1283 – Topical Doxycycline Inserts Show High Efficacy Against Vaginal Chlamydia Acquisition in Macaques

Background

Bacterial STIs are on the rise globally. Fast-dissolving dual-compartment (vaginal/rectal) inserts containing doxycycline (DOX) provide an alternate approach to STI prevention that can maximize local DOX concentrations while minimizing systemic distribution.   Here, we performed preclinical studies to evaluate the pharmacokinetics (PK) and protective efficacy following vaginal administration of CONRAD-developed inserts containing DOX against vaginal C. trachomatis (CT) infection in pigtail macaques.

Methods

Inserts were manufactured using a simple, easy-to-scale direct-compression process containing 10 or 50mg DOX. DOX PK was determined via HPLC-tandem mass spectrometry analysis of vaginal swabs and plasma samples collected from macaques following vaginal administration of a 50mg or 10mg DOX insert. A physiologically-relevant challenge dose of 10⁴ inclusion forming units (IFU) was identified for CT (serovar E) following a vaginal dose titration (10⁶-500 IFU). For efficacy studies, macaques were administered either a single vaginal insert containing DOX (50mg or 10mg), or no insert (Controls), at 4 hours (h) following vaginal challenge with 10⁴ IFU CT.  Animals were followed weekly, for 9 weeks, to monitor CT infection by testing vaginal swabs for the presence of CT rRNA via the Aptima Combo 2 target amplification assay. Macaques were considered to have an established CT infection if they exhibited Aptima positivity for 4 or more weeks following CT challenge.

Results

Among macaques administered 10mg DOX inserts, DOX concentrations in vaginal secretions were high at 24h (279μg/ml) and persisted for at least 7 days at levels above DOX’s MIC₉₀ for CT (0.064μg/ml), whereas DOX was undetectable in plasma. All CT-challenged macaques that received inserts containing 50mg (N=4) or 10mg (N=4) DOX were protected, whereas 83% (5/6) controls became infected (P=0.048, each DOX group vs Controls).

Conclusions

Vaginal delivery of DOX by inserts containing 10mg or 50mg DOX protected macaques against CT infection when administered 4h after CT challenge. Data provide the first evidence of a novel topical DOX modality for CT prevention.  PK data demonstrated lack of systemic DOX distribution and highlight the role of sustained vaginal DOX in protection against CT. Findings inform the clinical development of DOX inserts for on-demand CT prevention and support DOX coformulation into tenofovir alafenamide and elvitegravir-containing inserts, which are currently in clinical development for HIV prevention.