Ritonavir, Saquinavir Combination -- & Warning

Laboratory evidence suggests that two protease inhibitors, Abbott's ritonavir and Roche's saquinavir, might work particularly well together. (But caution: this combination will be very dangerous unless the dose of saquinavir is drastically reduced; since no one yet knows how much to reduce the dose, this must be tested in a carefully controlled study.) The possibility of combining the drugs was discussed by researchers from Abbott at the ICAAC late-breaker session.

The laboratory tests suggest two different rationales for research on this drug combination:

(1) HIV is known to develop resistance to all known protease inhibitors. But the initial mutations which confer resistance to ritonavir are different from the mutations which lead to saquinavir resistance. Therefore, combining the drugs may delay the development of resistance to both.

(2) An additional problem of saquinavir is that it is difficult to get adequate blood levels. In tests in rats, combining saquinavir with ritonavir greatly helps to overcome this problem.

The reason is that ritonavir blocks an enzyme which the liver uses to metabolize and eliminate saquinavir. (The same enzyme also metabolizes ritonavir itself; ritonavir has an unusually long half life in the body because it blocks this enzyme.) In tests in rats, combining the drugs increased the maximum blood concentration of saquinavir by 18-fold, and also greatly extended the time the drug was in the blood -- increasing total exposure to saquinavir by 290 times. Some researchers believe that the difference in humans, while still large, may not be that extreme.

Obviously it would be very dangerous to combine the drugs without reducing the saquinavir dose, because this would lead to a huge overdose of saquinavir. But properly managed combination use might be very beneficial -- especially since the main problem with saquinavir is getting enough of it into the blood.

For the same reason, ritonavir MUST NOT be used with certain common drugs -- at least not unless the doses of those other drugs are properly adjusted. Anyone using ritonavir must be especially careful to follow medical advice.