Pharmacokinetic model of TFV and intracellular TFV-DP and model of viral kinetics.

<p>A: Pharmacokinetic model. Parameters and are the absorption and elimination rate constants of the central compartment <b>C1</b> (which resembles plasma pharmacokinetics of TFV) respectively. The parameters and denote the influx and outflux rate constant to-/from the peripheral compartment <b>C2</b> respectively. Both compartments (central-/peripheral-) have the same volume of distribution . The dotted line from the central compartment to the intracellular compartment <b>C3</b> represents subsumed processes, namely the cellular uptake of TFV and subsequent phosphorylation to TFV-DP, which were related to the plasma concentration of TFV (<b>C1</b>) by Michaelis-Menten kinetics, with parameters and individual parameter . The parameter is the individual, cellular elimination rate constant of TFV-DP. B: Virus dynamics model. T-cell and macrophage target cells (, ) can become successfully infected by infective virus with lumped infection rate constants and , respectively, creating early infected cells and . Infection can also be unsuccessful after the irreversible step of fusion (rate constant and , dashed lines), eliminating the virus and rendering the cell uninfected. Early infected cells and can destroy essential viral proteins or DNA prior to integration with rate constants and (dashed lines) returning the cell to an uninfected stage. The genomic viral DNA can become integrated with rate constants and creating late infected cells and , which can release new infectious- and non infectious virus and with rate constants and , respectively. All cellular compartments can get destroyed by the immune system with respective rate constants and the free virus gets cleared with rate constant (thin dashed lines). The pharmacologically active form of tenofovir (tenofovir-diphosphate, TFV-DP, green box) inhibits successful cell-infection (parameter ) and increases the rate of unsuccessful infection (parameter ).</p

Pharmacokinetic and pharmacodynamic parameters.

<p>median parameter and range. see Table 4 for individual values. value set to 1 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040382#pone.0040382-Gagnieu1" target="_blank">[28]</a>. parameter from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040382#pone.0040382-BarditchCrovo1" target="_blank">[12]</a>. computed using eq. (S2), <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040382#pone.0040382.s008" target="_blank">Text S1</a>.</p

Predicted % infections prevented vs. intracellular TFV-DP concentrations for distinct virus inoculum sizes.

<p>The solid blue-, dash-dotted green, dashed red and dotted black lines show the concentration-response profile for virus inoculum size 1, 5, 20 and 100 respectively. The thick dashed horizontal black line indicates the TFV-DP concentration, which prevents 50% of infections (). The dark grey area indicates the TFV-DP concentration range achieved during once daily 300 mg oral TDF dosing with 100% adherence, whereas the light grey extension to the left indicates the range of concentrations resulting from imperfect adherence. Predictions are based on the approximate analytic solution derived in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040382#pone.0040382.s009" target="_blank">Text S2</a>.</p

Predicted TFV-DP intracellular pharmacokinetics following a single dose oral 300 mg TDF and accumulation of TFV-DP after daily 300 mg oral TDF.

<p>A: Predicted intracellular pharmacokinetics of TFV-DP in PBMCs after a single 300 mg oral TDF dose. Solid black circle and horizontal error bar indicate the value and its range. B: Trough levels of TFV-DP in PBMCs following 300 mg oral TDF every 24hours, indicating the accumulation of active compound. The solid black circle and the horizontal error bar indicate the time until plateau concentrations are reached and the range for this parameter. Blue cirles, black squares, green diamonds, red downward pointing triangles, magenta upward-pointing triangles, cyan right-ward pointing triangles, black left-pointing triangles and blue asterisks indicate individual predictions for 8 patients.</p

Pharmacokinetics of TFV for different doses of oral TDF at plateau and intracellular TFV-DP concentrations after treatment cessation.

<p>A: Predicted pharmacokinetics of TFV after once daily 75-, 150-, 300- and 600 mg oral TDF (lines) together with data from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040382#pone.0040382-Droste1" target="_blank">[7]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040382#pone.0040382-Chittick1" target="_blank">[9]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040382#pone.0040382-BarditchCrovo1" target="_blank">[12]</a> (markers). B: Goodness-of-fit plot for the plasma pharmacokinetics of TFV with data from 3 clinical studies and 4 different dosing schemes <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040382#pone.0040382-Droste1" target="_blank">[7]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040382#pone.0040382-Chittick1" target="_blank">[9]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040382#pone.0040382-BarditchCrovo1" target="_blank">[12]</a>. The dashed red line indicates the line of unity, whereas the green squares, -diamonds, triangles and filled dots represent the observed TFV concentrations in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040382#pone.0040382-BarditchCrovo1" target="_blank">[12]</a> following 75-, 150-, 300- or 600 mg once daily administration of TDF. The blue left-pointing triangles and the magenta right-pointing triangles represent observed TFV concentrations after 300 mg once daily oral administration from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040382#pone.0040382-Chittick1" target="_blank">[9]</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040382#pone.0040382-Droste1" target="_blank">[7]</a> respectively. C: Predicted pharmacokinetics of intracellular TFV-DP after stopping of 300 mg once daily oral TDF dosing (lines) together with data from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040382#pone.0040382-Hawkins1" target="_blank">[11]</a> (markers). D: Goodness-of-fit plot for intracellular TFV-DP. The up- and downward pointing filled and open triangles, open- and filled circles, filled squares and filled diamonds indicate intracellular TFV-DP pharmacokinetics after stopping 300 mg once daily oral TDF dosing in 8 different individuals from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040382#pone.0040382-Hawkins1" target="_blank">[11]</a>.</p

Parameters used for the viral model.

<p>All parameters refer to the absence of drug treatment . All parameters in units [1/day], except and (unit less). <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040382#pone.0040382-vonKleist3" target="_blank">[29]</a>.</p

Efficacy & fitness.

<p>Residual DNA-dependent polymerase activity of HIV's RT in resting T-cells in the presence of ddATP and fitness and selective advantage with regard to DNA polymerization for the ‘K65R’ mutant. Calculations are based on formulas (1)–(4).</p

Expected discounted costs for an infinite time horizon.

<p>Expected discounted costs for an infinite time horizon.</p

Simplified HIV Model.

<p>A: Transitions between copy number states <i>n</i>_<i>C</i>. B: Transitions in between viral strains <i>M</i>.</p

Parameters of the HIV-model.

<p>Parameters of the HIV-model.</p