking of receptor occupancy with Leronlimab and I believe macaque studies that demonstrated duration. This is Jay saying we could use additional data on kinetics to help physicians with dosing. Any approval should include administration standards for drug dosing. I am personally of the opinion for critical Covid19 the patient should get a loading dose via IV to quell the cytokine storm as quickly as possible. Maybe SQ would be ok subsequently but kinetic studies would provide more confidence. Oncology is a different indication so stay tuned for the data to come in.
Sorry for the long post but many on this board may have no clue what that protocol addition was for and I’m just trying to add some color knowing pharmacokinetics for aminoglycosides in great detail.
“Assessment of PK parameters of leronlimab during the 12-month treatment period.
PK parameters will be calculated following multiple dosing during the Treatment Period (12 months) and will include the following:
Cmax, Tmax, AUC0-168, AUC0-last, and AUC0-τ, trough concentrations
AUC0-inf, t1/2, CL/F, and Vz/F.
From enrollment through end of treatment at 12 months.”
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