Model Linking Plasma and Intracellular Tenofovir/Emtricitabine with Deoxynucleoside Triphosphates.
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.
University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United States of America.
Xinhui
http://orcid.org/0000-0001-5022-3323
X
Chen
University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United States of America.
Sharon M
http://orcid.org/0000-0001-5092-7910
SM
Seifert
University of Colorado, School of Medicine, Division of Infectious Diseases, Aurora, CO, United States of America.
Jose R
JR
Castillo-Mancilla
University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United States of America.
Lane R
LR
Bushman
University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United States of America.
Jia-Hua
JH
Zheng
University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United States of America.
Jennifer J
JJ
Kiser
University of Colorado, Colorado School of Public Health, Department of Biostatistics and Informatics, Aurora, CO, United States of America.
Samantha
S
MaWhinney
University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United States of America.
Peter L
PL
Anderson
D000328:Adult; D019380:Anti-HIV Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003198:Computer Simulation; D003838:Deoxyadenine Nucleotides / Q000378:metabolism*; D003845:Deoxycytosine Nucleotides / Q000378:metabolism*; D011756:Diphosphates / Q000378:metabolism; D000068679:Emtricitabine / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D006678:HIV / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011122:Polyphosphates / Q000378:metabolism; D011446:Prospective Studies; D000068698:Tenofovir / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D055815:Young Adult
C115030:2'-deoxyadenosine-3'-triphosphate; D019380:Anti-HIV Agents; D003838:Deoxyadenine Nucleotides; D003845:Deoxycytosine Nucleotides; D011756:Diphosphates; D011122:Polyphosphates; C031764:3'-deoxycytidine 5'-triphosphate; D000068698:Tenofovir; D000068679:Emtricitabine; C005692:triphosphoric acid