Noncompartmental Pharmacokinetic Parameters (^*Insufficient data to perform NCA on CD4- and CD4+ PBMC; see companion publication Richardson-Harmon et.al for exposure-response analysis; ^**Composite Profile).

<p>*Insufficient data to perform NCA on CD4- and CD4+ PBMC; see companion publication Richardson-Harmon et.al for exposure-response analysis.</p><p>**Composite Profile.</p><p>Noncompartmental Pharmacokinetic Parameters (^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106196#nt101" target="_blank">*</a>}Insufficient data to perform NCA on CD4- and CD4+ PBMC; see companion publication Richardson-Harmon et.al for exposure-response analysis; ^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106196#nt102" target="_blank">**</a>}Composite Profile).</p

TFV quantification from rectal sponges is predictive of plasma TFV exposure during rectal dosing.

<p>Plasma TFV exposure is correlated linearly with rectal sponge TFV exposure. (p<0.001, robust RSE  = 0.38) The linear correlation is the same regardless of number of rectal doses. Shaded regions are the 10–90% confidence intervals of the mean predictions from robust linear regression model.</p

TFV (A) and TFVdp (B) concentrations in rectal tissue homogenate are predicted by Rectal Sponge TFV.

<p>(p<0.001, robust RSE_TFV  = 0.67, RSE_TFVdp  = 0.66) Shaded regions are the 10–90% confidence intervals of the mean predictions from robust linear regression model. The correlations are consistent regardless of administration route and number of doses.</p

Demographics.

<p>Demographics.</p

TFVdp in rectal tissue homogenate is predictive of intracellular TFVdp concentration in isolated rectal mucosal mononuclear cells (MMCs), with higher levels of phosphorylation in the CD4+ T cells compared to CD4- T cells.

<p>Intracellular TFVdp concentration in isolated rectal mucosal mononuclear cells increases linearly as TFVdp concentration in rectal tissue homogenate increases. (p<0.001, robust RSE  = 0.46) There is higher phosphorylation of TFV in CD4+ cells, seen in its higher y-intercept. The lines are the mean rectal tissue MMC TFVdp concentration predictions from robust linear regression model; solid is CD4+, dashed is CD4-. Shaded regions are the 10–90% confidence intervals of the mean prediction.</p

TFV Plasma Half-life is shorter (p = 0.02) during rectal administration.

<p>Plasma concentration-time profile is shown (median and interquartile range). Nominal time for single rectal dose was shifted right by 0.250 h and multiple rectal dose by 0.500 h for clarity. N = 18 for oral dose, 12 single rectal dose, 12 multiple rectal dose. (BLQ values are imputed as 0.01.)</p

Study Design.

<p>Study Design.</p

Rectal tissue exposure to TFV and TFVdp (median ± IQR) is higher during rectal dosing with multiple rectal dosing, resulting in accumulation of TFVdp.

<p>Each set of figures documents the 30 min drug quantification in the left-side graph and the 24 hr in the right side graph in rectal tissue biopsy homogenate (5A, 5B) and isolated mucosal mononuclear immune cells (MMC) (5C). Comparisons performed with paired Wilcoxon signed-rank test; only a subset of patients gave both C_{30 min} and C_{24 h} samples. Figure S5A  =  TFV_Tissue; Figure S5B  =  TFVdp_Tissue; Figure S5C  =  TFVdp_MMC. There is accumulation of TFV and TFVdp from multiple rectal dosing. Critical p for significance was 0.025 after Bonferroni correction.</p

Sample Collection.

<p>All 18 trial participants received a single oral dose of 300 mg TDF followed by intensive 24 h PK. After ∼2 week resting period, 12 subjects were randomized to receive a single rectal gel dose of 1% TFV gel with intensive 24 h PK followed, after ∼2 week resting period, by 6 sequential, daily, self-administered rectal 1% TFV gel doses with the 7th dose administered in-clinic with subsequent 24 h intensive PK.</p

Increasing TFV in Rectal Tissue Homogenate results in increased TFVdp.

<p>There is a linear correlation between rectal tissue homogenate TFVdp and TFV (p = 0.04, robust RSE  = 0.37) with oral dosing only (solid line is mean prediction of TFVdp in rectal tissue from oral dosing). Shaded regions are the 10–90% confidence intervals of the mean predictions from robust linear regression model. There is no correlation during rectal dosing.</p