Project Details
Description
Fungal infections are a common cause of opportunistic infections in immunocompromised persons. Among
the most severe infections is fungal meningitis. Cryptococcal meningitis is the most common cause of adult
meningitis in Africa, and Cryptococcus causes 15% of AIDS-related mortality globally.
Amphotericin B combination antifungal is the recommended therapy for cryptococcal meningitis; however,
in Sub-Saharan Africa outside of South Africa, amphotericin is rarely available in routine care. Barriers to
amphotericin availability and use include cold chain shipping and storage at 4⁰C, IV administration, and toxicity.
In the United States, the necessity on IV amphotericin administration prolongs hospitalization, increasing costs.
However, an innovative orally-absorbed encochleated amphotericin B (cAMB) has been developed. In
brief, this is amphotericin B wrapped in a soy-based lipoprotein (i.e. cochleate) that is absorbed and taken up
by monocytes and macrophages for targeted intra-cellular delivery. As such cAMB achieves high intracellular
concentrations where the phagocytosed yeast reside but low extracellular concentrations, resulting in minimal
systemic and nephrotoxicity. In intramural NIH mouse studies, oral cAMB at 25 mg/kg/day with flucytosine has
similar survival as injected amphotericin and flucytosine, which is considered the goal standard of therapy.
Human phase I single ascending dose studies have been completed in the U.S. where 200-800mg doses
have been well tolerated with only mild GI side effects observed at 800mg given as a single dose. An ongoing
NIH phase II trial of chronic mucocutaneous candidiasis (n=3) in persons living with hyper-IgE Job syndrome
has demonstrated safety and efficacy of 400mg cAMB taken 1-2x daily (i.e. up to 800mg/day) for >12 months.
We propose to conduct phase I multiple ascending dose finding trial to determine pharmacokinetics, safety,
and oral tolerability of cAMB administered in multiple doses per day in Africans. Second, we will conduct a
phase II trial to investigate the 8-week safety and tolerability as consolidation therapy. Third, we will investigate
microbiologic effects of cAMB on CSF Cryptococcus clearance rate in Ugandans with cryptococcal meningitis.
Specific Aims:
1. Determine the pharmacokinetic, safety, and tolerability of encochleated oral cAMB given in multiple doses
per day to discover the maximum safe and tolerable daily dose.
2. Determine the longer-term safety and efficacy of oral cAMB when used for cryptococcal meningitis
consolidation antifungal therapy from 2 to 10 weeks after meningitis diagnosis.
3. Determine if an encochleated oral cAMB achieves non-inferior rate of CSF Cryptococcus clearance as
compared to IV amphotericin B in HIV-infected Ugandans with cryptococcal meningitis.
Hypotheses: We hypothesize that cAMB is well tolerated at ~25mg/kg/day in divided doses, orally absorbed
and will have a non-inferior rate of CSF sterilization compared with IV amphotericin in cryptococcal meningitis.
Status | Finished |
---|---|
Effective start/end date | 3/1/19 → 2/28/23 |
Funding
- National Institute of Neurological Disorders and Stroke: $563,377.00
- National Institute of Neurological Disorders and Stroke: $637,925.00
- National Institute of Neurological Disorders and Stroke: $654,844.00
- National Institute of Neurological Disorders and Stroke: $632,233.00
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