Pharmacokinetics and pharmacodynamics of the reverse transcriptase inhibitor tenofovir and prophylactic efficacy against HIV-1 infection

Abstract

Antiviral pre-exposure prophylaxis (PrEP) through daily drug administration can protect healthy individuals from HIV-1 infection. While PrEP was recently approved by the FDA, the potential long-term consequences of PrEP implementation remain entirely unclear. The aim of this study is to predict the efficacy of different prophylactic strategies with the pro-drug tenofovir-disoproxil-fumarate (TDF) and to assess the sensitivity towards timing- and mode of TDF administration (daily- vs. single dose), adherence and the number of transmitted viruses. We developed a pharmacokinetic model for TDF and its active anabolite tenofovir-diphosphate (TFV-DP) and validated it with data from 4 different trials, including 4 distinct dosing regimes. Pharmacokinetics were coupled to an HIV model and viral decay following TDF mono-therapy was predicted, consistent with available data. Subsequently, a stochastic approach was used to estimate the % infections prevented by (i) daily TDF-based PrEP, (ii) one week TDF started either shortly before, or -after viral exposure and (iii) a single dose oral TDF before viral challenge (sd-PrEP). Analytical solutions were derived to assess the relation between intracellular TFV-DP concentrations and prophylactic efficacy. The predicted efficacy of TDF was limited by a slow accumulation of active compound (TFV-DP) and variable TFV-DP half-life and decreased with increasing numbers of transmitted viruses. Once daily TDF-based PrEP yielded [Formula: see text]80% protection, if at least 40% of pills were taken. Sd-PrEP with 300 mg or 600 mg TDF could prevent [Formula: see text]50% infections, when given at least before virus exposure. The efficacy dropped to [Formula: see text]10%, when given 1 h before 24 h exposure. Efficacy could not be increased with increasing dosage or prolonged administration. Post-exposure prophylaxis poorly prevented infection. The use of drugs that accumulate more rapidly, or local application of tenofovir gel may overcome the need for drug administration long before virus exposure.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Pharmacokinetic model of TFV and intracellular TFV-DP and model of viral kinetics.

A: Pharmacokinetic model. Parameters and are the absorption and elimination rate constants of the central compartment C1 (which resembles plasma pharmacokinetics of TFV) respectively. The parameters and denote the influx and outflux rate constant to-/from the peripheral compartment C2 respectively. Both compartments (central-/peripheral-) have the same volume of distribution . The dotted line from the central compartment to the intracellular compartment C3 represents subsumed processes, namely the cellular uptake of TFV and subsequent phosphorylation to TFV-DP, which were related to the plasma concentration of TFV (C1) 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 ).

Figure 2. Pharmacokinetics of TFV for different doses of oral TDF at plateau and intracellular TFV-DP concentrations after treatment cessation.

A: Predicted pharmacokinetics of TFV after once daily 75-, 150-, 300- and 600 mg oral TDF (lines) together with data from , , (markers). B: Goodness-of-fit plot for the plasma pharmacokinetics of TFV with data from 3 clinical studies and 4 different dosing schemes , , . The dashed red line indicates the line of unity, whereas the green squares, -diamonds, triangles and filled dots represent the observed TFV concentrations in 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 and respectively. C: Predicted pharmacokinetics of intracellular TFV-DP after stopping of 300 mg once daily oral TDF dosing (lines) together with data from (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 .

Figure 3. Predicted TFV-DP intracellular pharmacokinetics following a single dose oral 300 mg TDF and accumulation of TFV-DP after daily 300 mg oral TDF.

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.

Figure 4. Viral load log10 kinetics during- and after 28 days of TDF mono-therapy.

Black dashed vertical lines indicate the withdrawal of TDF dosing. Solid lines represent predicted median viral kinetics using the coupled PK-PD model, whereas dashed lines represent the observed viral kinetics . Once daily 75mg TDF dosing. B: Once daily 150 mg TDF dosing. C: Once daily 300 mg TDF dosing. D: Once daily 600 mg TDF dosing.

Figure 5. Predicted % infections prevented by distinct TDF-based prophylactic strategies for various parameter sets.

A: Predicted % infections prevented by once daily 300 mg TDF taken at different levels of adherence and with distinct virus inoculum sizes. prophylactic efficacy depends on adherence at the p 0.05 or p 0.01 level respectively. B: Predicted % infections prevented by a one week 300 mg TDF (1w-PrEP/PEP) when started at distinct times before/after exposure with distinct numbers of viruses. prophylactic efficacy depends on the timing of start of TDF administration at the p 0.05 or p 0.01 level respectively. C: Predicted % infections prevented by a single dose 300 mg TDF (sd-PrEP) when taken at distinct times before exposure with distinct virus inoculum sizes. prophylactic efficacy depends on the timing of TDF single dose administration at the p 0.05 or p 0.01 level respectively. D: Predicted % infections prevented by a single dose 600 mg TDF (sd-PrEP) when taken at distinct times before exposure with distinct virus inoculum sizes. Error bars represent confidence bounds calculated using Greenwood’s formula. prophylactic efficacy depends on the inoculum size. The predicted probability of infection in the absence of drugs was , , and when  = 1, 5, 20 or 100, respectively, viruses were inoculated.

Figure 6. Predicted % infections prevented vs. intracellular TFV-DP concentrations for distinct virus inoculum sizes.

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 Text S2.