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. METHODS: This double-blind, randomized, placebo-controlled, parallel group study evaluated the effect of P218 on electrocardiographic parameters following oral administration of seven single-ascending doses up to 1000 mg in 56 healthy volunteers. Participants were randomized to treatment or placebo at a 3:1 ratio. P218 was administered in the fasted state with standardized lunch served 4 hours after dosing. 12-lead ECGs were recorded in triplicate at regular intervals on the test day, and at 48, 72, 120, 168, 192 and 240 hours thereafter. Blood samples for pharmacokinetic evaluations were collected at similar time points. Concentration-effect modelling was used to assess the effect of P218 and its metabolites on cardiac intervals. RESULTS: Concentration-effect analysis showed that P218 does not prolong the QTcF, J-Tpeak or TpTe interval at all doses tested. No significant changes in QRS or PR intervals were observed. Two-sided 90% confidence intervals of subinterval effects of P218 and its metabolites were consistently below the regulatory concern threshold for all doses. Study sensitivity was confirmed by significant shortening of QTcF after a meal. CONCLUSION: Oral administration of P218 up to 1000 mg does not prolong QTcF and does not significantly change QRS or PR intervals, suggesting low risk for drug-induced proarrhythmia.

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. Eight subjects/cohort were randomized (3:1) to receive either a single oral dose of P218 (10, 30, 100, 250, 500, 750 and 1000 mg) or placebo. Part B was an open-label, cross-over, fed/fasted cohort (eight subjects) that received a 250 mg single dose of P218 in two treatment periods. RESULTS: P218 was generally well tolerated across all doses; 21 treatment-emergent adverse events occurred in 15/64 subjects. Nine adverse events in five subjects, all of mild intensity, were judged drug related. No clinically relevant abnormalities in ECG, vital signs or laboratory tests changes were observed. P218 was rapidly absorbed, with Cmax achieved between 0.5 and 2 hours post dose. Plasma concentrations declined bi-exponentially with half-life values ranging from 3.1 to 6.7 hours (10 and 30 mg), increasing up to 8.9 to 19.6 hours (doses up to 1000 mg). Exposure values increased dose-proportionally between 100 and 1000 mg for P218 (parent) and three primary metabolites (P218 ß-acyl glucuronide, P218-OH and P218-OH ß-acyl glucuronide). Co-administration of P218 with food reduced Cmax by 35% and delayed absorption by 1 hour, with no significant impact on AUC. CONCLUSION: P218 displayed favourable safety, tolerability and pharmacokinetics. In view of its short half-life, a long-acting formulation will be needed for malaria chemoprotection.

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 MgSO4 . 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. Twenty-five healthy nonpregnant women of reproductive age were enrolled (Part A: n = 12; Part B: n = 13). RESULTS: OBE022, alone or in combination with standard-of-care medications, was well tolerated. Headache and dizziness were the most frequently reported adverse events; dizziness occurred more often with the nifedipine/OBE022 combination. There were no clinically significant pharmacokinetic interactions when coadministered with MgSO4 . Co-administration had no notable effect on atosiban exposure. Atosiban reduced exposure to OBE002 (peak concentration [Cmax ] 22%, area under the concentration-time curve [AUC] 19%). Coadministration with betamethasone slightly increased betamethasone exposure (Cmax  + 18%, AUC +27%) and OBE002 exposure (Cmax  + 35%, AUC +15%). These changes were not considered clinically significant. Coadministration with nifedipine slightly increased OBE002 exposure (Cmax  + 29%, AUC +24%) and markedly increased nifedipine exposure (Cmax by 2-fold and AUC by 2-fold), which may be clinically significant. CONCLUSIONS: The use of OBE022, a PGF2α antagonist prodrug, in combination with standard-of-care medicines may provide new treatment alternatives for preterm labour. All tested combinations were well tolerated. Nifedipine doses could potentially be reduced or staggered when coadministered with OBE022.

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.g. integrated trials) raise potential issues with risk management, which, if also too complex, presents challenges for both regulators and investigators to implement. Therefore, there is a clear need for a standard, template, or algorithm-based approach to risk management, in particular rules concerning adverse reactions. The purpose of this manuscript is to present template stopping (or adverse reaction, AR) rules that fulfil regulatory requirements and that can be adapted, taking into account trial design, nature of the investigational medicinal product, and anticipated effects. METHODS: The template AR rules that use a systematic, objective and consistent process were developed, taking into account severity (using an objective grading system), seriousness, frequency and reversibility of ARs. These rules control decisions relating to individual trial participants, dosing regimens and dose escalation and/or progression to successive trial parts. For ease of use, the template rules consist of a single, one-page table. RESULTS: The template AR rules have been successfully applied to many early phase adaptive integrated trials that received regulatory authorisation and were performed in the UK. This manuscript presents the template rule table and case studies of some trial-specific adaptations. CONCLUSIONS: This work demonstrates how a systematic, objective and consistent approach to risk management of large integrated trials can be simple yet robust, facilitating effective decision making and trial progression whilst safeguarding participant safety.

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 F2α receptor has significant advantages for a tocolytic. The prodrug OBE022 and its metabolite OBE002 are novel prostaglandin F2α receptor antagonists under development for treating preterm labour. METHODS: We performed a prospective, first in human, Phase I, dose escalation, placebo-controlled, randomized trial at a clinical trial site in the UK. Placebo, single ascending doses of 10, 30, 100, 300, 1000 or 1300 mg, and multiple ascending doses over 7 days of 100, 300 or 1000 mg day-1 ; were administered to postmenopausal female volunteers. Food interaction was additionally evaluated. RESULTS: Subjects tolerated OBE022 well at all single and multiple doses. No clinically relevant changes in safety parameters were shown and there were no serious adverse events. Observations showed that prodrug OBE022 was readily absorbed and rapidly converted into its equally active stable metabolite OBE002. The plasma level of OBE002 rose with increasing doses, reaching exposure levels that were anticipated to be clinically relevant within 1 h following administration. There was no clinically significant food interaction, with peak exposures reduced to 80% and area under the curve staying bioequivalent. The mean half-life of OBE002 ranged between 8 and 11 h following administration of a single dose and 22-29 h after multiple doses. CONCLUSIONS: Administration of OBE022 was safe and had favourable pharmacokinetic characteristics and no clinically relevant interaction with food. Our results allow further investigation of OBE022 in preterm labour patients.

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. Towards this end, we studied the distribution of two crayfishes, Euastacus woiwuru and Euastacus armatus, along an altitudinal gradient, and for both species conducted experiments to determine the temperature-dependence of: (1) aerobic scope (the difference between maximum and basal metabolic rate; purported to be a proxy of the thermal niche); and (2) burst locomotor performance (primarily fuelled using anaerobic pathways). E. woiwuru occupied cooler habitats than E. armatus, but we found no difference in aerobic scope between these species. In contrast, locomotor performance curves differed significantly and strongly between species, with peak locomotor performances of E. woiwuru and E. armatus occurring at ~10 and ~18 °C, respectively. Crayfish from different thermal landscapes may have similar aerobic thermal performance curves but different anaerobic thermal performance curves. Our results support a growing body of literature implying different components of ectotherm fitness have different thermal performance curves, and further challenge our understanding of the ecology and evolution of thermal niches.

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. A total 13,332 venous blood samples obtained from 7,157 healthy male and female volunteers at the time of screening or admission (predosing) who took part in 35 phase I trials over a period of seven years were pooled and the data were analyzed using generalised estimating equation models. Adjusted RI of total WBC count and its individual parameters were then calculated according to time of day (morning vs. evening) for both black and nonblack populations. This study indicates that black individuals on average had lower total WBC, neutrophil, monocyte, eosinophil, and basophil counts than individuals from nonblack racial groups. Black volunteers had higher mean lymphocyte counts relative to their nonblack counterparts. These differences were deemed statistically significant. Statistically significant increases in total WBC, neutrophil, lymphocyte, and monocyte counts were also observed over the course of daily sampling. Eosinophil counts decreased during this time period, but this finding was only statistically significant in the nonblack population. Despite an observed mild diurnal increase in basophil count in both populations, this was not considered statistically significant. This high-powered study adds significant weight to the known evidence for diurnal and racial variation in WBC parameters. Importantly, it proposes specific RIs that more precisely reflect race and time of day. These could ensure increased participation of black volunteers in clinical trials for improved population representation. Furthermore, the proposed RIs allow for more accurate postdose safety monitoring and reporting, and ensure improved monitoring of postdose WBC count changes.

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. METHODS: This article builds on the authors' published work demonstrating the practical implementation of the adaptive protocol writing methodology and discussing the challenges and efficiencies. It describes the integration of an early development program of OBE022, a novel, oral, selective prostaglandin F2a receptor antagonist, intended as a treatment for preterm labor, using 2 interdependent, adaptive trial protocols. The program consisted of first-in-human single and multiple ascending dose parts with assessments of food effect, cardiac safety, proof of concept, and interactions of OBE022 with 4 standard of care medicines. RESULTS: The manuscript shows how the trials were tailored to OBE022's pharmacokinetic and pharmacodynamic characteristics and its therapeutic indication. The use of 2 large interdependent, adaptive protocols was facilitated by the United Kingdom's (UK's) regulatory environment and its acceptance of a rules-guided progression through the program. Changes to the planned trial conduct could be made without impacting on timelines, because they used predefined adaptive options within their authorized boundaries, and could therefore be made as nonsubstantial amendments. The program was successful and achieved its objectives. It was efficient and fast: it required a small number of participants (n=83) and completed from start of protocol writing to first draft of the clinical study report in just 11 months. CONCLUSIONS: This program included all key elements of early drug development in 2 interlinked protocols: the assessment of single and multiple ascending doses, food effect, cardiac safety and proof of concept. The approach described in this article demonstrates how early-phase programs can be designed to be performed, analyzed and reported time- and cost-efficiently.

Confirmation of the Cardiac Safety of PGF2α Receptor Antagonist OBE022 in a First-in-Human Study in Healthy Subjects, Using Intensive ECG Assessments.

OBE022, a new orally active prostaglandin F2α  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. OBE022 was administered after a standardized breakfast on day 1 and in the fasted state from day 3 to day 9 wth a standardized lunch 4 hours after administration. Concentration-effect modeling was used to assess the effect of prodrug OBE022 and parent OBE002 on QTc after a single dose (days 1 and 3) and multiple doses (day 9). The concentration-response analysis showed the absence of QTc prolongation at all doses tested. Two-sided 90% confidence intervals of the geometric mean Cmax  for estimated QTc effects of OBE022 and OBE002 of all dose groups were consistently below the threshold of regulatory concern. The sensitivity of this study to detect small changes in the QTc was confirmed by a significant shortening of the QTc on days 1, 3, and 9 after standardized meals. This study establishes that neither prodrug OBE022 nor parent OBE002 prolong the QTc interval. The observed food effect on the QT interval validated the assay on all assessment days. Both the change from predose, premeal and the change from premeal, postdose demonstrated the specificity of the method.