Pharmacokinetic Interception of Latency Reversal in HIV Eradication: A PBPK Modeling Approach to Overcoming the Romidepsin 'Long Tail' Mismatch via Timed Broadly Neutralizing Antibody Administration

The "Shock and Kill" (or "Kick and Kill") hypothesis for the eradication of the Human Immunodeficiency Virus (HIV) relies on the administration of Latency Reversing Agents (LRAs) to reactivate latent proviral reservoirs, followed by an immune-mediated clearance mechanism. Despite promising preclinical models, human clinical trials utilizing Histone Deacetylase Inhibitors (HDACi), such as romidepsin, combined with immunotherapies have consistently failed to prevent viral rebound upon analytical treatment interruption. This study investigates the biophysical and pharmacokinetic mechanisms driving these clinical failures. Employing advanced Physiologically Based Pharmacokinetic (PBPK) modeling (via PK-Sim and MoBi software environments), a standard 73-kg virtual patient was subjected to an in silico clinical trial. The protocol combined romidepsin (an LRA) with a triple cocktail of broadly neutralizing antibodies (bNAbs: 3BNC117, 10-1074, VRC07). The simulation revealed a critical Pharmacokinetic (PK) Mismatch: the high lipophilicity of romidepsin (LogP 1.9) caused extensive tissue partitioning and delayed release, resulting in a prolonged biological tail that significantly outlasted the systemic clearance of the hydrophilic bNAbs (LogP 0). This mismatch facilitated a robust viral rebound at Day 10-14. Viral rebound in LRA-based eradication trials is primarily driven by a pharmacokinetic mismatch rather than inherent drug failure. By engineering a targeted, multi-dose protocol, specifically administering a precisely timed booster dose of the bNAb cocktail at Hour 240, the simulation successfully intercepted the LRA's long biological tail. The replenished antibody shield suppressed the delayed reactivation of latent cells, achieving complete and sustained in silico viral eradication. These findings strongly advocate for the recalibration of clinical trial dosing schedules to account for the physical partitioning of small-molecule LRAs.