Lenacapavir: Playing the Long Game in the New Era of Antiretrovirals.

The mainstay of antiretroviral therapy (ART) has been combination oral therapy. While oral ART is highly effective, nonadherence remains a chief concern. Addressing this concern in recent years is the emergence of long-acting antiretrovirals for the treatment and prevention of HIV-1 infection.

Safety and pharmacokinetics of VRC07-523LS administered via different routes and doses (HVTN 127/HPTN 087): A Phase I randomized clinical trial.

Background: Broadly neutralizing antibodies (bnAbs) are a promising approach for HIV-1 prevention. In the Antibody Mediated Prevention (AMP) trials, a CD4-binding site targeting bnAb, VRC01, administered intravenously (IV), demonstrated 75% prevention efficacy against highly neutralization-sensitive viruses but was ineffective against less sensitive viruses. VRC07-523LS is a next-generation bnAb targeting the CD4-binding site and was engineered for increased neutralization breadth and half-life.

Consensus recommendations for the use of novel antiretrovirals in persons with HIV who are heavily treatment-experienced and/or have multidrug-resistant HIV-1: Endorsed by the American Academy of HIV Medicine, American College of Clinical Pharmacy.

Treatment options are currently limited for persons with HIV-1 (PWH) who are heavily treatment-experienced and/or have multidrug-resistant HIV-1. Three agents have been approved by the U.S.

Pharmacokinetic Modeling to Guide Preclinical Development of an Islatravir-Eluting Reservoir-Style Biodegradable Implant for Long-Acting HIV PrEP.

Long-acting injectable cabotegravir is more effective than daily oral PrEP at preventing HIV transmission due to improved adherence, but requires bi-monthly large-volume intramuscular injections. Subcutaneous (SC) contraceptive implants can be formulated with antiretrovirals for extended-duration HIV PrEP. Islatravir (ISL) is a first-in-class, investigational antiretroviral with pharmacologic properties well-suited for implant delivery.

Mediation analysis of chronic kidney disease risk factors using kidney biomarkers in women living with HIV.

Objective: Novel urinary biomarkers reflecting kidney tubule health are associated with chronic kidney disease (CKD) risk in persons living with HIV. However, it is unknown whether these biomarkers provide mechanistic insight into the associations between clinical risk factors for CKD and subsequent CKD risk.

Methods: Among 636 women living with HIV in the Women's Interagency HIV Study with estimated glomerular filtration rate (eGFR) >60 ml/min/1.

Impact of Pregnancy on the Pharmacokinetics and Metabolism of Nicotinamide in Humans.

In pre-eclampsia models, nicotinamide (NAM) has protective effects in pre-eclampsia and is being evaluated as a therapeutic nutraceutical in clinical studies. NAM undergoes extensive hepatic metabolism by NAM N-methyltransferase to methylnicotinamide (MNA), which is subsequently metabolized to methyl-2-pyridone-5-carboxamide (M2PY) by aldehyde oxidase. However, the pharmacokinetics of NAM and its major metabolites has never been studied in pregnant individuals.

Reciprocal stabilization of coagulation factor XIII-A and -B subunits is a determinant of plasma FXIII concentration.

Transglutaminase factor XIII (FXIII) is essential for hemostasis, wound healing, and pregnancy maintenance. Plasma FXIII is composed of A and B subunit dimers synthesized in cells of hematopoietic origin and hepatocytes, respectively. The subunits associate tightly in circulation as FXIII-A2B2.

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).

Tubular Secretory Solute Clearance and HIV Infection.

Background: Tubular secretion is an important kidney function responsible for the clearance of numerous medications, including antibiotics and antivirals. It is unknown whether persons living with HIV have lower secretion compared with HIV-uninfected persons, which might predispose them to the risk of progressive kidney disease or adverse drug events.

Setting And Methods: We evaluated a panel of 6 endogenous secretory solutes in 199 women living with HIV (WLWH) and 100 women without HIV enrolled in the Women's Interagency HIV Study.

A Novel Algorithm to Improve PrEP Adherence Monitoring Using Dried Blood Spots.

Tenofovir diphosphate (TFVdp; an active metabolite of oral HIV pre-exposure prophylaxis (PrEP)) is measured in dried blood spots (DBS) to estimate adherence. However, TFVdp's long half-life in whole blood may lead to misclassification following a recent change in adherence. PrEP's other metabolite, emtricitabine triphosphate (FTCtp), has a shorter half-life in whole blood but adherence thresholds are undefined.

Silk fibers assisted long-term 3D culture of human primary urinary stem cells via inhibition of senescence-associated genes: Potential use in the assessment of chronic mitochondrial toxicity.

Despite being widely applied in drug development, existing models are not suitable to assess chronic mitochondrial toxicity. A novel assay system mimicking in vivo microenvironment for this purpose is urgently needed. The goal of this study is to establish a 3D cell platform as a reliable, sensitive, cost-efficient, and high-throughput assay to predict drug-induced mitochondrial toxicity.

Leveraging physiologically based pharmacokinetic modeling to optimize dosing for lopinavir/ritonavir with rifampin in pediatric patients.

Study Objective: Treatment of HIV and tuberculosis co-infection leads to significant mortality in pediatric patients, and treatment can be challenging due to the clinically significant drug-drug interaction (DDI) between lopinavir/ritonavir (LPV/RTV) and rifampin. Doubling LPV/RTV results in insufficient lopinavir trough concentrations in pediatric patients. The objective of this study was to leverage physiologically based pharmacokinetic (PBPK) modeling to optimize the adjusted doses of LPV/RTV in children receiving the WHO-revised doses of rifampin (15 mg/kg daily).

Plasma and breast milk pharmacokinetics of tenofovir alafenamide in mothers with chronic hepatitis B infection.

Background: Antenatal antiviral therapy (AVT) is effective in preventing mother-to-child transmission (MTCT) in chronic hepatitis B (CHB); tenofovir disoproxil fumarate (TDF) is the preferred agent. Tenofovir alafenamide (TAF) is a prodrug of tenofovir (TFV) similar to TDF, with improved bone and renal safety. There are no data on TAF breast milk pharmacokinetics and exposure to breastfeeding infants in CHB.

A phase I evaluation of the effect of curcumin on dose-limiting toxicity and pharmacokinetics of irinotecan in participants with solid tumors.

Curcumin inhibits UDP-glucuronyltransferases, a primary metabolic pathway for cancer chemotherapeutic agents like irinotecan. Concurrent administration of both agents may exacerbate irinotecan toxicity. We conducted this phase I study to determine the safety of concurrent curcumin and irinotecan administration.

The effect of age on CD4+ T-cell recovery in HIV-suppressed adult participants: a sub-study from AIDS Clinical Trial Group (ACTG) A5321 and the Bone Loss and Immune Reconstitution (BLIR) study.

Older age could be a risk factor for suboptimal CD4+ T-cell recovery in HIV-infected patients despite successful viral suppression. However, evaluation of this effect could be confounded by age-related immune processes such as decreased thymus output, increased immune activation and exhaustion. Here, we established a semi-mechanistic population model simultaneously describing naïve and memory CD4+ T-cell trajectories in 122 participants.

Implementation and Initial Evaluation of a Research and Scholarship Training Pathway in a Doctor of Pharmacy Curriculum.

To design, implement, and assess the initial impact of a pharmacy student research and scholarship training pathway. The Research and Scholarship in Pharmacy (RASP) pathway was designed to create a longitudinal, elective pathway within a Doctor of Pharmacy (PharmD) curriculum at a single institution. The pathway consisted of three elective courses built around a faculty-mentored scholarly project where students framed an answerable question, generated and interpreted relevant data, and communicated their findings in oral and written form.

Intracellular Tenofovir and Emtricitabine Concentrations in Younger and Older Women with HIV Receiving Tenofovir Disoproxil Fumarate/Emtricitabine.

The altered immune states of aging and HIV infection may affect intracellular metabolism of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC); increased cellular senescence decreases FTC-triphosphate (FTCtp) concentrations. The effects of age and inflammation on the ratio of intracellular metabolites (IMs; tenofovir diphosphate [TFVdp] and FTCtp) to their endogenous nucleotides (ENs; dATP and dCTP), a potential treatment efficacy marker, were assessed among participants of the Women's Interagency HIV Study (WIHS), who ranged from 25 to 75 years. Samples from women receiving TDF-FTC with viral loads of <200 copies/ml were dichotomized by age at collection into two groups (≤45 years and ≥60 years).

Population Pharmacokinetic/Pharmacodynamic Modeling of Methylprednisolone in Neonates Undergoing Cardiopulmonary Bypass.

Methylprednisolone is used in neonates to modulate cardiopulmonary bypass (CPB)-induced inflammation, but optimal dosing and exposure are unknown. We used plasma methylprednisolone and interleukin (IL)-6 and IL-10 concentrations from neonates enrolled in a randomized trial comparing one vs. two doses of methylprednisolone to develop indirect response population pharmacokinetic/pharmacodynamic models characterizing the exposure-response relationships.

Population Modeling Highlights Drug Disposition Differences Between Tenofovir Alafenamide and Tenofovir Disoproxil Fumarate in the Blood and Semen.

Understanding antiretroviral disposition in the male genital tract, a distinct viral compartment, can provide insight for the eradication of HIV. Population pharmacokinetic modeling was conducted to investigate the disposition of tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and emtricitabine and their metabolites in blood and semen. Blood plasma and seminal plasma (SP) concentrations of tenofovir and emtricitabine were measured, as were tenofovir-diphosphate and emtricitabine-triphosphate concentrations in peripheral blood mononuclear cells (PBMCs) and seminal mononuclear cells.