Purpose: The main objectives of the study are to assess the safety, tolerability, and antiviral activity of ABT-378/ritonavir and to determine the steady-state pharmacokinetic profile of the combination in healthy, treatment-naive, adult HIV-infected males and females. ABT-378 is an HIV-1 protease inhibitor being developed by Abbott Laboratories which has approximately 10-fold greater in vitro potency than ritonavir and is active against ritonavir-resistant isolates; but ABT- 378 demonstrated poor bioavailability in pre-clinical trials. Co-administration of ABT-378 with ritonavir, however, substantially improves the pharmacokinetic profile of ABT-378. This is attributable to the inhibition of ABT-378 metabolism by ritonavir. Methods: Protocol M97-720 is a Phase I/II, randomized, ABT-378 dose-blinded, multi-center study of oral ABT-378/ritonavir in combination with two marketed reverse transcriptase inhibitor antiretroviral agents [stavudine (d4T) and lamivudine (3TC)] in approximately thirty-two healthy, treatment-naive, adult HIV- infected males and females. On Day -1 patients will be equally randomized to one of two blinded treatment arms: i) 200 mg ABT-378/100 mg ritonavir Q12H and ii) 400 mg ABT-378/100 mg ritonavir Q12H. All patients will add stavudine (d4T) and lamivudine (3TC) to their ABT-378/ritonavir regimen on Day 22. Study drug administration will begin with ABT-378/ritonavir on Study Day 1. All doses of study drug will be directly observed by study personnel (in the GCRC) for Study Days 1-14. After Study Day 14, follow-up visits will be planned for Study Days 16 and 18, Day 21 (Week 3), and Day 28 (Week 4). Following Day 28, visits will be scheduled biweekly until Week 12 and monthly, thereafter. Measurements of vital signs, physical examinations, ECGs, routine clinical laboratory evaluations, determinations of antiviral activity, and quality of life questionnaires will be repeated at regularly scheduled intervals. Blood samples for determination of plasma levels of ABT-378 and ritonavir plasma levels and protein binding will also be obtained. Any patient who discontinues ABT-378/ritonavir will be followed at regularly scheduled study visits for 60 days after the last dose of ABT-378/ritonavir. Results: Twelve male HIV-seropositive subjects have enrolled in the trial. One subject dropped out of the trial after the first visit and has been lost to follow-up. The other eleven subjects have continued to take the study medication and have had increases in CD4 counts and sustained HIV-1 viral suppression below the limits of detection. Two of the eleven subjects have developed some peripheral neuropathy. Four serious adverse events have been reported among the eleven subjects (a mitral valve replacement, a post-surgical ileus, dependence on narcotics, and chest pain, which was found to be gastrointestinal in nature). None of the subjects who experienced serious adverse events had to discontinue the trial, and all have continued to respond well to the study medication. The most common side effects related to the study medication have been loose stools and diarrhea. The most common laboratory abnormalities have been increases in serum cholesterol and triglycerides, which are side effects common to other protease inhibitors. Based on data collected thus far, the study medication appears to be safe, well-tolerated, and effective in suppressing HIV-1 RNA levels below the limits of detection. Significance: Safe, well-tolerated medications that lead to sustained HIV-1 viral suppression to undetectable levels have the potential to decrease stress on the immune system, resulting in higher CD4+ cell counts, longer disease-free survival time, and improved quality of life for people with HIV infection. Future Plans: All subjects in the study will continue to receive study medication beyond the initial 12-month trial, with laboratory evaluation every 3 months. The pharmaceutical sponsor plans to continue to provide the medication to all subjects until either the drug is approved by the FDA or development is discontinued.
Showing the most recent 10 out of 128 publications
