Concentration-QT modelling of the novel DHFR inhibitor P218 in healthy male volunteers.

Aims: Given the increasing emergence of drug resistance in Plasmodium, new antimalarials are urgently required. P218 is an aminopyridine that inhibits dihydrofolate reductase being developed as a malaria chemoprotective drug. Assessing the effect of new compounds on cardiac intervals is key during early drug development to determine their cardiac safety.

Time- and Race-Specific Haematological Reference Intervals for Healthy Volunteer Trials: A Retrospective Analysis of Pooled Data From Multiple Phase I Trials.

Most UK hospitals, laboratories, and research institutions use uniform reference intervals (RI) that do not take into account known diurnal and racial variation in total white blood cells (WBC) count and its constituent parameters. These risks of excluding potentially suitable ethnic minority volunteers from participating in phase I clinical trials could call into question the validity of a trial's findings or limit its scientific applications and ability to accurately observe drug effects upon WBC parameters. This study pools data from multiple phase I trials, assesses the effects of race and time of day on WBC count, and compares it to the existing literature to establish race and time-specific RIs.

Efficient Design of Integrated and Adaptively Interlinked Protocols for Early-Phase Drug Development Programs.

Background: Adaptive trial designs have the potential to address common challenges in drug development; they decrease timelines and costs of early drug development and efficiently create data that support future trials in target populations. While allowing for flexibility and evolution, adaptive strategies introduce some complexity to the design and implementation of trial protocols. Previously published work by the authors include a retrospective analysis of time savings using adaptive design and a systematic, 3- step methodology for writing early-phase adaptive integrated protocols.

First-in-human clinical trial to assess the safety, tolerability and pharmacokinetics of P218, a novel candidate for malaria chemoprotection.

Aims: This first-in-human clinical trial of P218, a novel dihydrofolate reductase inhibitor antimalarial candidate, assessed safety, tolerability, pharmacokinetics and food effects in healthy subjects.

Methods: The study consisted of two parts. Part A was a double-blind, randomized, placebo-controlled, parallel group, ascending dose study comprising seven fasted cohorts.

Coadministration of the prostaglandin F2α receptor antagonist preterm labour drug candidate OBE022 with magnesium sulfate, atosiban, nifedipine and betamethasone.

Aims: To investigate presence or absence of clinically relevant drug interactions (pharmacokinetic and safety/tolerability) of OBE022 with standard-of-care medicines for preterm labour, enabling coadministration and further clinical development.

Methods: Part A: open-label, randomized, 3-period crossover assessing coadministration of single doses of OBE022 (1100 mg) and MgSO . Part B: open-label, single-sequence crossover assessing the interactions following administration of OBE022 (1000 mg/day) at steady state coadministered with single doses of atosiban, nifedipine and betamethasone.

Practical risk management in early phase clinical trials.

Purpose: Stopping rules are an essential part of risk management in early phase clinical trials. As well as being necessary for ensuring the safety of participants on clinical trials, they are also a requirement under the revision to the European Medicine Agency's first-in-human and early clinical trial guideline. The increasing complexity and size of modern trial designs (e.

Pharmacokinetics, safety and tolerability of OBE022, a selective prostaglandin F2α receptor antagonist tocolytic: A first-in-human trial in healthy postmenopausal women.

Aims: Preterm birth remains a significant risk for later disability. The selective inhibition of the prostaglandin F receptor has significant advantages for a tocolytic. The prodrug OBE022 and its metabolite OBE002 are novel prostaglandin F receptor antagonists under development for treating preterm labour.

Confirmation of the Cardiac Safety of PGF Receptor Antagonist OBE022 in a First-in-Human Study in Healthy Subjects, Using Intensive ECG Assessments.

OBE022, a new orally active prostaglandin F  receptor antagonist (OBE022) with myometrial selectivity is being developed to reduce uterine contractions during preterm labor. This first-in-human study evaluated the effect of OBE022 following multiple doses on the QT interval in 23 healthy postmenopausal women, using the effect of a meal on QTc to demonstrate assay sensitivity. We report the cardiac safety outcome performed during the multiple ascending part of this trial.

What do metabolic rates tell us about thermal niches? Mechanisms driving crayfish distributions along an altitudinal gradient.

Humans are rapidly altering thermal landscapes, so a central challenge to organismal ecologists is to better understand the thermal niches of ectotherms. However, there is much disagreement over how we should go about this. Some ecologists assume that a statistical model of abundance as a function of habitat temperature provides a sufficient approximation of the thermal niche, but ecophysiologists have shown that the relationship between fitness and temperature can be complicated, and have stressed the need to elucidate the causal mechanisms underlying the response of species to thermal change.