Lenacapavir at the Spatiotemporal Limit: Tissue Pharmacokinetics, Pharmacokinetic Tail Dynamics, and the Emergence of Capsid Resistance in Long-Acting HIV Prevention.

Background: Lenacapavir (LEN), a first-in-class HIV-1 capsid inhibitor administered subcutaneously twice yearly, has demonstrated near-perfect efficacy in Phase 3 trials, generating justified enthusiasm for its potential to reconfigure HIV prevention. However, its revolutionary success obscures critical spatiotemporal vulnerabilities. We critically examined the protective envelope of LEN, specifically focusing on the gap between systemic pharmacokinetics (PK) and mucosal distribution, the dynamics of the prolonged PK tail, and the clinical emergence of capsid resistance. Methods: A systematic narrative synthesis was conducted through April 2026. We integrated screening and data parameters from the PURPOSE and CAPELLA trials alongside advanced PK-PD modeling and structural biology datasets to comprehensively map the spatiotemporal parameters of lenacapavir-based PrEP. Findings: We characterize the Limitations of Systemic Surrogacy, highlighting that no published empirical data exist characterizing LEN concentrations in human mucosal sanctuary sites; the sole registered tissue distribution trial (Pro00043856) remains unpublished four years post-registration. While modeling baseline assumptions establish a wild-type 95% preventive plasma concentration (EC Conclusion: Optimizing the public health impact of lenacapavir requires transitioning from simple serum-based monitoring toward tissue-informed clinical stewardship. Unlike conventional oral PrEP, twice-yearly lenacapavir involves an extended pharmacological commitment of nearly 12 months, requiring pre-planned clinical protocols for bridging therapy during drug discontinuation. Implementation requires the evaluation of high-sensitivity viral surveillance tools (