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Infectious Diseases

Trouble with Sovaldi, Or Not?

I wish that this were some sort of April Fool’s entry, but it isn’t. There appears to be an outside chance that Gilead’s huge-selling Sovaldi (sofosbuvir) for hepatitis C has some cardiovascular problems. There have been a few reports from the field, and the FDA has asked for a label change when the drug is used in patients who have taken amiodarone. But this commentary at Medscape is arguing that the problem might be bigger.
The amiodarone interaction could be explained by inhibition of PGP, changing the pharmacokinetics of Sovaldi in some susceptible patients. (Amiodarone has odd PK and a particularly long half-life, raising the chances that you might see something). And/or there could be something intrinsic to sofosbuvir, and that’s the open question (the kind of question you can really only answer once a drug’s on the market). There’s a large patient population taking the drug, and getting larger all the time, so if there’s something out there to be seen, the adverse events should show up. But for now, Gilead is just waiting to see what happens – if anything.

9 comments on “Trouble with Sovaldi, Or Not?”

  1. Beyond Chemistry says:

    Funny reading this coming from Vertex Scientist….
    Good or Bad, Vertex monetized HCV industry way better than any other old time HCV players including Vertex..

  2. Pete says:

    A particularly long half life could be the result of a slow off-rate?

  3. weirdo says:

    Pete — Um, I think you’re confusing PK half-life and PD “half-life”.

  4. Pete says:

    weirdo (@3) I might not be as confused as you think that I am. If the off-rate is slow then the dissociation of the target-drug complex becomes the rate-determining step for elimination of drug. My guess is that, in this situation, drug concentration in plasma will be very low (probably below detection limits) but the rate of change of that concentration will also be low. Slow binding/dissociation kinetics is equivalent to slow distribution.

  5. Matt says:

    Derek, I know when you wrote PGP you meant P-gp.

  6. AndrewD says:

    @4 I know the pharmaceutical industry is in a bad way, but I think that would be a truly radical career change for Derek. What would “In the Pipeline” become?
    The Blue Jays will win every thing this year.

  7. TX raven says:

    Pete,
    You say “Slow binding/dissociation kinetics is equivalent to slow distribution”.
    In general, I am not sure I agree with that statement. In my view, the distribution is controlled by the non-specific binding to different tissues. The dissociation kinetics from these non-specific interactions is typically different than that for the target…
    If I am wrong, do you have any literature on the topic?
    I am aware of the case called target-dependent disposition, especially for highly expressed targets. That is not the typical case, though.
    Thanks for any input.

  8. Pete says:

    TX raven, I sometimes follow that statement by asking whether one would design a drug to distribute slowly. Strictly the statement is not correct because I don’t define ‘equivalent’ and I make the statement to provoke discussion. Let’s suppose we can monitor receptor occupancy in vivo as a function of time for an intracellular target. If we observe receptor occupancy to change slowly with time then we also need to be able to monitor free intracellular concentration in order to be able to distinguish slow binding kinetics from slow distribution. Right now we can’t measure receptor occupancy or free intracellular concentration in real time in live humans but hopefully the thought experiment is helpful.
    My challenge to those who tout the benefits of slow off-rates is that they often (usually) ignore potential problems associated with slow on-rates. Making an analogy with distribution kinetics effectively forces people to think a bit more about on-rates.

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