Rapamycin, also known as sirolimus, has demonstrated great potential for application in longevity medicine. However, the bioavailability of generic and compounded rapamycin at longevity doses in normative aging individuals remains unknown. We conducted a retrospective, real-world study determining the 24-hour blood rapamycin levels to establish the relative bioavailability, dose-to-blood level linearity and inter-individual heterogeneity in a normative aging cohort. Participants received either compounded rapamycin (n = 23, dosages 5, 10, or 15 mg) or generic rapamycin (n= 44, dosages 2, 3, 6, or 8 mg) once per week, and were asked to obtain a sirolimus level blood draw 24 hours after dose self-administration. Similar blood rapamycin levels and a linear dose-to-blood level relationship were observed for both formulations, although a higher bioavailability per milligram of rapamycin was noted for the generic formulation (compounded averaged 0.287 (28.7%) bioavailability relative to generic rapamycin in (ng/mL) / mg rapamycin). While substantial inter-individual heterogeneity in blood rapamycin levels was observed for both formulations, repeat tests for individuals demonstrated high test-retest reliability. As we detected no significant association between bioavailability and measures of body mass index (BMI), sex, age, or length of time taking rapamycin, we suggest that individualized dosing and routine monitoring of blood rapamycin levels should be applied to ensure optimal longevity efficacy. Finally, we contextualize our data with a brief review of the literature on the currently available knowledge of rapamycin's bioavailability in normative aging populations, and provide implications for the clinical use of rapamycin in longevity medicine moving forward.

GH, VL, AN, MM, BV, CT, SLM, AI, and SZ are employees and shareholders of AgelessRx. MW and JH have received financial compensation from AgelessRx for their contributions. KK is an employee and shareholder of Venture Plant AB and Rapamycin Longevity Lab, which has received a donation from AgelessRx for research coordination in partnership with Ora Biomedical.

NCT06550271

This study was funded by AgelessRx.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Institutional Review Board of the Institute of Regenerative and Cellular Medicine (IRCM, approval number IRCM-2022-352) gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors