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 (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

Study flow diagram.

<p>Paired measures from compartment concentrations (CC) and both CC and biopsy samples (*) taken at the bolded visits: V3 (Visit 3: ∼30 mins post single oral dose), V5 (1–6 days post V3 dose), V6 (7–9 days post V3 dose), V7 (∼30 mins post single topical dose), V9 (1–3 days post V7 dose), V10 (7–12 days post V7 does) and V12 (∼30 mins post 7^th daily dose) used in the dose-response analysis.</p

CONSORT flowchart.

<p>CONSORT flowchart.</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

Compartment TFV and TFVdp efficacy concentrations (EC_50,90,95) predicted by logistic regression to suppress HIV infection following single oral TDF, single topical TFV 1% gel and 7-day topical TFV 1% gel <i>in vivo</i> product use.

§<p>Predicted compartment dose concentrations to suppress 50, 90 and 95% of HIV infection interpolated from the logistic regression probability curve where infection was defined as cumulative p24 pg/mL ≥500.</p><p>Actual drug concentrations in the delivered product were 300 mg tenofovir disoproxil fumarate in the oral pill (equivalent to 245 mg of tenofovir disoproxil) and 40 mg/4 mL tenofovir in each topical gel application.</p><p>Compartment TFV and TFVdp efficacy concentrations (EC_50,90,95) predicted by logistic regression to suppress HIV infection following single oral TDF, single topical TFV 1% gel and 7-day topical TFV 1% gel <i>in vivo</i> product use.</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