Abstract No. 364: Co-Administration of Indinavir 1200 mg With Nelfinavir 1250 mg in a Twice Daily Regimen: Preliminary Safety, PK Activity
Interest in combination PI therapy has been ongoing now for a couple of years. Numerous combinations are being looked at in the development of reliable pharmacokinetic data. In this study, the authors looked at IDV and NFV, both protease inhibitors. By way of background, the authors comment that favorable PK interaction between protease inhibitors may result in increased drug exposure and reduced dosage frequency. Simplified antiviral regimens could lead to improved adherence and improved outcome. Prior studies showed that drug exposure to both IDV and NFV was increased compared to single PI therapy in subjects receiving combination IDV/NFV in a single dose pharmacokinetic study. A larger multi-dose trial study was therefore initiated to address three key aspects of this combination:
- Pharmacokinetics of multi-dose IDV/NFV regimen.
- Antiviral activity.
21 patients (HIV-1-infected, protease inhibitor naive with viral load (vRNA) >30,000 copies/mL and CD4 count >100 cells/mm3) were enrolled to recieve increasing doses of IDV and NFV to optimize the dose of both agents. 13 patients now received IDV 1200 mg and NFV 1250 mg q12h starting at median study week 63.
One of the important parameters looked at was virologic and CD4 activity. Of thirteen patients, ten have HIV RNA less than 400 copies/mL (by the Amplicor assay) at median week 72. Of twelve patients with ultrasensitive assay data, at week 66, eleven patients are below 50 copies. The mean increase in CD4 cells over baseline was 243 cells at median week 72. Adverse reactions include one rash and a total of fourteen patients with GI complaints including nausea, bloating, diarrhea. There was nephrolithiasis in two patients.
The authors concluded:
- Concomitant IDV, 1200 mg q12H, given within NFV 1250 mg q12H results in a C max, AUC 24H and trough comparable to IDV 800 mg q8h without NFV.
- NFV plasma levels are not obviously affected by IDV.
- Virologic suppression and CD4 response was sustained in 10 of 13 subjects started on the IDV 1000 mg and NFV 750 mg q12h combination, median 72 weeks.
- The combination IDV/NFV was generally well-tolerated.
- PK data supports using IDV 1200 mg and NFV 1250 mg in a b.i.d. regimen
I think the data speaks for itself and there continues to be an accumulation of pharmacokinetic information that supports the use of twice daily dosing of combined PI regimens where three times per day dosing would have been used if these agents were given individually. All this speaks to further simplification of available regimens, which one would hope would lead to increased adherence.