OA13.01
Background: Early clinical trials of topical microbicides only defined drug levels in tissue and luminal fluids. We are now determining if the drug quantity is sufficient to inhibit HIV. We theorize increased drug levels will correlate to decreased HIV infection.
Methods: In the FAME-02 clinical trial, 60 women were randomized to use dapivirine (DPV) gel or film, placebo or active. After 7 daily doses of product, a 10 ml cervicovaginal lavage (CVL) and two vaginal biopsies were taken. For pharmacokinetic (PK) determination, DPV was quantified using LC-MS/MS. For pharmacodynamic (PD) activity, CVL was tested using an in vitro TZM-bl assay and tissue was tested using the ex vivo challenge assay. PK/PD relationships were determined by linear regression.
Results: Women using the films and gels had no serious adverse events and found them to be acceptable. However, 5 women in the DPV film arm had not placed the films correctly and were excluded from this analysis. DPV levels in CVL ranged from 174-834 ng/ml in film compared to 489-794 ng/ml in gel users. DPV levels in vaginal tissue ranged from 0.06-25 ng/mg in film compared to 25-79 ng/mg in gel users. CVL showed a strong correlation between amount of DPV and inhibition of HIV infection from film (P<0.0001; r2=0.635) and gel (P<0.0001; r2=0.684) users. Likewise, vaginal biopsies showed a strong correlation between the DPV levels and inhibition of HIV infection in the tissue from film (P=0.002; r2=0.349) and gel (P<0.0001; r2=0.530) users. For both CVL and tissue, there was no significant difference in drug levels or activity between film or gel users.
Conclusions: To define the potency of a topical microbicide, PK and PD relationships are being defined. CVL had 10-100-fold higher DPV levels than vaginal tissue which was reflected in better PK/PD correlations in CVL as compared to tissue. While luminal concentrations were higher, these data show DPV was effectively delivered to both lumen and tissue compartments.
