Empirical PK/PD Model for Differentiating Intrinsic Dosing Rules by Therapeutic Indication With Relevance for HIV-1 Latency Reversal.

Authors

Lauren A R Tompkins, Amanda Poliseno, Airlie Ward, Edward P Browne, Cassandra Gilbert, Craig Sykes, Angela D M Kashuba, Mackenzie L Cottrell

Published in

Clinical pharmacology and therapeutics. Sep 27, 2026. Epub Sep 27, 2026.

Abstract

Romidepsin (RMD), an FDA-approved histone deacetylase inhibitor for treating cancer, demonstrates potent latency-reversing activity in vitro but has yielded suboptimal outcomes in kick-and-kill HIV-cure trials when administered as a 5 mg/m² infusion. We hypothesized that distinct pharmacokinetic targets exist between the pharmacodynamic goals of cytotoxicity for cancer therapy and latency reversal for HIV cure. To address this question, we designed an empirical modeling framework incorporating patient pharmacokinetics as a New Approach Methodology. Using clonal- and primary cell models of HIV-1 latency with readouts for different stages of latency-reversing activity, we performed exposure-response and dose-fractionation studies to define pharmacokinetic drivers of efficacy in latency, then designed tailored dosing strategies to meet these targets in static- and dynamic-culture systems, including a hollow-fiber model. Across all systems, the only consistent pharmacokinetic parameter driving latency-reversing activity, was RMD exposure time, with maximal activity achieved in cells exposed to ~4-6 ng/mL RMD for ≥ 20 hours (AUCs of ~80-120 ng*hour/mL). With current clinical-dosing strategies achieving AUCs of 240-600 ng*hour/mL, the same outcome occurred only when RMD concentrations greatly exceeded a cytotoxicity threshold, suggesting response was a byproduct of cytotoxic processes rather than targeted latency reversal. These findings indicate that conventional oncologic dosing strategies for RMD might not be directly applicable to HIV-1 latency reversal, offering a mechanistic explanation for suboptimal clinical outcomes. We provide proof-of-concept for RMD's limited clinical efficacy and propose a "low and slow" dosing strategy targeting time-driven, toxicity-minimized drug exposure, demonstrating how in vitro pharmacokinetic/pharmacodynamic investigations applying clinical pharmacokinetic data may inform dose optimization for clinical trials of latency reversal.

PMID:
42802563
Bibliographic data and abstract were imported from PubMed on 28 Sep 2026.

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