The administration of oral tenofovir disoproxil fumarate (TDF) results in 100-fold higher exposure of tenofovir (TFV) and its active moiety, tenofovir diphosphate (TFVdp), in colorectal tissues compared to female genital tract tissues. This may contribute to PrEP adherence forgiveness in MSM compared to women. Tenofovir alafenamide (TAF), a novel TFV prodrug, achieves higher concentrations of TFVdp in peripheral blood mononuclear cells (PBMCs) compared to TDF. We sought to characterize genital and rectal tissue pharmacokinetics (PK) in women after a single dose of TAF.
A phase I PK study to describe TAF, TFV, and TFVdp exposure over 14 days in blood and tissues was conducted in 8 healthy women given one 25mg dose of TAF. Each participant provided 10 plasma, 9 PBMC, 9 cervicovaginal fluid (CVF) samples, and 2 biopsies from the cervix, vagina, and rectum. TAF, TFV, and TFVdp concentrations were determined by validated LC-MS/MS methods. TAF lower limit of quantification (LLOQ) in plasma was 0.05ng/ml and 0.005ng/ml in tissues. TFVdp LLOQ was 0.02ng/ml in tissues and PBMCs. TFV LLOQ was 0.25ng/ml in plasma and 2ng/ml in CVF. Noncompartmental PK analysis was conducted using WinNonlin v6.4. 48h PK parameters, from an earlier single 300mg dose of TDF in healthy women were used as reference values. Data are reported as median (min-max) except for tissues where pooled sample analysis was used.
PK data are listed in the table. In plasma, compared to TDF, the area under the TFV concentration time curve (AUC)0-48hrs was 95% lower with TAF. By 6h, TAF was mostly unquantifiable in plasma, with an AUC0-6hrs of 38 (20.5-119.6) ng*h/ml. TAF was undetectable in tissue. Conversely, in PBMCs, TFVdp AUC0-48hrs was 808% higher with TAF. In all mucosal tissues TFV AUC0-48hrs was 20-90% lower with TAF. TFVdp was detectable in only 2 vaginal and cervical (12.5%) and 4 rectal (25%) tissue samples of women dosed with TAF, compared to 50%, 100%, and 100% for TDF, respectively.
After TAF dosing, plasma TFV PK and PBMC TFVdp PK were consistent with previous reports. Unlike TDF dosing, TFVdp was undetectable in most (83%) tissues after TAF dosing. Although the appropriate biomarkers of HIV protection for PrEP are currently unknown, these biopsy findings warrant further investigation.