Rapamycin in Cerebral Cavernous Malformations: What Doses to Test in Mice and Humans.

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.