A Phase I Randomized Dose/Formulation Comparison Study of SC-52151

A Phase I Randomized Dose/Formulation Comparison Study of SC-52151

PRIMARY: To evaluate the safety, tolerability, pharmacokinetics, and ethanol exposure of two dose regimens and formulations of SC-52151.

SECONDARY: To evaluate the preliminary anti-HIV activity of these treatment regimens and the relationship between day 14 plasma concentrations of SC-52151 and immunological and virological markers and toxicity.

Since viral isolates with decreased susceptibility to the protease inhibitor SC-52151 occur in vitro after multiple passages, and since prolonged post infectious effects occur in vitro, comparison of two formulations, an elixir and a self-emulsifying drug delivery system (SEDDS), is needed to determine the appropriate dose formulation for Phase II studies.

Since viral isolates with decreased susceptibility to the protease inhibitor SC-52151 occur in vitro after multiple passages, and since prolonged post infectious effects occur in vitro, comparison of two formulations, an elixir and a self-emulsifying drug delivery system (SEDDS), is needed to determine the appropriate dose formulation for Phase II studies.

Patients are randomized to four treatment arms to receive SC-52151 elixir or SEDDS formulation at 1 of 2 doses for 2 weeks, with follow-up for 14 days.

Inclusion Criteria

Concurrent Medication:

Required for patients with CD4 count <= 200 cells/mm3:

• PCP prophylaxis using TMP/SMX or aerosolized pentamidine.

Allowed:

• Topical antifungal agents.
• Up to 1000 mg/day acyclovir as maintenance therapy for herpes simplex virus.
• Antibiotics for bacterial infections.
• Antipyretics, analgesics, nonsteroidal anti-inflammatory agents, antiemetics, and methadone for symptomatic treatment.

Patients must have:

• HIV infection.
• CD4 count 150 - 500 cells/mm3.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

• Unable to tolerate the standard diet required for the study.
• Unable to give informed consent.

Concurrent Medication:

Excluded:

• Antiretrovirals and biologic response modifiers (including HIV vaccines).
• Maintenance with ketoconazole, fluconazole, itraconazole, ganciclovir, foscarnet, pyrimethamine, sulfadiazine, clindamycin, azithromycin, isoniazid, rifampin, rifabutin, ethambutol, pyrazinamide, clofazimine, or clarithromycin.
• Prophylaxis for Mycobacterial infection or fungal infections other than Candidiasis.
• Allopurinol.
• Omeprazole.
• Astemizole.
• Terfenadine.
• Loratadine.
• Psychotropics.
• Phenylbutazone.
• Barbiturates.
• Benzodiazepines.
• Monoamine oxidase inhibitors.
• H-2 blockers.
• Anticonvulsants.
• Coumadin anticoagulants.
• Oral contraceptives.
• Antiarrhythmics.
• Diltiazem.
• Metronidazole.
• Erythromycin.
• Chloramphenicol.
• Fluoroquinolones.
• Disulfiram.
• Erythropoietin.
• G-CSF or GM-CSF.
• Systemic corticosteroids.
• Alcohol, including alcohol-containing medications.

Patients with the following prior conditions are excluded:

• Unexplained temperature >= 38.5 C for any 7 days within the 30 days prior to study entry.
• Chronic diarrhea (>= three stools per day) for any 15 days within the 30 days prior to study entry.
• Malignancy other than basal or squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, and minimal Kaposi's sarcoma.

Prior Medication:

Excluded at any time:

• Prior HIV protease inhibitor.

Excluded within 30 days prior to study entry:

• Investigational drugs.
• Recombinant erythropoietin.
• G-CSF or GM-CSF.
• Interferon or interleukin.
• Any HIV-1 vaccine.

Excluded within 14 days prior to study entry:

• Antiretrovirals.
• Acute therapy for any opportunistic or other serious infection.
• Therapy for malignancy.
• Maintenance with ketoconazole, fluconazole, itraconazole, ganciclovir, foscarnet, pyrimethamine, sulfadiazine, clindamycin, azithromycin, isoniazid, rifampin, rifabutin, ethambutol, pyrazinamide, clofazimine, or clarithromycin.
• Prophylaxis for Mycobacterial infection or fungal infections other than Candidiasis.

Excluded within 7 days prior to study entry:

• Allopurinol.
• Omeprazole.
• Astemizole.
• Terfenadine.
• Loratadine.
• Psychotropics.
• Phenylbutazone.
• Barbiturates.
• Benzodiazepines.
• Monoamine oxidase inhibitors.
• H-2 blockers.
• Anticonvulsants.
• Coumadin anticoagulants.
• Oral contraceptives.
• Antiarrhythmics.
• Diltiazem.
• Metronidazole.
• Erythromycin.
• Chloramphenicol.
• Fluoroquinolones.
• Disulfiram.

Risk Behavior: Excluded:

• History of substance or alcohol abuse.
• Ingestion of more than 50 g alcohol daily within 6 months prior to study entry.
• Recovered alcoholic.