July 8, 2002
For patients with high levels of resistance to many drugs, clinicians have been interested in trying novel strategies. One popular strategy is to combine two protease inhibitors that can both be boosted with ritonavir (r), such as ritonavir-boosted lopinavir (LPV) and amprenavir (APV), lopinavir and saquinavir, as well as more novel combinations.
Both lopinavir (Kaletra) and amprenavir (Agenerase) are active against many strains of protease-inhibitor-resistant virus. Both can reach higher levels when boosted with ritonavir as two drug combinations which may overcome moderate levels of resistance. Thus, combining the two as lopinavir plus amprenavir is very attractive. Preliminary pharmacologic (PK) studies, however, have shown the level of complexity that develops with these three-way combinations. These studies have shown conflicting results, and no clear consensus exists as to how to best dose them.
This poster described trough levels of amprenavir and lopinavir at different doses as prescribed by the physician. Doses included APV 900 mg and LPV/r 400/100 mg both BID (n = 5), APV 750 mg and LPV/r 400/100 mg (n = 5), APV 600 mg (the usual dose with ritonavir) and LPV/r 400/100 mg (n = 3), and APV 600 mg and APV/r 533/133 mg (n = 1). Trough levels were measured at a commercial lab approximately 12 hours after an unobserved dose.
For all of the groups, the median trough levels of amprenavir and lopinavir were substantially below the median levels when each drug had been given with ritonavir alone in previous studies. However, there was substantial patient-to-patient variation.
This study confirms a number of previous studies that showed a two-way interaction, where both the lopinavir and ritonavir levels were decreased with the combination. However, it is worth noting the limitation of this and previous studies. First, the dose was not observed, so timing or compliance may affect the measurement. Second, there is a substantial increase in the levels when given with food, and there was no control over food intake. Third, the commercial lab may (or may not) have been less accurate than research labs at precisely measuring levels. Fourth, all levels remained above the IC50 for wild-type virus, but what may matter more is the relationship of the patients' virus with the amount of free drug.
What then are we to do? First, we clearly need properly controlled formal PK studies. Secondly, if the person-to-person variation is an issue, we probably need to be able to accurately measure individual drug levels in these complex unorthodox salvage regimens.
In Europe, this is considered standard of care, but in the U.S., we do not routinely have access to high quality, validated drug levels. With all of these cautions, if a patient was most likely to benefit from lopinavir and amprenavir tomorrow, before these problems can be met, one might consider increasing both the lopinavir dose to four capsules (533/133 mg) and the amprenavir dose to 750 or 900 mg both BID.
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