Oh, wow. I misunderstood what the press release meant by “ PAXLOVID™ (PF-07321332; ritonavir)”
PAXLOVID is the brand name for the combination therapy of both agents. Normal convention would have been to write this as PAXLOVID™ (PF-07321332 + ritonavir), but the press release used a semicolon, which typically means “or” in medical shorthand.
Not being very familiar with ritonavir (I’m not an HIV expert), I missed this, so nice catch. I will correct.
I'm very disappointed that there don't appear to be any plans for pediatric trials currently.
I could envision a future where, essentially, careful people perform home tests multiple times a week, taking a course of antivirals at the first sign of infection to prevent progression to serious disease. Of course, this is a non-starter when antigen tests run $10 a piece.
Generally, they don't do pediatric trials until after safety and efficacy are established in adults (except, obviously, for medications used primarily in children).
PAXLOVID is currently targeting high-risk individuals. The high-risk pediatric population is exceptionally small and probably not large enough to conduct a meaningful trial.
When PAXLOVID conducts trials to expand its use into general patient populations, there will probably be a better case for doing trials in children.
I actually am going to take a rapid antigen test as soon as I finish this comment. No, I'm not sick, but tomorrow I'm going to visit some relatives, and I happen to like them. I don't want to risk bringing a deadly disease with me.
I saw speculation that molnupiravir, despite being meant only to cause mutagenesis in viruses, can do the same to human DNA. For one example:
Re: rapid tests, my statement on your plan here is: "This is the way."
On molnupiravir mutagenesis...I have a feeling that the dosage given, over the time period that it is given, makes this a minimal concern if it even matters at all, but that is a supposition. I'll explain my reasoning: The potentially mutagenic metabolite here is being rapidly incorporated into virus RNA, which is being produced in much much greater volumes than host DNA. Meanwhile the metabolite in question has a very short half-life in the human body, around 1-2 hours (see here for PK work done in the clinical trial program: https://pubmed.ncbi.nlm.nih.gov/33649113/ )
With only a short period of administration--and pharmacokinetic as well as pharmacodynamic experiments supporting an optimized dosing approach--I think this is probably not a major risk, at least in adult patients who are not pregnant or trying to become pregnant. Adult cells do not do a lot of DNA replication, so transient exposure to a potentially mutagenic compound is not as worrisome there. Also, humans have more capacity for error-correction in genome replication than coronaviruses do. We're a much more robust system.
In pregnant patients, children, or patients trying to become pregnant I would be cautious about the use of this drug. In those contexts, there is much more active DNA replication taking place than in adults, and while I have no specific evidence showing the drug is mutagenic, I'd still be cautious in the vacuum of data here.
This is all speculative, however. I do think this warrants further investigation. However, in the meantime, if I had symptomatic COVID-19 and this drug is made available for use in my care? I would take it. COVID-19 is the more immediate threat.
Correction: Paxlovid (PF-07321332) is not ritonavir, but rather is given in combination with ritonavir.
Oh, wow. I misunderstood what the press release meant by “ PAXLOVID™ (PF-07321332; ritonavir)”
PAXLOVID is the brand name for the combination therapy of both agents. Normal convention would have been to write this as PAXLOVID™ (PF-07321332 + ritonavir), but the press release used a semicolon, which typically means “or” in medical shorthand.
Not being very familiar with ritonavir (I’m not an HIV expert), I missed this, so nice catch. I will correct.
Ritonavir is commonly used in combo with other protease inhibitors as a booster because it inhibits CYP3A4. Most likely that's what's happening here.
Yep! I added a footnote to that effect with my correction yesterday.
I'm very interested in Pfizer's ongoing EPIC-PEP trial, which is looking at the efficacy of Paxlovid for post-exposure prophylaxis. See slide 28 here: https://s21.q4cdn.com/317678438/files/doc_financials/2021/q3/Q3-2021-Earnings-Charts-FINALv2.pdf.
I'm very disappointed that there don't appear to be any plans for pediatric trials currently.
I could envision a future where, essentially, careful people perform home tests multiple times a week, taking a course of antivirals at the first sign of infection to prevent progression to serious disease. Of course, this is a non-starter when antigen tests run $10 a piece.
Generally, they don't do pediatric trials until after safety and efficacy are established in adults (except, obviously, for medications used primarily in children).
PAXLOVID is currently targeting high-risk individuals. The high-risk pediatric population is exceptionally small and probably not large enough to conduct a meaningful trial.
When PAXLOVID conducts trials to expand its use into general patient populations, there will probably be a better case for doing trials in children.
I actually am going to take a rapid antigen test as soon as I finish this comment. No, I'm not sick, but tomorrow I'm going to visit some relatives, and I happen to like them. I don't want to risk bringing a deadly disease with me.
I saw speculation that molnupiravir, despite being meant only to cause mutagenesis in viruses, can do the same to human DNA. For one example:
https://www.pharmaceutical-technology.com/features/molnupiravir-safety-questions-approvals-approach/
Or this letter to the BMJ: https://www.bmj.com/content/375/bmj.n2422/rr-5
Your opinion?
Doing the search to find that, I was surprised to find out how many publications there are on molnupiravir and its metabolites, so many that there is already at least one systematic review (https://www.researchgate.net/publication/355787582_Molnupiravir_in_COVID-19_A_systematic_review_of_literature)
Re: rapid tests, my statement on your plan here is: "This is the way."
On molnupiravir mutagenesis...I have a feeling that the dosage given, over the time period that it is given, makes this a minimal concern if it even matters at all, but that is a supposition. I'll explain my reasoning: The potentially mutagenic metabolite here is being rapidly incorporated into virus RNA, which is being produced in much much greater volumes than host DNA. Meanwhile the metabolite in question has a very short half-life in the human body, around 1-2 hours (see here for PK work done in the clinical trial program: https://pubmed.ncbi.nlm.nih.gov/33649113/ )
With only a short period of administration--and pharmacokinetic as well as pharmacodynamic experiments supporting an optimized dosing approach--I think this is probably not a major risk, at least in adult patients who are not pregnant or trying to become pregnant. Adult cells do not do a lot of DNA replication, so transient exposure to a potentially mutagenic compound is not as worrisome there. Also, humans have more capacity for error-correction in genome replication than coronaviruses do. We're a much more robust system.
In pregnant patients, children, or patients trying to become pregnant I would be cautious about the use of this drug. In those contexts, there is much more active DNA replication taking place than in adults, and while I have no specific evidence showing the drug is mutagenic, I'd still be cautious in the vacuum of data here.
This is all speculative, however. I do think this warrants further investigation. However, in the meantime, if I had symptomatic COVID-19 and this drug is made available for use in my care? I would take it. COVID-19 is the more immediate threat.
In another forum, I was pointed to this Science blog that agrees with you in much more detail:
https://www.science.org/content/blog-post/molnupiravir-mutations
This is a great piece, Carl! Thanks for sharing it. I'll circulate this with Friday's issue.