Pharmacokinetics and Safety of Bedaquiline in Human Immunodeficiency Virus (HIV)-Positive and Negative Older Children and Adolescents With Rifampicin-Resistant Tuberculosis.

BACKGROUND: Pharmacokinetic data for bedaquiline in children are limited. We described the pharmacokinetics and safety of bedaquiline in South African children and adolescents receiving treatment for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) in routine care. METHODS: In this observational cohort study, children aged 6-17 years receiving bedaquiline at recommended doses as part of MDR/RR-TB treatment underwent semi-intensive pharmacokinetic sampling. Bedaquiline and the M2 metabolite plasma concentrations were quantified, and nonlinear mixed-effects modeling performed. Pediatric data were described using a pre-established model of bedaquiline pharmacokinetics in adults. The exposure reference was 187 µg ⋅ h/mL, the median weekly area under the curve (AUC) of adults at week 24 of treatment with bedaquiline. Safety was assessed through monthly clinical, blood and electrocardiogram monitoring, and treatment outcomes described. RESULTS: Fifteen children (3 human immunodeficiency virus [HIV]-positive) with median age 13.3 years (range 6.5-16.3) were included. A bedaquiline pharmacokinetic model was adapted to be allometrically scaled in clearance and volume, centered in the median child population weight. Bedaquiline bioavailability was 57% of that in adults. Overall bedaquiline exposures were below target, and AUC reference attainment was achieved in only 3 (20%) children. Ten children experienced 27 adverse events at least possibly related to bedaquiline; no adverse events led to bedaquiline withdrawal. Two adverse events (arthritis and arthralgia) were considered severe, and 2 children had mild QT interval corrected for heart rate using Fridericia's formula (QT) prolongation. CONCLUSIONS: The evaluated doses of bedaquiline in children ≥ 6 years of age were safe but achieved slightly lower plasma concentrations compared to adults receiving the recommended dose, possibly due to delayed food intake relative to bedaquiline administration.

Association between tuberculosis and pregnancy outcomes: a retrospective cohort study of women in Cape Town, South Africa.

BACKGROUND: Tuberculosis (TB) remains a leading cause of mortality among women of childbearing age and a significant contributor to maternal mortality. Pregnant women with TB are at high risk of adverse pregnancy outcomes. This study aimed to determine risk factors for an adverse pregnancy outcome among pregnant women diagnosed with TB. METHODS: Using TB programmatic data, this retrospective cohort analysis included all women who were routinely diagnosed with TB in the public sector between October 2018 and March 2020 in two health subdistricts of Cape Town, and who were documented to be pregnant during their TB episode. Adverse pregnancy outcome was defined as either a live birth of an infant weighing <2500 g and/or with a gestation period <37 weeks or as stillbirth, miscarriage, termination of pregnancy, maternal or early neonatal death. Demographics, TB and pregnancy characteristics were described by HIV status. Logistic regression was used to determine risk factors for adverse pregnancy outcome. RESULTS: Of 248 pregnant women, half (52%) were living with HIV; all were on antiretroviral therapy at the time of their TB diagnosis. Pregnancy outcomes were documented in 215 (87%) women, of whom 74 (34%) had an adverse pregnancy outcome. Being older (35-44 years vs 25-34 years (adjusted OR (aOR): 3.99; 95% CI: 1.37 to 11.57), living with HIV (aOR: 2.72; 95% CI: 0.99 to 4.63), having an unfavourable TB outcome (aOR: 2.29; 95% CI: 1.03 to 5.08) and having presented to antenatal services ≤1 month prior to delivery (aOR: 10.57; 95% CI: 4.01 to 27.89) were associated with higher odds of an adverse pregnancy outcome. CONCLUSIONS: Pregnancy outcomes among women with TB were poor, irrespective of HIV status. Pregnant women with TB are a complex population who need additional support prior to, during and after TB treatment to improve TB treatment and pregnancy outcomes. Pregnancy status should be considered for inclusion in TB registries.

Adolescent tuberculosis.

Adolescence is characterised by a substantial increase in the incidence of tuberculosis, a known fact since the early 20th century. Most of the world's adolescents live in low-income and middle-income countries where tuberculosis remains common, and where they comprise a quarter of the population. Despite this, adolescents have not yet been addressed as a distinct population in tuberculosis policy or within tuberculosis treatment services, and emerging evidence suggests that current models of care do not meet their needs. This Review discusses up-to-date information about tuberculosis in adolescence, with a focus on the management of infection and disease, including HIV co-infection and rifampicin-resistant tuberculosis. We outline the progress in vaccine development and highlight important directions for future research.

2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists. 3. Synthesis, pharmacokinetics, and in vivo potency.

A short, efficient, and highly stereoselective synthesis of a series of (3R,6R,7R)-2,5-diketopiperazine oxytocin antagonists and their pharmacokinetics in rat and dog is described. Prediction of the estimated human oral absorption (EHOA) using measured lipophilicity (CHI log D) and calculated size (cMR) has allowed us to rank various 2,5-diketopiperazine templates and enabled us to focus effort on those templates with the greatest chance of high bioavailability in humans. This rapidly led to the 2',4'-difluorophenyl-dimethylamide 25 and the benzofuran 4 with high levels of potency (pK(i)) and good bioavailability in the rat and dog. Dimethylamide 25 is more potent (>20-fold) than 4 in vivo and has a high degree of selectivity toward the vasopressin receptors, >10,000 for hV1a/hV1b and approximately 500 for hV2. It has a good Cyp450 profile with no time dependent inhibition and was negative in the genotoxicity screens with a satisfactory oral safety profile in rats.

Direct small-molecule kinase activation: Novel approaches for a new era of drug discovery.

The pharmaceutical industry has traditionally targeted the inhibition of dysregulated kinases to treat diseases such as cancer and inflammatory disorders. In contrast to the human genome sequencing project, which aimed to identify novel biological targets, the possibility of activating kinases uses known targets in a novel manner. In an approach that is similar to other target classes (eg, GPCRs and nuclear receptors), transient upregulation of kinase function using small molecules has been increasingly demonstrated to lead to favorable disease outcomes. This review discusses direct small-molecule kinase activators: specifically, how these molecules were discovered, characterized, evaluated and developed into drug leads. The choice of potential targets, the mechanisms of activation and the common strategies used to discover activators are also highlighted.