RITONAVIR+INDINAVIR
Many of you have heard about the recent attention paid to the utility of this relatively newly researched regimen. Cassy Workman was the first to report clinical use of this combination dosed at 400mg RTV+400mg bid IDV (twice daily) without food restrictions. She reported data in treatment naive and experienced at Geneva and Glasgow. As reported in the most recent NATAP newsletter (posted to the NATAP web site), Workman reported at Glasgow on individuls receiving a two-drug regimen consisting only of IDV+RTV 400mg bid of both drugs (twice daily). In the naive group the baseline CD4 and viral load were 400 and 150,000 copies/ml, respectively. At weeks 28 and 52 she reported 11/11 had <40 copies/ml and 7/7 had <40 copies/ml, respectively. At week 52, 7 patients had a CD4 increase of 425 on average. At week 20, 11 patients had a CD4 increase of 225, on average. She also reported on several individuals who had previously failed saquinavir or IDV and received IDV+RTV alone. Viral load reductions of 1.5 to 2.0 logs were achieved by these PI experienced individuals, and these viral load reductions were generally sustained during the period reported.
In a 2nd study reported by a German research group at Glasgow in November '98 and also reviewed in the NATAP newsletter, 71 treatment naive individuals received RTV+IDV+2 NRTIs. Their median baseline CD4 was 229, and viral load was 229,000 copies/ml. At week 24, data was available for 17 patients, and they had an average viral load reduction of 3.6 log, and 17/17 had <400 copies/ml; 67% had <80 copies/ml.
At Retrovirus Mike Youle reported follow-up data from a small study (n=52) he first reported at ICDCD in December '98. Individuals with extensive PI and NRTI experience received IDV+RTV+a NNRTI (NVP or EFV)+hydroxyurea and NRTIs including DDI.
Youle reported at the December ICDCD meeting that 80% of patients in his study had <400 copies/ml. The baseline viral load was high at 526,000 copies/ml and the CD4 count was low at 97. At Retrovirus, in the abstract book he reported 9/15 (60%) who had reached week 24 had <400 copies/ml, but upon my visual observation of the graph he displayed in his poster the percent appeared to be 65%. The study participants' prior PI experience was-- IDV n=36 (69%), NFV 21 (40%), RTV 38 (73%), SQV 26 (50%). He reported at ICDCD that he started study participants at a dose of 400 mg bid of both RTV and IDV, but switched the dosing to 800 mg IDV bid + 100 mg RTV bid.
Merck Pharmackinetic Data. Researchers at Merck reported at Retrovirus PK data (abstract 362) from an initial small study of the interactions of these two drugs at various doses. The following two tables report their findings on Cmax, AUC, and Cmin.
As you can see in the tables, the AUC, Cmax, and Cmin are higher for the 800/100 and 800/200 dosing regimens than the 400/400 dosing with low or high fat meals. Cmax is the peak drug level in blood after taking a dose; AUC is the total amount of drug in blood over the dosing period, in this case Merck is reporting the AUC over a 24 hour period. The Cmin is the lowest level of drug in blood which occurs at the end of the dosing period, which in this case is 12 hours. Since adequate clinical trials have yet to be conducted using 800/200 or 800/100, it is uncertain if the higher blood levels for these regimens will prove to be more effective than the 400/400 dosing regimens.
Theoretically, higher Cmin and AUC may translate into more potency. It is thought that the 800/100 dose regimen may be adequate for treatment naive individuals. Several small pilot test-of-concept studies using 800/200 are expected to explore salvage therapy for individuals who have failed indinavir or nelfinavir. The higher blood levels of IDV that are attained by using 200 mg RTV with 800 mg IDV rather than 100 mg RTV may be more effective in suppressing IDV or NFV resistant virus than the 100 mg dose of RTV with 800 mg IDV. Because individuals can have variable IDV drug levels it is hoped that achieving higher Cmin with 800/200 than 800/100 will address that concern.
Food and Hydration
Study data from Abbott says there is no food effect on this combination. The Merck pk data compared low fat with high fat. As you can see from the data in Tables 1 and 2 at the lower RTV doses of 100 and 200 mg bid the blood levels of IDV are higher with a low-fat meal than with a high-fat meal. Merck reported PK data that a high fat meal produced lower blood levels of RTV than when taking RTV with a low fat meal, but only at the lower doses of 100mg or 200 mg of RTV. But it is probably not clinically significant. I think you can conclude from the Merck data also, that there is no significant food effect. Although the studies discussed above suggest that you can take IDV+RTV without any food I think you should eat the equivalent of a sandwich when taking taking this combination.
Regarding hydration, as you may know adequate hydration is important to reducing the risk of kidney stones, which can result from taking IDV. Merck says a person should continue the usual hydration for IDV when taking IDV+RTV, regardless of which dosing regimen you're using. The usual recommendation is to drink at least 50 ounces of water per day. It is also recommended that a person drink a 2 or more 8 ounce glasses of water when actually taking the IDV pills. Researchers have speculated that kidney stones, a side effect associated with taking IDV, may be associated with the Cmax or total AUC. From reports of anecdotal experiences it appears as though there may not be added incidence of kidney stones when increasing the AUC and Cmax. Merck suggests the urine is already saturated when taking IDV at the usual dose of 800 mg every 8 hours, therefore additional IDV blood levels should not increase the incidence of kidney stones. Hopefully, planned clinical trials using the 800/100 and 800/200 doses will answer this question. Since Mike Youle switched his patients to 800/100, its possible data may be available soon on the incidence of kidney stones.
NATAP is holding a large community forum to review information reported at the Retrovirus Conference held in Chicago in early February. We will discuss IDV+RTV at this forum. The forum will be on Saturday Feb 27 at 10am at NYU Med Ctr; call NATAP for info (212 219-0106).