Model Linking Plasma and Intracellular Tenofovir/Emtricitabine with Deoxynucleoside Triphosphates

Abstract

The coformulation of the nucleos(t)ide analogs (NA) tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC) is approved for HIV-infection treatment and prevention. Plasma TFV and FTC undergo complicated hybrid processes to form, accumulate, and retain as their active intracellular anabolites: TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP). Such complexities manifest in nonlinear intracellular pharmacokinetics (PK). In target cells, TFV-DP/FTC-TP compete with endogenous deoxynucleoside triphosphates (dNTP) at the active site of HIV reverse transcriptase, underscoring the importance of analog:dNTP ratios for antiviral efficacy. However, NA such as TFV and FTC have the potential to disturb the dNTP pool, which could augment or reduce their efficacies. We conducted a pharmacokinetics-pharmacodynamics (PKPD) study among forty subjects receiving daily TDF/FTC (300 mg/200 mg) from the first-dose to pharmacological intracellular steady-state (30 days). TFV/FTC in plasma, TFV-DP/FTC-TP and dNTPs in peripheral blood mononuclear cells (PBMC) were quantified using validated LC/MS/MS methodologies. Concentration-time data were analyzed using nonlinear mixed effects modeling (NONMEM). Formations and the accumulation of intracellular TFV-DP/FTC-TP was driven by plasma TFV/FTC, which was described by a hybrid of first-order formation and saturation. An indirect response link model described the interplay between TFV-DP/FTC-TP and the dNTP pool change. The EC50 (interindividual variability, (%CV)) of TFV-DP and FTC-TP on the inhibition of deoxyadenosine triphosphate (dATP) and deoxycytidine triphosphate (dCTP) production were 1020 fmol/106 cells (130%) and 44.4 pmol/106 cells (82.5%), resulting in (90% prediction interval) 11% (0.45%, 53%) and 14% (2.6%, 35%) reductions. Model simulations of analog:dNTP molar ratios using IPERGAY dosing suggested that FTC significantly contributes to the protective effect of preexposure prophylaxis (PrEP). Simulation-based intracellular operational multiple dosing half-lives of TFV-DP and FTC-TP were 6.7 days and 33 hours. This model described the formation of intracellular TFV-DP/FTC-TP and the interaction with dNTPs, and can be used to simulate analog:dNTP time course for various dosing strategies.

Population Pharmacokinetic Model Linking Plasma and Peripheral Blood Mononuclear Cell Concentrations of Efavirenz and Its Metabolite, 8-Hydroxy-Efavirenz, in HIV Patients

“…We also report that the CYP2B6 genotype was the only covariate that significantly influenced the PK of efavirenz and 8OHEFV. The efficacy and toxicity of antiretroviral drugs may largely depend on intracellular dispositions in addition to their systemic exposure (16)(17)(18)(19). As reviewed by Almond et al, measurement of intracellular concentrations may give a better indication of antiviral exposure as the site of action (20).…”

“…This may suggest that a lack of knowledge of the relationship between plasma and intracellular concentrations of EFV limits the ability to fully understand the pharmacokinetic-pharmacodynamic relationships of EFV and to predict treatment and toxicity outcomes. A few PK models characterizing other antiretroviral drugs in plasma and the intracellular compartment have been developed (16,17,19,25).…”

HIV Antiretroviral Pre‐Exposure Prophylaxis: Development Challenges and Pipeline Promise

“…Using clinical data, Cottrell (UNC) and Chen (Colorado), separately, developed pharmacometric models that aligned well with RCT outcomes . The one narrow exception to this alignment is underpredicting the high degree of success of oral TDF alone in women in Partners PrEP—71% in the intent‐to‐treat analysis and 100% in their nested adherence enhancement substudy .…”

“…Multiple groups have reported substantial cervicovaginal vs. colorectal differences in tissue PK of the active form of TFV (TFV diphosphate (TFV‐DP)) and FTC (FTC triphosphate (FTC‐TP)) and deoxynucleotide triphosphates (dNTP), dATP, and dCTP, respectively, the natural competitors of nucleoside reverse transcriptase inhibitor (NRTIs) for HIV reverse transcriptase . A complex PK picture emerges indicating an important role for both drugs in both anatomic locations, more rapid phosphorylation and clearance of FTC than TFV, 10 to 100‐fold higher concentrations of the active TFV‐DP in colorectal tissue and 100‐fold higher active FTC‐TP in cervicovaginal tissue, and 10‐fold lower dNTP concentrations in colorectal tissue.…”

“…Multiple groups have reported substantial cervicovaginal vs. colorectal differences in tissue PK of the active form of TFV (TFV diphosphate (TFV-DP)) and FTC (FTC triphosphate (FTC-TP)) and deoxynucleotide triphosphates (dNTP), dATP, and dCTP, respectively, the natural competitors of nucleoside reverse transcriptase inhibitor (NRTIs) for HIV reverse transcriptase. 27,28 A complex PK picture emerges indicating an important role for both drugs in both anatomic locations, more rapid phosphorylation and clearance of FTC than TFV, 10 to 100-fold higher concentrations of the active TFV-DP in colorectal tissue and 100-fold higher active FTC-TP in cervicovaginal tissue, and 10-fold lower dNTP concentrations in colorectal tissue. Although there are competing methods for incorporation of the dNTP data into complex PK-viral dynamics models of these interactions, 18,27,28 the data help explain the need for at least 6-7 weekly doses of TDF/FTC in women (whose primary risk is receptive vaginal intercourse (RVI)), less frequent 4 per week dosing in MSM and TGW (whose primary risk is receptive anal intercourse (RAI)), and how only a few doses seems to provide rapid protection in MSM and TGW as in Ipergay.…”