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Published on: September 4, 2017
Rapamycin in Cerebral Cavernous Malformations: What Doses to Test in Mice and Humans
Matthew J Hagan1, Robert Shenkar1, Abhinav Srinath1
1Neurovascular Surgery Program, Department of Neurological Surgery, University of Chicago Medicine and Biological Sciences, Chicago, Illinois 60637, United States.
Abstract:
Cerebral cavernous malformations (CCMs) are hemorrhagic neurovascular lesions that affect more than 1 million people in the United States. Rapamycin inhibits CCM development and bleeding in murine models. The appropriate dosage to modify disease phenotype remains unknown. Current approved indications by the U.S. Food and Drug Administration and clinicaltrials.gov were queried for rapamycin human dosing for various indications. A systematic literature search was conducted on PubMed to investigate mouse dosimetry of rapamycin. In humans, low daily doses of <2 mg/day or trough level targets <15 ng/mL were typically used for benign indications akin to CCM disease, with relatively low complication rates. Higher oral doses in humans, used for organ rejection, result in higher complication rates. Oral dosing in mice, between 2 and 4 mg/kg/day, achieved blood trough levels in the 5-15 ng/mL range, a concentration likely to be targeted in human studies to treat CCM. Preclinical studies are needed utilizing dosing strategies which achieve blood levels corresponding to likely human dosimetry.
Insights
Rapamycin shows promise for treating cerebral cavernous malformations (CCMs). Mouse studies suggest a specific dosage range may be effective for human CCM treatment, requiring further preclinical investigation.
Area of Science:
- Neurovascular Diseases
- Pharmacology
- Translational Medicine
Background:
- Cerebral cavernous malformations (CCMs) are prevalent hemorrhagic neurovascular lesions.
- Rapamycin demonstrates efficacy in inhibiting CCM development and bleeding in preclinical models.
- Optimal rapamycin dosage for modifying CCM disease phenotype in humans is currently unknown.
Purpose of the Study:
- To determine appropriate rapamycin dosing strategies for potential human CCM treatment.
- To correlate human and murine rapamycin dosages and resulting blood trough levels.
Main Methods:
- Systematic literature search of PubMed for murine rapamycin dosimetry.
- Querying U.S. Food and Drug Administration and clinicaltrials.gov for human rapamycin dosing across indications.
- Analysis of human and mouse dosing data to identify potential therapeutic ranges.
Main Results:
- Human studies for benign indications use low daily rapamycin doses (<2 mg/day) or target trough levels (<15 ng/mL) with low complication rates.
- Higher oral rapamycin doses in humans, used for organ rejection, are associated with increased complications.
- Murine oral dosing of 2-4 mg/kg/day achieves blood trough levels of 5-15 ng/mL, a potentially relevant range for CCM treatment.
Conclusions:
- A rapamycin trough level of 5-15 ng/mL may be a suitable target for human CCM studies.
- Further preclinical research is necessary to validate dosing strategies that achieve human-relevant blood levels.
- Translating effective murine rapamycin dosing to humans requires careful consideration of safety and efficacy.
