Read on Twitter
Regarding the FDA letter to revoke the EUA/HCQ for COVID, it was partially based on the drugs clinical pharmacology/dosing
https://www.fda.gov/media/138945/download
FDA concludes that current dosing would produce concentration well below EC50, not sufficient to produce an antiviral effect
https://www.fda.gov/media/138945/download
FDA concludes that current dosing would produce concentration well below EC50, not sufficient to produce an antiviral effect
To my knowledge, their are 3 papers that evaluated HCQ dosing for COVID
1) PBPK model adults
https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa237/5801998
2) POP PK/PD https://ascpt.onlinelibrary.wiley.com/doi/full/10.1002/cpt.1856
3) PBPK in adults/peds https://jamanetwork.com/journals/jamapediatrics/fullarticle/2767020
1) PBPK model adults
https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa237/5801998
2) POP PK/PD https://ascpt.onlinelibrary.wiley.com/doi/full/10.1002/cpt.1856
3) PBPK in adults/peds https://jamanetwork.com/journals/jamapediatrics/fullarticle/2767020
Papers 1 & 2 conclude current dosing can achieve antiviral effect, paper 3 concludes it cannot,
The 3 papers used differ modeling tech, but all corrected for protein binding and had similar predicted concentration
All 3 compared predicted conc at target cite relative to EC50
The 3 papers used differ modeling tech, but all corrected for protein binding and had similar predicted concentration
All 3 compared predicted conc at target cite relative to EC50
Difference is how each paper defined target cite
paper 1&2 looked at intraceullar conc at lung VS EC50
paper 3 looked at extraceullar conc (lung interstitial fluid) VS EC50
FDA letter agrees with paper 3 that extracullar conc should be used and not intraceullar
paper 1&2 looked at intraceullar conc at lung VS EC50
paper 3 looked at extraceullar conc (lung interstitial fluid) VS EC50
FDA letter agrees with paper 3 that extracullar conc should be used and not intraceullar
Their explanation seems reasonable, the in vitro experiments that estimated EC50 were based on extraceullar not intracellular conc
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078228/
therefore extracell (lung interstitial fluid) conc is a better predictor of antiviral effect
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078228/
therefore extracell (lung interstitial fluid) conc is a better predictor of antiviral effect
This means current dosing used not sufficient to produce antiviral effect
If HCQ works then maybe due to its immunomodulatng effect
In RECOVERY trial they noticed this and used higher doses compared to other studies (2.4 g LD day 1, then 800 mg daily) https://www.recoverytrial.net
If HCQ works then maybe due to its immunomodulatng effect
In RECOVERY trial they noticed this and used higher doses compared to other studies (2.4 g LD day 1, then 800 mg daily) https://www.recoverytrial.net
Explanation by Dr. James Watson on the rationale behind the high doses used and why they think its safe
https://twitter.com/jwato_watson/status/1272734279659778048
To my knowledge study was stopped due lack of efficacy not safety concerns, meaning the higher doses were safe but not effective
https://twitter.com/jwato_watson/status/1272734279659778048
To my knowledge study was stopped due lack of efficacy not safety concerns, meaning the higher doses were safe but not effective
Important to note, we still have limited understanding on PKPD of antivirals in general and HCQ
Other studies ongoing evaluating early treatment with HCQ, that will give us a better answer
but based on this most likely not to work
Other studies ongoing evaluating early treatment with HCQ, that will give us a better answer
but based on this most likely not to work
