Analysis of the Endogenous Deoxynucleoside Triphosphate Pool in HIV-Positive and -Negative Individuals Receiving Tenofovir-Emtricitabine

Chen, Xinhui; Castillo‐Mancilla, José; Seifert, Sharon M; McAllister, Kevin B.; Zheng, Jia‐Hua; Bushman, Lane R.; MaWhinney, Samantha; Anderson, Peter L.

doi:10.1128/aac.01019-16

Cited by 11 publications

(17 citation statements)

References 38 publications

(49 reference statements)

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“…In the previous study of this data, dNTPs were shown to decrease during TDF/FTC treatment [30]. Thus, intracellular TFV-DP/FTC-TP models were linked to the reduction of the zero-order production rate constant ( K 0 in ) of the corresponding intracellular endogenous dNTPs.…”

Section: Resultsmentioning

confidence: 71%

“…TDF and FTC were well tolerated throughout the study (see Fig 1). 34 (among 40) subjects completed all study visits, two HIV negative and four HIV-positive subjects stopped the study early [22, 30], but all available longitudinal data prior to dropout were included in the model development.…”

Section: Resultsmentioning

confidence: 99%

“…On days 1 (first-dose) and 30, blood was collected at 1, 2, 4, 8, and 24 hours post-dose, and on days 3, 7, and 20, blood was collected pre-dose, 2 and 8 hours post-dose. Single blood samples were collected on days 35, 45, and 60 [22, 30]. The sample size was chosen to detect a ~60% increase (63%) in TFV-DP in HIV-negative versus HIV-infected persons using a significance level of 0.05, a power of 80%, a coefficient of variation for TFV-DP of 50%, and a two-sample t-test.…”

Section: Methodsmentioning

confidence: 99%

“…The dNTP pool components were quantified in PBMC samples from baseline, 1, 2, 4, 8, 24 hours post-dose on day 1, and 8 hours post-dose in all other visits. TFV/FTC in plasma and TFV-DP/FTC-TP in PBMC were assayed at all time points [22, 30]. …”

Section: Methodsmentioning

confidence: 99%

“…We previously characterized the dNTP pool reductions during TDF/FTC therapy, in the same participants included in this communication [22, 30], and used non-compartmental analysis (NCA) to describe TFV-DP/FTC-TP concentration-time profiles [22]. However, there is a need to understand the pharmacokinetic-pharmacodynamic (PKPD) relationships and to model non-linearities between plasma and intracellular TFV/FTC along with dNTP changes [19, 20, 31].…”

Section: Introductionmentioning

confidence: 99%

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Model Linking Plasma and Intracellular Tenofovir/Emtricitabine with Deoxynucleoside Triphosphates

et al. 2016

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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.

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Section: Resultsmentioning

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Model Linking Plasma and Intracellular Tenofovir/Emtricitabine with Deoxynucleoside Triphosphates

et al. 2016

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REverSe TRanscrIptase chain termination (RESTRICT) for selective measurement of nucleotide analogs used in HIV care and prevention

Olanrewaju

Sullivan

Gim

et al. 2022

Bioengineering & Transla Med

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Sufficient drug concentrations are required for efficacy of antiretroviral drugs used in HIV care and prevention. Measurement of nucleotide analogs, included in most HIV medication regimens, enables monitoring of short‐ and long‐term adherence and the risk of treatment failure. The REverSe TRanscrIptase Chain Termination (RESTRICT) assay rapidly infers the concentration of intracellular nucleotide analogs based on the inhibition of DNA synthesis by HIV reverse transcriptase enzyme. Here, we introduce a probabilistic model for RESTRICT and demonstrate selective measurement of multiple nucleotide analogs using DNA templates designed according to the chemical structure of each drug. We measure clinically relevant concentrations of tenofovir diphosphate, emtricitabine triphosphate, lamivudine triphosphate, and azidothymidine triphosphate with agreement between experiment and theory. RESTRICT represents a new class of activity‐based assays for therapeutic drug monitoring in HIV care and could be extended to other diseases treated with nucleotide analogs.

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

Hendrix

2018

Clin Pharma and Therapeutics

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The US Food and Drug Administration (FDA) approved oral daily tenofovir/emtricitabine (Truvada) for pre-exposure prophylaxis of human immunodeficiency virus (HIV) infection in 2012 on the basis of two randomized controlled trials (RCTs), one in men who have sex with men (MSM) and another in HIV serodiscordant heterosexual couples. Subsequently, even greater efficacy has been demonstrated in MSM with rapid population-level incidence reductions in some locations. In contrast, studies of antiretroviral pre-exposure prophylaxis (PrEP) in heterosexual women showed only modest or no efficacy, largely attributed to low adherence. The mixed results of antiretroviral-based PrEP bear witness to unique drug development challenges at this complicated intersection of sexual behavior, public health, and drug development. Multiple innovative methods and formulation strategies followed to address unmet medical needs of persons struggling with daily oral PrEP adherence or preference for nonsystemic PrEP options. Clinical pharmacology plays essential roles throughout this PrEP development process, especially in early product development and through pharmacologically informed enhancement and interpretation of clinical trials.

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Analysis of the Endogenous Deoxynucleoside Triphosphate Pool in HIV-Positive and -Negative Individuals Receiving Tenofovir-Emtricitabine

Cited by 11 publications

References 38 publications

Model Linking Plasma and Intracellular Tenofovir/Emtricitabine with Deoxynucleoside Triphosphates

Model Linking Plasma and Intracellular Tenofovir/Emtricitabine with Deoxynucleoside Triphosphates

REverSe TRanscrIptase chain termination (RESTRICT) for selective measurement of nucleotide analogs used in HIV care and prevention

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

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