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 ).