Rapamycin, an mTOR inhibitor used clinically for immunosuppression, shows promise for repurposing in age-related disorders including Alzheimer's disease (AD). While the pharmacokinetics of daily rapamycin are well-characterized in transplant populations, limited data exist on intermittent dosing regimens in patients with neurodegenerative conditions. This open-label pilot study investigated the pharmacokinetic properties of weekly oral rapamycin in 13 patients with early-stage AD. Participants received 7 mg weekly (11 patients) or reduced doses (2 mg and 4 mg; 2 patients) for 26 weeks. Blood concentrations were measured at four timepoints (pre-dose/Cmin, and 1-, 3-, and 48-hours post-dose) during week 13. Moderate interindividual variability was observed (coefficient of variation 0.28-0.40 across timepoints), with the 48-hour sample showing the lowest variability (CoV = 0.28) and strongest correlation with Cmin from the previous dosing (r = 0.72). Terminal half-life and mean residence time estimates (68.9 ± 13.6 and 83.3 ± 28.0 hours, respectively) aligned with previous studies. Blood concentrations at Cmin was below immunosuppressive levels in all participants. Our findings suggest that weekly rapamycin administration in AD patients results in acceptable pharmacokinetic variability, supporting fixed-dose regimens in future trials. The 48-hour post-dose measurement appears optimal for monitoring blood concentrations. Additionally, our investigation into blood-brain barrier permeability revealed methodological challenges in directly measuring rapamycin in cerebrospinal fluid due to analytical sensitivity limitations.

The authors have declared no competing interest.

NCT06022068

This study was supported by a Longevity Impetus grant from the Norn Group, Åhlen Stiftelsen, Demensfonden, The Swedish Society of Medicine (SLS), Loo and Hans Osterman Stiftelse, Stiftelsen för Ålderssjukdomar Karolinska Institutet, Stiftelsen för Gamla Tjänarinnor, Tore Nilssons Stiftelse för Medicinsk Forskning, Åke Wibergs stiftelse (M24-0117), Swedish Brain Foundation (PD2024-0444), and Magnus Bergvall stiftelse.

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