Pharmacokinetics, Safety, Efficacy and Acceptability of Daclatasvir Plus Sofosbuvir in Young Children With Chronic HCV Infection.

Background And Aims: Sofosbuvir (SOF) plus daclatasvir (DCV) is a primary chronic hepatitis C virus (HCV) treatment in low- and middle-income countries. WHO guidelines recommend a half-adult dose for children (14-25 kg) based on pharmacokinetic modelling, requiring clinical validation. We evaluated the pharmacokinetics, safety, efficacy and acceptability of DCV (30 mg) and SOF (200 mg) in children weighing 14 to < 17 kg and 17-35 kg.

Brief Report: Can a Fraction of the Dolutegravir Dispersible Tablet Solution be Used to Dose Neonates?

Background: The smallest dolutegravir (DTG) dose approved is 5 mg once-daily in infants ≥4 weeks and weighing ≥3 to <6 kg using a dispersible tablet (DT). Neonates (<28 days of life) may require a lower dose due to immature organ development. We evaluated the aqueous dispersibility of the generic DTG-DT 10-mg scored tablets (Viatris Inc.

Pharmacokinetics of first-line tuberculosis drugs rifampin, isoniazid, ethambutol, and pyrazinamide during pregnancy and postpartum with and without efavirenz-based antiretroviral treatment: IMPAACT P1026s study.

The pharmacokinetics (PK) of antituberculosis drugs may be altered by both pregnancy-induced physiological changes and drug interactions in individuals living with HIV who develop tuberculosis. Within the multicenter International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s study, we assessed the PK of rifampin, isoniazid, ethambutol, and pyrazinamide during pregnancy and postpartum (PP) in women on efavirenz-based antiretroviral therapy (ART). Results were compared to a previously published non-HIV group and described minimum targets.

Efficacy, Safety and Tolerability of Dispersible and Immediate Release Abacavir/Dolutegravir/Lamivudine Tablets in Children With HIV: IMPAACT 2019 Week 48 Results.

Background: Dispersible and immediate-release fixed-dose combinations (FDC) of abacavir, dolutegravir, and lamivudine are priority first-line antiretroviral therapy (ART) in children with HIV-1 (CWHIV). We report safety, efficacy and tolerability of these regimens through 48 weeks of treatment.

Methods: IMPAACT 2019 was a phase I/II, international, multisite, open-label, noncomparative study of dispersible and immediate-release FDC abacavir/dolutegravir/lamivudine (ABC/DTG/3TC) in participants with HIV-1 <12 years of age weighing 6 to <40 kg.

No significant drug-drug interaction between oral TAF-based PrEP and feminizing hormone therapy among transgender women in Thailand: the iFACT-3 study.

Introduction: Concerns regarding potential drug-drug interaction (DDI) between feminizing hormone therapy (FHT) and HIV pre-exposure prophylaxis (PrEP) may hinder PrEP use among transgender women. We assessed the potential DDI between FHT and emtricitabine-tenofovir alafenamide (F/TAF)-based PrEP among transgender women.

Methods: Transgender women without HIV who never underwent orchiectomy were enrolled between January and February 2022.

Assessment of the steady-state drug-drug interactions between dolutegravir and ritonavir-boosted darunavir in adolescents.

Objectives: DTG is primarily metabolized by the UDP-glycosyltransferase (UGT) 1A1, and to a lesser extent by the cytochrome P450 (CYP) 3A4. Co-administration of DRV/r has been reported to decrease DTG plasma concentrations. Our aim was to distinguish the extent of the drug-drug interactions between DRV/r and DTG, and to evaluate the consequences of this interaction, in adolescents at steady state.

Accelerating access to paediatric medicines: lessons learned from the Global Accelerator for Paediatric Formulations, a WHO-hosted network.

Despite progress in reducing neonatal and child mortality, access to age-appropriate medicines remains inequitable, particularly in low-income and middle-income countries. The Global Accelerator for Paediatric Formulations (GAP-f), a WHO-hosted network established in 2020, addresses these gaps by uniting 33 partners to promote innovation and access to child-friendly formulations. Phase 2 (2022-24) of GAP-f's work focused on therapeutic areas where innovation and access efforts often did not have stakeholder alignment and coordination of designing and implementing innovative clinical trial methodology, engaging with regulators to address systemic barriers, identifying novel technologies for safe and effective delivery, and collaborating across stakeholders for product roll out.

Pharmacokinetics of Generic Pediatric Abacavir/Lamivudine Dispersible Tablets in Thai Young Children Living With HIV Weighing Below Twenty Kilograms.

We investigated the steady-state pharmacokinetics of generic abacavir (ABC)/lamivudine (3TC) dispersible tablets (DTs) in young children living with HIV aged 3 months to <7 years, weighing 6 to <20 kg. Twenty-eight Thai children were enrolled and received ABC/3TC-DT plus pediatric dolutegravir-DT once daily. ABC/3TC was administered using WHO weight band (WB) doses: 180/90 mg, 240/120 mg and 300/150 mg for children weighing 6 to <10 kg (WB 1, n = 7), 10 to <14 kg (WB2, n = 9) and 14 to <20 kg (WB3, n = 12), respectively.

Exploring potential drug-drug interactions between masculinizing hormone therapy and oral pre-exposure prophylaxis (F/TDF and F/TAF) among transgender men (iMACT study): a randomized, open-label pharmacokinetic study in Thailand.

Introduction: Concerns regarding potential drug-drug interactions (DDIs) between hormone therapy and pre-exposure prophylaxis (PrEP) may hinder PrEP use among transgender persons. Transgender men have often been overlooked in biomedical HIV research, and potential DDIs between masculinizing hormone therapy (MHT) and PrEP have not been addressed. We aimed to assess the potential DDIs between MHT and daily oral PrEP among transgender men.

Simplifying medicine dosing for children by harmonising weight bands across therapeutic areas.

Generally, dose recommendations for children are expressed as fixed dosing increments related to bodyweight, known as weight bands. The weight bands recommended in WHO treatment guidelines vary between diseases, leading to complexity and potential dosing errors when treating children for multiple diseases simultaneously. The introduction of a harmonised weight banding approach for orally administered drugs across disease areas could streamline dosing for young children, but implementing such an approach would require changes in current dosing recommendations.

Validation of the REverSe TRanscrIptase Chain Termination assay for measuring tenofovir diphosphate in dried blood spots from a clinical pharmacokinetic trial.

Background: Tenofovir diphosphate concentration in red blood cells is an objective measure of long-term oral pre-exposure prophylaxis (PrEP) or antiretroviral therapy (ART) adherence. However, current methods for measuring tenofovir diphosphate are equipment and capital intensive, limiting widespread adoption.

Objectives: Low cost, rapid diagnostics for measuring tenofovir diphosphate may drive clinical adoption of routine drug level measurement as a tool for adherence monitoring of tenofovir disoproxil fumarate-based PrEP or ART.

Virological outcomes and genotypic resistance on dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial.

Background: ODYSSEY showed superior efficacy for dolutegravir-based antiretroviral therapy (ART) versus standard of care (SOC) in children living with HIV starting first-line or second-line ART aged 4 weeks or older. Here, we aim to compare virological outcomes and resistance in the dolutegravir group versus SOC for first-line and second-line ART up to 96 weeks.

Methods: ODYSSEY was an open-label, multicentre, randomised, non-inferiority trial done in 29 centres in seven countries (Germany, Spain, South Africa, Thailand, the UK, Uganda, and Zimbabwe).

Single Doses of Pediatric Dolutegravir Dispersible Tablets in Neonates Support Multidosing: PETITE-Dolutegravir Study.

Background: Dolutegravir dispersible tablets (DTG-DTs) are approved for infants 4 weeks or older and ≥3 kg but their suitability for neonates remains unknown.

Methods: PETITE-DTG is a phase I/II, open-label, single-center, 2-stage trial in South Africa to evaluate the pharmacokinetics (PK) and safety of DTG in term neonates of pregnant individuals receiving DTG-based therapy. In stage 1, neonates on standard antiretroviral prophylaxis received a single dose of 5 mg DTG-DT between ≥14 and <28 days of life (cohort 1A) or <14 days of life (cohort 1B), followed by PK and safety assessments.

Favipiravir pharmacokinetics in Thai adults with mild COVID-19: A sub-study of interpatient variability and ethnic differences in exposure.

This sub-study sought to characterize the pharmacokinetics (PK) of favipiravir (FPV) within Thai adults and quantitatively assess differences in exposure to those previously reported in other populations as a basis to understand putative differences in efficacy between studies conducted in different regions. It was nested within a prospective trial of adults with symptomatic COVID-19 infection without pneumonia receiving 1800 mg FPV twice-daily on day 1 and 800 mg twice-daily thereafter. Individual PK profiles were fitted with a one-compartment disposition model (first-order absorption).

Pharmacodynamics of Rivaroxaban and Dabigatran in Adults with Diffuse Large B-Cell Lymphoma Receiving R-CHOP Immunochemotherapy.

: Rivaroxaban and dabigatran are commonly used for thromboembolic disease management in active cancer patients. However, limited research explores the impact of concurrent chemotherapy on the pharmacodynamics of direct oral anticoagulants (DOAC). The aim of our study was to evaluate the impact of combined chemotherapy with rivaroxaban and dabigatran on the pharmacodynamics in patients with diffuse large B-cell lymphoma (DLBCL).

Optimising Paediatric HIV Treatment: Recent Developments and Future Directions.

Treatment options for children living with HIV have historically been less effective, less practical and more difficult to implement compared with those for adults, as the research and development of new drugs for children has lagged behind. Significant progress has been achieved in response to the paediatric HIV epidemic over the last decade. Several optimised paediatric antiretroviral formulations are currently available or in development, including fixed-dose combination tablets containing a complete World Health Organization-recommended regimen.

Lamivudine dosing for preterm infants exposed to HIV: a population pharmacokinetic modelling and simulation study.

Objectives: To develop a pragmatic twice daily lamivudine dosing strategy for preterm infants from 24 to 37 completed weeks of gestation.

Methods: Data were combined from eight pharmacokinetic studies in neonates and infants receiving lamivudine oral solution. A population pharmacokinetic model was developed using non-linear mixed effects regression.

Assessment of three antibiotic combination regimens against Gram-negative bacteria causing neonatal sepsis in low- and middle-income countries.

Gram-negative bacteria (GNB) are a major cause of neonatal sepsis in low- and middle-income countries (LMICs). Although the World Health Organization (WHO) reports that over 80% of these sepsis deaths could be prevented through improved treatment, the efficacy of the currently recommended first- and second-line treatment regimens for this condition is increasingly affected by high rates of drug resistance. Here we assess three well known antibiotics, fosfomycin, flomoxef and amikacin, in combination as potential antibiotic treatment regimens by investigating the drug resistance and genetic profiles of commonly isolated GNB causing neonatal sepsis in LMICs.

D3/Penta 21 clinical trial design: A randomised non-inferiority trial with nested drug licensing substudy to assess dolutegravir and lamivudine fixed dose formulations for the maintenance of virological suppression in children with HIV-1 infection, aged 2 to 15 years.

Background: There is increasing interest in utilising two-drug regimens for HIV treatment with the goal of reducing toxicity and improve acceptability. The D3 trial evaluates the efficacy and safety of DTG/3TC in children and adolescents and includes a nested pharmacokinetics(PK) substudy for paediatric drug licensing.

Methods: D3 is an ongoing open-label, phase III, 96-week non-inferiority randomised controlled trial(RCT) conducted in South Africa, Spain, Thailand, Uganda and the United Kingdom.

A pilot program of HIV pre-exposure prophylaxis in Thai youth.

Introduction: There are gaps in knowledge and experience of antiretroviral pre-exposure prophylaxis (PrEP) delivery in adolescents.

Methods: This pilot study enrolled Thai adolescents 14-20 year-old without HIV who reported risk behaviour. All participants were offered daily tenofovir/emtricitabine (TDF-FTC) and followed for 24 weeks.