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Concerning drug concentrations and resistance
Dec 9, 1999

Hello ;

I was wondering, since sometimes one reads reports that state some drugs inhibit HIV in "nanomolar" concentrations or concentrations "a hundred to a thousand times below cytotoxic", and others that define resistance as "at least four-fold" or "ten-fold" increase in concentration needed to suppress replication.

Since resistance is defined as 4 to 10 fold resistance, this would appear a natural scale for it. Then to my question:

Would it not be possible to overcome or prevent resistance by using drug concentrations much higher than required to suppress wild-type virus? If the drug concentration is 100 times what is needes to suppress the virus, then a strain that is 4 times less susceptible does not gain an evolutionary advantage, and resistance would develop much slower, no?

If soft capsule saquinavir reaches a blood level 8 times higher than the hard capsule, is resistance thus less likely to emerge against the new formulation? Is this an issue with ABT-378, since its therapeutic index appears to permit a much higher blood level than needed to suppress the wild-type virus?

Thanks for bearing with me..

Response from Dr. Cohen

No problem bearing with you - and you have got it exactly right. This approach - of increasing drug concentrations is precisely what is being done with many of the medications now in our attempt to make them that much more successful.

As you point out, resistance can sometimes be just to a small degree - one that might be overcome by increasing drug concentrations to a level that is still active despite the resistance to a lower concentration of drug. However keep in mind that this balance of drug versus virus isn't static - if the virus is exposed to a higher concentration of drug it can either be stopped by the drug, or it can, if able to grow and mutate further, create even a higher degree of resistance that allows it to "ignore" the higher concentration of drug.

This approach is very much what is being tried now for the protease inhibitors. As you point out, saquinavir is now given at a dose that is improved compared to the initial preparation. ABT 378 is using this same principle - higher drug levels - that allows it to remain active against viral strains that have developed resistance to the many protease inhibitors now being used.

Not all meds can safely be used at higher levels of course. Sometimes we can increase the level and the drug can continue to be well tolerated - but not always. That "ceiling" on dose is one of the hurdles in using this approach. However - the latest is to not must increase the level, but in particular to avoid the low concentrations of drug seen just before someone is due to take the next dose. That window is thought to be the likely time that HIV is able to grow again (if the drug level is too low to stop HIV's growth) - maintaining an adequate drug level in a consistent way may be another key to maintaining benefit from these meds. That approach is being explored by using some dose of ritonavir in combination with the other PI's as ritonavir increases their levels, and slows the "clearance" of the other PI so that the blood levels stay higher for longer. Thus in the next year we'll see studies of using some of the PI's even just once a day in combination with a dose of ritonavir.

Hope that helps. CC



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