Pharmacokinetics of tenofovir alafenamide, emtricitabine, and dolutegravir in a patient on peritoneal dialysis.

INTRODUCTION: Peritoneal dialysis (PD) is an effective renal replacement modality in people with HIV (PWH) with end-stage kidney disease (ESKD), particularly those with residual kidney function. Data on pharmacokinetics (PK) of antiretrovirals in patients on peritoneal dialysis are limited. METHODS: A single-participant study was performed on a 49-year-old gentleman with ESKD on PD and controlled HIV on once daily dolutegravir (DTG) 50 mg + tenofovir alafenamide (TAF) 25 mg / emtricitabine (FTC) 200 mg. He underwent serial blood plasma, peripheral blood mononuclear cell, and urine PK measurements over 24 h after an observed DTG + FTC/TAF dose. RESULTS: Plasma trough (Cmin) concentrations of TAF, tenofovir (TFV), FTC, and DTG were 0.05, 164, 1,006, and 718 ng/mL, respectively. Intracellular trough concentrations of TFV-DP and FTC-TP were 1142 and 11,201 fmol/million cells, respectively. Compared to published mean trough concentrations in PWH with normal kidney function, observed TFV and FTC trough concentrations were 15.5- and 20-fold higher, while intracellular trough concentrations of TFV-DP and FTC-TP were 2.2-fold and 5.4-fold higher, respectively. TFV and FTC urine levels were 20 times lower than in people with normal GFR. CONCLUSIONS: In a single ESKD PWH on PD, daily TAF was associated with plasma TFV and intracellular TFV-DP trough concentrations 15-fold and 2-fold higher than those of people with uncompromised kidney function, potentially contributing to nephrotoxicity. This suggests that TFV accumulates on PD; thus, daily TAF in PD patients may require dose adjustment or regimen change to optimize treatment, minimize toxicity, and preserve residual kidney function.

Cell-Penetrating Drug Carrier by Molecular Recognition of Sphingomyelin on Plasma Membranes.

Plasma membranes not only maintain the intracellular microenvironment through their phospholipid bilayer but also eliminate exogenous compounds outside the cell membranes. Most drugs especially with high polarity are prevented from entering into cells to exert their effects. Therefore, it is of great significance to design effective drug carriers with a penetrating ability toward plasma membranes. In this study, a dual-templated MIP (dt-MIPs) carrier with controllable microstructure and high drug loading capacity was prepared using highly expressed sphingomyelin on the plasma membrane and tenofovir (TFV), a first-line drug for HIV and chronic hepatitis B, as template molecules. The drug release experiments performed in vitro under simulated physiological conditions demonstrated that sustained and stable adsorption of TFV on dt-MIPs was more than 80% over 50 h. By a combination of flow cytometry and confocal microscopy, dt-MIPs were found to have efficient cell permeability. Furthermore, mass-spectrometry-based intracellular pharmacokinetic studies demonstrated that TFV was delivered completely into cells within 30 min with the delivery of dt-MIPs. The study presented above suggested that dt-MIPs are expected to be alternative nanoscale drug carriers for enhanced drug permeability and controlled release.

Relative Bioavailability of Dolutegravir (DTG) and Emtricitabine/Tenofovir Alafenamide Fumarate (F/TAF) Administered as Paediatric Tablet Formulations in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: Within the UNIVERSAL project (RIA2019PD-2882) we aim to develop a paediatric dolutegravir (DTG)/emtricitabine (FTC or F)/tenofovir alafenamide (TAF) fixed-dose combination. To inform dosing of this study, we undertook a relative bioavailability (RBA) study in healthy volunteers to investigate a potential pharmacokinetic effect when paediatric formulations of DTG and F/TAF are taken together. METHODS: Participants received all of the following treatments as paediatric formulations in randomised order: a single dose of 180/22.5 mg F/TAF; a single dose of 30 mg DTG; a single dose of 180/22.5 mg F/TAF plus 30 mg DTG. Blood concentrations of DTG, FTC, TAF, and tenofovir (TFV) were measured over 48 h post-dose. If the 90% confidence intervals (CIs) of the geometric least squares mean (GLSM) ratios of area under the curve (AUC) and maximum concentration (Cmax) of each compound were within 0.70-1.43, we considered this as no clinically relevant PK interaction. RESULTS: A total of 15 healthy volunteers were included. We did not observe a clinically relevant PK interaction between the paediatric DTG and F/TAF formulations for the compounds DTG, FTC, and TFV. For TAF, the lower boundaries of the 90% CIs of the GLSM ratios of the AUC0-∞ and Cmax fell outside our acceptance criteria of 0.70-1.43. CONCLUSIONS: Although TAF AUC and Cmax 90% CIs fell outside the pre-defined criteria (0.62-1.11 and 0.65-1.01, respectively), no consistent effect on TAF PK was observed, likely due to high inter-subject variability. Moreover, there are several reasons to rely on TFV exposure as being more clinically relevant than TAF exposure. Therefore, we found no clinically relevant interactions in this study.

Pharmacokinetics and safety of coformulated bictegravir, emtricitabine, and tenofovir alafenamide in children aged 2 years and older with virologically suppressed HIV: a phase 2/3, open-label, single-arm study.

BACKGROUND: Coformulated bictegravir, emtricitabine, and tenofovir alafenamide is a single-tablet regimen and was efficacious and well tolerated in children and adolescents with HIV (aged 6 years to <18 years) in a 48-week phase 2/3 trial. In this study, we report data from children aged at least 2 years and weighing 14 kg to less than 25 kg. METHODS: We conducted this open-label, multicentre, multicohort, single-arm study in South Africa, Thailand, Uganda, and the USA. Participants were virologically suppressed children with HIV, aged at least 2 years, weighing 14 kg to less than 25 kg. Participants received bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) once daily, switching to bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) upon attaining a bodyweight of at least 25 kg. The study included pharmacokinetic evaluation at week 2 to confirm the dose of coformulated bictegravir, emtricitabine, and tenofovir alafenamide for this weight band by comparing with previous adult data. Primary outcomes were bictegravir area under the curve over the dosing interval (AUCtau) and concentration at the end of the dosing interval (Ctau) at week 2, and incidence of treatment-emergent adverse events and laboratory abnormalities until the end of week 24 in all participants who received at least one dose of bictegravir, emtricitabine, and tenofovir alafenamide. This study is registered with ClinicalTrials.gov, NCT02881320. FINDINGS: Overall, 22 participants were screened (from Nov 14, 2018, to Jan 11, 2020), completed treatment with bictegravir, emtricitabine, and tenofovir alafenamide (until week 48), and entered an extension phase. The geometric least squares mean (GLSM) ratio for AUCtau for bictegravir was 7·6% higher than adults (GLSM ratio 107·6%, 90% CI 96·7-119·7); Ctau was 34·6% lower than adults (65·4%, 49·1-87·2). Both parameters were within the target exposure range previously found in adults, children, or both". Grade 3-4 laboratory abnormalities occurred in four (18%) participants by the end week 24 and six (27%) by the end of week 48. Drug-related adverse events occurred in three participants (14%) by the end of week 24 and week 48; none were severe. No Grade 3-4 adverse events, serious adverse events, or adverse events leading to discontinuation occurred by the end of week 24 and week 48. INTERPRETATION: Data support the use of single-tablet coformulated bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) for treatment of HIV in children aged at least 2 years and weighing 14 kg to less than 25 kg. FUNDING: Gilead Sciences.

Phase 1 randomized pharmacokinetic and safety study of a 90-day tenofovir vaginal ring in the United States.

INTRODUCTION: Tenofovir-based oral pre-exposure prophylaxis is currently approved for HIV prevention; however, adherence in women has been low. A vaginal gel containing tenofovir (TFV) demonstrated partial protection to HIV but protection was not confirmed in additional studies. Vaginal rings offer user-controlled long-acting HIV prevention that could overcome adherence and protection challenges. TFV may also help prevent herpes simplex virus type 2 acquisition when delivered intravaginally. We evaluated the pharmacokinetics, safety, adherence and acceptability of a 90-day TFV ring. METHODS: Between January and June 2019, Microbicide Trials Network (MTN)-038 enrolled 49 HIV-negative participants into a phase 1, randomized (2:1) trial comparing a 90-day ring containing 1.4 grams (g) TFV to a placebo ring. TFV concentrations were quantified in plasma, cervicovaginal fluid (CVF), rectal fluid and cervical tissue, and TFV-diphosphate (TFV-DP) in cervical tissue. Used rings were analysed for residual TFV. Safety was assessed by adverse events (AEs); acceptability and adherence by self-report. RESULTS: Mean age was 29.5; 46 identified as cisgender-female and three gender non-conforming. There were no differences in the proportion of participants with grade ≥2 genitourinary AEs in the TFV versus placebo arms (p = 0.41); no grade ≥3 AEs were reported. Geometric mean TFV concentrations increased through day 34 in CVF/rectal fluid and day 59 in plasma, but declined across compartments by day 91. Geometric mean TFV-DP tissue concentrations exceeded the 1000 fmol/mg target through day 56, but fell to 456 fmol/mg at day 91. Among 32 rings returned at the end of the study, 13 had no or low (<0.1 g) residual TFV. Residual TFV did not differ by socio-demographics, sexual activity, Nugent Score or vaginal microbiota. Most participants reported being fully adherent to ring use: 85% and 81% in the TFV and placebo arms, respectively (p = 1.00). A majority of participants reported liking the ring (median 8 on a 10-point Likert scale) and reported a high likelihood of using the ring in the future, if effective (median 9). CONCLUSIONS: The 90-day TFV ring was well-tolerated, acceptable and exceeded target cervical tissue concentrations through day 56, but declined thereafter. Additional studies are needed to characterize the higher release from TFV rings in some participants and the optimal duration of use.

Physiologically based Pharmacokinetic Model Validated to Enable Predictions Of Multiple Drugs in a Long-acting Drug-combination Nano-Particles (DcNP): Confirmation with 3 HIV Drugs, Lopinavir, Ritonavir, and Tenofovir in DcNP Products.

Drug-Combination Nanoparticles (DcNP) are a novel drug delivery system designed for synchronized delivery of multiple drugs in a single, long-acting, and targeted dose. Unlike depot formulations, slowly releasing drug at the injection site into the blood, DcNP allows multiple-drug-in-combination to collectively distribute from the injection site into the lymphatic system. Two distinct classes of long-acting injectables products are proposed based on pharmacokinetic mechanisms. Class I involves sustained release at the injection site. Class II involves a drug-carrier complex composed of lopinavir, ritonavir, and tenofovir uptake and retention in the lymphatic system before systemic access as a part of the PBPK model validation. For clinical development, Class II long-acting drug-combination products, we leverage data from 3 nonhuman primate studies consisting of nine PK datasets: Study 1, varying fixed-dose ratios; Study 2, short multiple dosing with kinetic tails; Study 3, long multiple dosing (chronic). PBPK validation criteria were established to validate each scenario for all drugs. The models passed validation in 8 of 9 cases, specifically to predict Study 1 and 2, including PK tails, with ritonavir and tenofovir, fully passing Study 3 as well. PBPK model for lopinavir in Study 3 did not pass the validation due to an observable time-varying and delayed drug accumulation, which likely was due to ritonavir's CYP3A inhibitory effect building up during multiple dosing that triggered a mechanism-based drug-drug interaction (DDI). Subsequently, the final model enables us to account for this DDI scenario.

Determinants of early change in serum creatinine after initiation of dolutegravir-based antiretroviral therapy in South Africa.

AIMS: Dolutegravir increases serum creatinine by inhibiting its renal tubular secretion and elimination. We investigated determinants of early changes in serum creatinine in a southern African cohort starting first-line dolutegravir-based antiretroviral therapy (ART). METHODS: We conducted a secondary analysis of data from participants in a randomized controlled trial of dolutegravir, emtricitabine and tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide fumarate (TAF) (ADVANCE, NCT03122262). We assessed clinical, pharmacokinetic and genetic factors associated with change in serum creatinine from baseline to Week 4 using linear regression models adjusted for age, sex, baseline serum creatinine, HIV-1 RNA concentration, CD4 T-cell count, total body weight and co-trimoxazole use. RESULTS: We included 689 participants, of whom 470 had pharmacokinetic data and 315 had genetic data. Mean change in serum creatinine was 11.3 (SD 9.9) µmol.L-1. Factors that were positively associated with change in serum creatinine at Week 4 were increased log dolutegravir area under the 24-h concentration-time curve (change in creatinine coefficient [ß] = 2.78 µmol.L-1 [95% confidence interval (CI) 0.54, 5.01]), TDF use (ß = 2.30 [0.53, 4.06]), male sex (ß = 5.20 [2.92, 7.48]), baseline serum creatinine (ß = -0.22 [-0.31, -0.12]) and UGT1A1 rs929596 A→G polymorphism with a dominant model (ß = -2.33 [-4.49, -0.17]). The latter did not withstand correction for multiple testing. CONCLUSIONS: Multiple clinical and pharmacokinetic factors were associated with early change in serum creatinine in individuals initiating dolutegravir-based ART. UGT1A1 polymorphisms may play a role, but further research on genetic determinants is needed.

Pharmacokinetic and Bioequivalence Evaluation of Single-Tablet and Separate-Tablet Regimens for Ainuovirine, Lamivudine, and Tenofovir Disoproxil Fumarate in Chinese Healthy Subjects.

This was a single-dose, randomized, open-label, 2-period crossover study to evaluate the bioequivalence of the ACC008 (test formulation [T]) versus coadministered ainuovirine (ANV) 150 mg, lamivudine (3TC) 300 mg, and tenofovir disoproxil fumarate 300 mg (reference formulation [R]) in the fasted state among the Chinese healthy adults. Eligible subjects were randomized into 2 cohorts to received treatment in 1 of 2 sequences (T â†’ R, R â†’ T). PK samples were collected from 1 hour before dosing to 144 hours after dosing in each period. The concentrations of ANV, 3TC, and tenofovir in plasma were determined by liquid chromatography-tandem mass spectrometry. Phoenix WinNonlin software was used for pharmacokinetic parameter calculation and bioequivalence evaluation. All the 90% confidence intervals of maximum concentration, area under the concentration-time curve from time zero to the last detectable time, and area under the concentration-time curve from time zero to infinity fell within the bioequivalence range. The safety was comparable between the 2 treatments, with no Grade III/VI or serious adverse events. ACC008 was bioequivalent to administration of its individual components, including ANV 150 mg, 3TC 300 mg, and tenofovir disoproxil fumarate 300 mg with favorable safety profile.

A multicompartment population PK model to predict tenofovir and emtricitabine mucosal tissue concentrations for HIV prevention.

A priori use of mathematical modeling and simulation to predict outcomes from incomplete adherence or reduced frequency dosing strategies may mitigate the risk of clinical trial failure with HIV pre-exposure prophylaxis regimens. We developed a semi-physiologic population pharmacokinetic model for two antiretrovirals and their active intracellular metabolites in three mucosal tissues using pharmacokinetic data from a phase I, dose-ranging study. Healthy female volunteers were given a single oral dose of tenofovir disoproxil fumarate (150, 300, or 600 mg) or emtricitabine (100, 200, or 400 mg). Simultaneous co-modeling of all data was performed on a Linux cluster. A 16 compartment, bolus input, linear kinetic model best described the data, containing 986 observations in 23 individuals across three matrices and four analytes. Combined with a defined efficacious concentration target in mucosal tissues, this model can be used to optimize the dose and dosing frequency through Monte-Carlo simulations.

Preparation and Characterization of 3D-Printed Dose-Flexible Printlets of Tenofovir Disoproxil Fumarate.

The aim of this work was to design pediatric-friendly, dose-flexible orally disintegrating drug delivery systems (printlets) of the antiviral drug tenofovir disoproxil fumarate (TDF) by selective laser sintering (SLS) for potential use in hospitals along with other antiviral drugs. In order to obtain a consistent quality of printlets with desired properties, it is important to understand certain critical quality attributes for their main and interactions effect. The printlets were optimized by Box-Behnken's design of the experiment by varying process variables while keeping the composition constant. The composition contained 16.3% TDF, 72.7% polyvinyl pyrrolidone K16-18, 8% magnesium aluminum silicate, 3% Candurin® NXT Ruby Red, and 0.3% colloidal silicon dioxide. The process variables studied were surface (X1), chamber temperatures (X2), and laser scanning speed (X3). The range of variable levels was 75-85°C for X1, 50-70°C for X2, and 200-240 mm/s for X3, respectively. The responses studied were hardness, disintegration time, dissolution, physiochemical, and pharmacokinetic characterization. X-ray powder diffraction indicated partial or complete conversion of the crystalline drug into amorphous form in the printlets. Comparative pharmacokinetics between Viread® (generic) and printlets in rats were superimposable. Pharmacokinetic parameters showed statistically insignificant differences between the two formulations in terms of Tmax, Cmax, and AUC of (p > 0.05). Printlets were bioequivalent to Viread® as per FDA bioequivalence criteria. Thus, the SLS printing method showed the fabrication of dose-flexible printlets with quality, and in vivo performance equivalent to commercial tablets.

Tenofovir Concentration Is Not Enough in Intraocular Tissues of Patients With HIV infection.

OBJECTIVE: To determine tenofovir (TFV) penetration into intraocular tissues using ultra high-performance liquid chromatography/tandem mass spectrometry (UHPLC-MS/MS). METHODS: Nineteen participants taking tenofovir in combination antiretroviral therapy (cART) regimen who underwent pars plana vitrectomy (PPV) surgery were enrolled in the observational retrospective study between January 2019 and August 2021. The participants were divided into mild, moderate, and severe groups according to retinal manifestations. Basic information was recorded during PPV surgery. Paired blood plasma and vitreous humor samples (n = 19) were collected for UHPLC-MS/MS. RESULTS: The median plasma and vitreous tenofovir concentrations were 106.00 ng/mL (interquartile range[IQR], 54.6-142.5) and 41.40 ng/mL (IQR 9.4-91.6), respectively. The median vitreous/plasma concentration ratio from the paired samples was 0.42 (IQR 0.16-0.84). The plasma and vitreous tenofovir concentrations were significantly correlated (r = 0.483, P = 0.036). The median vitreous tenofovir concentration was the lowest in the mild group (4.58 ng/mL). Six vitreous samples were below 50% inhibitory concentration (IC50) (11.5 ng/mL), and 2 of them were undetectable. Significant differences were noted in vitreous/plasma and vitreous tenofovir concentrations ( P = 0.035 and P = 0.045, respectively) among the 3 groups but not in plasma tenofovir concentration ( P = 0.577). No correlation was noted between vitreous HIV-1 RNA and vitreous tenofovir concentrations (r = 0.049, P = 0.845). CONCLUSION: Vitreous tenofovir did not reliably or consistently achieve concentrations sufficient to inhibit viral replication in intraocular tissues due to poor penetration of the blood-retinal barrier (BRB). The higher vitreous tenofovir concentrations were associated with moderate or severe disease compared with mild disease, indicating an association with the severity of BRB disruption.

Physiologically-Based Pharmacokinetic Modeling of Tenofovir Disoproxil Fumarate in Pregnant Women.

PURPOSE: Physiological changes during pregnancy can affect antiretroviral drug processes and further influence drug efficacy and safety. Physiologically-based pharmacokinetic (PBPK) modeling offers a unique modality to predict PK in pregnant women. The objective of this study was to establish a PBPK modeling of tenofovir disoproxil fumarate (TDF) in pregnant women, to provide a reference for the clinical use of TDF. METHODS: A full PBPK modeling of tenofovir (TFV) and TDF following i.v. and p.o. administration was developed using the simulation software PK-Sim®. The modeling was then extrapolated to pregnant women based on pregnancy- related physiological parameters in Mobi® Simulator. The mean fold error (MFE) and geometric mean fold error (GMFE) methods were used to compare the differences between predicted and observed values of PK parameters (Cmax, tmax, AUC0-∞) to evaluate the accuracy of PBPK modeling. RESULTS: The developed PBPK modeling successfully predicted the TDF disposition in the non-pregnant population, wherein the MFE average and GMFE of all predicted PK parameters were within a 1.5-fold error range, and more than 96.30% of the predicted drug concentration values were within a 2-fold error range of the measured values. After the extrapolation of these models to the third trimester of pregnancy, the scaling anatomy/physiology and hepatic intrinsic clearance made the pregnant population PBPK modeling meet the standard requirement of 0.5 < MFE and GMFE value < 2. It was more appropriate to simulate the in vivo process of low-dose TDF in pregnant women. CONCLUSION: The non-pregnant population PBPK modeling of TDF established in our study can be extrapolated to pregnant women. Our study provides a reference for realizing clinical personalized medication for pregnant women.

Impact of feminizing hormone therapy on tenofovir and emtricitabine plasma pharmacokinetics: a nested drug-drug interaction study in a cohort of Brazilian transgender women using HIV pre-exposure prophylaxis.

OBJECTIVES: Potential interactions between feminizing hormone therapy (FHT) and pre-exposure prophylaxis (PrEP) may be a barrier to PrEP use among transgender women (TGW). We aimed to assess the impact of FHT on PrEP plasma pharmacokinetics (PK) among TGW. METHODS: This was a PK substudy of the effects of FHT on tenofovir disoproxil fumarate/emtricitabine nested to a trans-specific PrEP demonstration study (NCT03220152). Participants were assigned to receive PrEP only (noFHT) or standardized FHT (sFHT; oestradiol valerate 2-6 mg plus spironolactone 100-300 mg) plus PrEP for 12 weeks, after which they could start any FHT (aFHT). Short- and long-term PK assessment occurred at Weeks 12 and 30-48, respectively (plasma samples prior and 0.5, 1, 2, 4, 6, 8 and 24 h after dose). Non-compartmental PK parameters of tenofovir and emtricitabine were compared as geometric mean ratios (GMRs) between noFHT and PrEP and FHT (sFHT at short-term PK; aFHT at long-term PK) participants. RESULTS: No differences in tenofovir and emtricitabine plasma PK parameters were observed between the short-term PK of noFHT (n = 12) and sFHT participants (n = 18), except for emtricitabine Cmax [GMR: 1.15 (95% CI: 1.01-1.32)], or between noFHT short-term PK and aFHT long-term PK (n = 13). Most participants were on oestradiol valerate 2 mg at the short-term PK (56%) and 4 mg at the long-term PK (54%). Median (IQR) oestradiol levels were 56.8 (43.2-65.4) pg/mL at short-term PK (sFHT) and 44.8 (24.70-57.30) pg/mL at long-term PK (aFHT). No participants in this analysis seroconverted during the study. CONCLUSIONS: Our results indicate no interaction of FHT on tenofovir levels, further supporting PrEP use among TGW using FHT.

Vaginal Microbiota and Mucosal Pharmacokinetics of Tenofovir in Healthy Women Using a 90-Day Tenofovir/Levonorgestrel Vaginal Ring.

Background: A relationship between the vaginal microbiota and tenofovir (TFV) concentrations and activity after topical administration has been previously reported. Objective: CONRAD A15-138 was a randomized, placebo-controlled Phase I study aimed at characterizing the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TFV and levonorgestrel (LNG) administered through a vaginal ring (IVR) for 90 days. Herein, we describe changes from baseline in the vaginal microbiota with IVR use and the impact of the vaginal microbiota on mucosal TFV PK. Methods: The study screened 68 participants and randomized 47 (37 TFV/LNG, 10 placebo), assessing the vaginal microbiota by sequencing the V3-V4 regions of 16S rRNA genes prior to IVR insertion and monthly for 3 months. Concentrations of TFV in vaginal fluid (VF), and TFV and TFV-diphosphate (TFV-DP) in vaginal tissue, and modeled PD against HIV-1 in vitro were measured before and after treatment. Results: There were no clinically significant changes in relative abundance of vaginal bacterial phylotypes from pre-insertion baseline at any month among active and placebo IVR users. There were no significant changes in community state type (CST) with IVR use. Participants with diverse, anaerobic CST IVA/B microbiota had higher in vivo release of TFV from the IVR compared to women with Lactobacillus-dominated (LbD) microbiota, who had expected in vivo TFV release rates. Median VF TFV concentrations were significantly higher among women with CST IVA/B microbiota in months 1 (3,135 ng/mg VF) and 2 (3,800 ng/mg). Women with LbD microbiota had significantly higher median VF TFV concentration (1,423 ng/mg) and median TFV (103 ng/mg) and TFV-DP (5,877 fmol/mg) tissue concentrations versus women with CST IVA/B microbiota at month 3. All women demonstrated a significant increase from pre-insertion baseline of in vitro HIV-1 inhibition by VF (p values <0.05). PD differences in tissue according to CST, however, were not statistically significant. Conclusion: TFV/LNG IVR use did not change the vaginal microbiota nor increase the incidence of CST IVA/B. Vaginal microbiota, and in particular CST IVA/B, possibly through increased vaginal pH, impacted in vivo TFV release and cervicovaginal (CV) PK, but both PK and PD data suggest CV protection against HIV-1. Clinical Trial Registration: ClinicalTrials.gov (#NCT03279120).

Effects of Genetic Polymorphisms of Cathepsin A on Metabolism of Tenofovir Alafenamide.

Cathepsin A (CatA) is important as a drug-metabolizing enzyme responsible for the activation of prodrugs, such as the anti-human immunodeficiency virus drug Tenofovir Alafenamide (TAF). The present study was undertaken to clarify the presence of polymorphisms of the CatA gene in healthy Japanese subjects and the influence of gene polymorphism on the expression level of CatA protein and the drug-metabolizing activity. Single-strand conformation polymorphism method was used to analyze genetic polymorphisms in healthy Japanese subjects. Nine genetic polymorphisms were identified in the CatA gene. The polymorphism (85_87CTG>-) in exon 2 was a mutation causing a deletion of leucine, resulting in the change of the leucine 9-repeat (Leu9) to 8-repeat (Leu8) in the signal peptide region of CatA protein. The effect of Leu8 on the expression level of CatA protein was evaluated in Flp-In-293 cells with a stably expressed CatA, resulting in the expression of CatA protein being significantly elevated in variant 2 with Leu8 compared with Leu9. Higher concentrations of tenofovir alanine (TFV-Ala), a metabolite of TAF, were observed in the Leu8-expressing cells than in the Leu9-expressing cells using LC/MS/MS. Our findings suggest that the drug metabolic activity of CatA is altered by the genetic polymorphism.

Lack of a Clinically Meaningful Drug Interaction Between the HIV-1 Antiretroviral Agents Islatravir, Dolutegravir, and Tenofovir Disoproxil Fumarate.

Islatravir, an investigational nucleoside reverse transcriptase translocation inhibitor, is in clinical development for the treatment and prevention of HIV-1 infection. Because islatravir may be coadministered with other antiretroviral agents, assessment of potential drug-drug interactions are warranted. This phase 1, open-label, fixed-sequence, 2-period trial in adults without HIV (N = 12) assessed the safety and pharmacokinetic interactions of islatravir administered with dolutegravir and tenofovir disoproxil fumarate (TDF). In period 1, participants received a single oral dose of islatravir (20 mg). In period 2, participants received oral doses of dolutegravir (50 mg) and TDF (300 mg) once daily on days 1 through 11, with a single oral dose of islatravir (20 mg) coadministered on day 8. There were no clinically significant changes in islatravir, dolutegravir, or TDF pharmacokinetics following coadministration. Islatravir was generally well tolerated when administered alone or in combination with dolutegravir and TDF. Coadministration of islatravir, dolutegravir, and TDF is supported, with no clinically meaningful effect on pharmacokinetics, safety, or tolerability in participants without HIV.

Transformation of tenofovir into stable ProTide nanocrystals with long-acting pharmacokinetic profiles.

Treatment and prevention of human immunodeficiency virus type one (HIV-1) infection was transformed through widespread use of antiretroviral therapy (ART). However, ART has limitations in requiring life-long daily adherence. Such limitations have led to the creation of long-acting (LA) ART. While nucleoside reverse transcriptase inhibitors (NRTI) remain the ART backbone, to the best of our knowledge, none have been converted into LA agents. To these ends, we transformed tenofovir (TFV) into LA surfactant stabilized aqueous prodrug nanocrystals (referred to as NM1TFV and NM2TFV), enhancing intracellular drug uptake and retention. A single intramuscular injection of NM1TFV, NM2TFV, or a nanoformulated tenofovir alafenamide (NTAF) at 75 mg/kg TFV equivalents to Sprague Dawley rats sustains active TFV-diphosphate (TFV-DP) levels ≥ four times the 90% effective dose for two months. NM1TFV, NM2TFV and NTAF elicit TFV-DP levels of 11,276, 1,651, and 397 fmol/g in rectal tissue, respectively. These results are a significant step towards a LA TFV ProTide.

Brief Report: Pharmacokinetics of Bictegravir and Tenofovir in Combination With Darunavir/Cobicistat in Treatment-Experienced Persons With HIV.

BACKGROUND: Bictegravir coformulated with emtricitabine and tenofovir alafenamide as a fixed-dose combination (BIC/FTC/TAF 50/200/25 mg) is recommended as an initial regimen in patients who are antiretroviral (ARV)-naïve or virologically suppressed on a stable ARV regimen. However, no real-world pharmacokinetic (PK) data are available in treatment-experienced patients with antiretroviral resistance receiving BIC/FTC/TAF plus a boosted protease inhibitor. SETTING/METHODS: This prospective, single-center, nonrandomized pharmacokinetic study enrolled adult treatment-experienced persons with HIV and creatinine clearance >30 mL/min receiving BIC/FTC/TAF + DRV/c as part of routine clinical care. Steady-state PK profiles of BIC, TAF, tenofovir (TFV), and DRV after daily dosing of BIC/FTC/TAF + darunavir/cobicistat (DRV/c) were obtained with samples at predose and 0.5, 1, 2, and 4 hours postdose. The AUC0-24 at steady state was extrapolated by imputing C0 for C24 for each participant (AUC0-tau,exp). RESULTS: Nine participants were enrolled with a median age of 59 years (range 54-67) and median number of years on ART of 19 (range 5.8-30). The median (interquartile range [IQR]) BIC AUC0-tau,exp and Cmax values were 128.9 µg*h/mL (78.1-159.5) and 6.9 µg/mL (5.1-9.8), respectively. The median (IQR) TAF AUC0-tau,exp and Cmax values were 0.376 µg*h/mL (0.199-0.430) and 0.276 µg/mL (0.149-0.543), respectively. Predose concentrations of TFV and DRV were comparable with historical data. CONCLUSION: Treatment-experienced persons with HIV receiving BIC/FTC/TAF + darunavir/cobicistat (DRV/c) had BIC exposures (AUC0-tau) that were increased by approximately 26% compared with historical PK data. Although TAF exposures were substantially increased, plasma TFV was only modestly higher. These results suggest that BIC/TAF/FTC + DRV/c is a viable antiviral regimen option for treatment-experienced persons.

Lopinavir and tenofovir interaction observed in non-pregnant adults altered during pregnancy.

WHAT IS KNOWN AND OBJECTIVE: Tenofovir exposure is increased in non-pregnant adults when tenofovir disoproxil fumarate is coadministered with lopinavir/ritonavir. In pregnant women, tenofovir exposure is decreased. Our objective is to describe the effect of lopinavir/ritonavir on tenofovir pharmacokinetics during pregnancy. METHODS: Data were collected through the International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) Network P1026s protocol. This was a nonrandomized, open-label, parallel-group and multicentre phase-IV prospective study in pregnant women with HIV. Intensive steady-state 24-h pharmacokinetic profiles were collected during the third trimester of pregnancy and postpartum. Tenofovir was measured in plasma using validated liquid chromatography-mass spectrometry method (quantification limit: 10 ng/ml). Statistical tests compared paired and between group pharmacokinetic data. RESULTS AND DISCUSSION: In women not receiving lopinavir/ritonavir (n = 28), tenofovir AUC0-24 was 27% lower (2.2 mcg·h/ml vs 2.8 mcg·h/ml, p = 0.002) and oral clearance was 27% higher (61 L/h vs 48 L/h, p = 0.001) during the third trimester compared to paired postpartum data. In women receiving lopinavir/ritonavir (n = 10), tenofovir AUC0-24 and oral clearance were not different antepartum compared to postpartum. Women with and women without concomitant lopinavir/ritonavir displayed no significant differences in postpartum tenofovir pharmacokinetics. WHAT IS NEW AND CONCLUSION: Tenofovir exposure during the third trimester was reduced compared to postpartum in pregnant women not receiving lopinavir/ritonavir, but not in pregnant women also receiving lopinavir/ritonavir. Our findings suggest that pregnancy confounds the expected decrease in tenofovir exposure with concomitant lopinavir/ritonavir in non-pregnant adults. These findings illustrate the need for drug-drug interaction studies in pregnant women as drug disposition differs significantly in pregnant women compared to non-pregnant adults.

Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide in adolescents and children with HIV: week 48 results of a single-arm, open-label, multicentre, phase 2/3 trial.

BACKGROUND: Bictegravir is a potent integrase strand-transfer inhibitor (INSTI) with a high genetic barrier to resistance. Bictegravir, coformulated with emtricitabine and tenofovir alafenamide, is recommended by key European and US HIV treatment guidelines as the preferred single-tablet regimen for adults and adolescents. The aim of this study was to assess the pharmacokinetics, safety, and efficacy of switching to this regimen in virologically suppressed children and adolescents with HIV. METHODS: In this single-arm, open-label trial, we enrolled virologically suppressed children and adolescents (aged 6 to <18 years) with HIV at 22 hospital clinics in South Africa, Thailand, Uganda, and the USA. Eligible participants had a bodyweight of at least 25 kg, were virologically suppressed (HIV-1 RNA <50 copies per mL) on a stable ART regimen for at least 6 months before screening, had a CD4 count of at least 200 cells per µL, and an estimated glomerular filtration rate of at least 90 mL/min per 1·73 m2 by the Schwartz formula at screening. All participants received the fixed-dose regimen of coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg once daily. Pharmacokinetic analysis was used for dosing confirmation, and results compared with adult values. The primary outcomes were area under the curve at the end of the dosing interval (AUCtau) and concentration at the end of the dosing interval (Ctau) of bictegravir, and incidence of treatment-emergent adverse events and laboratory abnormalities at week 24. Efficacy and safety analyses included all participants who received at least one dose of study drug. We report the 48-week results. This study is registered with ClinicalTrials.gov, NCT02881320. FINDINGS: Between Sept 29, 2016 and Feb 16, 2018, we enrolled 102 participants. 100 participants received bictegravir, emtricitabine, and tenofovir alafenamide (cohort 1 [adolescents aged 12 to <18 years], n=50; cohort 2 [children aged 6 to <12 years], n=50). The mean bictegravir AUCtau was 89 100 ng × h/mL (coefficient of variation 31·0%) in adolescents (cohort 1) and 128 000 ng × h/mL (27·8%) in children (cohort 2). Compared with adults, bictegravir Ctau was 35% lower in adolescents and 11% lower in children. The 90% CIs of both parameters were within the predefined pharmacokinetic equivalence boundary and within overall range of exposures observed in adults and deemed to be safe and efficacious (geometric least-squares mean ratio [GLSM] 86·3% [90% CI 80·0-93·0] for AUCtau and 65·4% [58·3-73·3] for Ctau in adolescents; GLSM 125% [90% CI 117-134] for AUCtau and 88·9% [80·6-98·0] for Ctau for children). Bictegravir, emtricitabine, and tenofovir alafenamide was well tolerated; most adverse events were grade 2 or less in severity and no study drug-related serious adverse events were reported. One participant discontinued study drug due to adverse events (grade 2 insomnia and anxiety). Virological suppression (HIV-1 RNA <50 copies per mL) was maintained by all 100 participants at week 24 and by 98 (98%) of 100 at week 48; no participants had treatment-emergent resistance. INTERPRETATION: In adolescents and children with HIV, the bictegravir, emtricitabine, and tenofovir alafenamide single-tablet regimen was well tolerated and maintained virological suppression. Our data support the treatment of HIV in adolescents and children with this single-tablet regimen. At present, the single-tablet regimen is recommended as first-line treatment in the USA for adolescents and as an alternative regimen in children and has the potential to represent an important regimen in the paediatric population. FUNDING: Gilead Sciences.