Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ACT-451840 in Healthy Subjects (Part A)

Idorsia Pharmaceuticals Ltd.40 enrolled

Overview

The primary objective of the study was to evaluate the safety and tolerability of ACT-451840 in healthy male subjects.Secondary objectives were : to investigate the pharmacokinetics (PK) of ACT-451840; to investigate the effect of food on the PK of ACT-451840; to evaluate the urinary excretion of ACT-451840 and to investigate the antimalarial activity of ACT-451840.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

OTHER

Masking

TRIPLE

Enrollment

Conditions

Healthy

Interventions

ACT-451840 10 mgDRUG

ACT-451840 was provided as dry powder, which was reconstituted as a suspension with 25 mL of tap water

ACT-451840 50 mgDRUG

ACT-451840 was provided as dry powder, which was reconstituted as a suspension with 25 mL of tap water

ACT-451840 200 mgDRUG

ACT-451840 was provided as dry powder, which was reconstituted as a suspension with 25 mL of tap water

Eligibility

Sex: MALEMin age: 18 YearsMax age: 45 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Signed informed consent in the local language prior to any study-mandated procedure. * Body mass index (BMI) of 18.0 to 28.0 kg/m2 (inclusive) at screening. * Systolic blood pressure 100-145 mmHg, diastolic blood pressure 50-90 mmHg, and pulse rate 45-90 beats per minute (inclusive), measured on the dominant arm, after 5 min in the supine position at screening. * 12-lead electrocardiogram without clinically relevant abnormalities, measured after 5 min in the supine position at screening. * Hematology, coagulation, clinical chemistry, and urinalysis test results not deviating from the normal range to a clinically relevant extent at screening. * No clinically significant findings on the physical examination at screening. * Negative results from urine drug screen at screening. * Ability to communicate well with the investigator, in the local language, and to understand and comply with the requirements of the study. * Subject covered by Health Insurance system and/or in compliance with the recommendations of the National Law in force relating to biomedical research. * If the subject's partner could become pregnant, reliable methods of contraception must be used from the time of the first administration of study medication until 3 months following administration of the last dose of study medication. Exclusion Criteria: * Known allergic reactions or hypersensitivity to any excipient of the drug formulation(s). * History or clinical evidence of any disease and/or existence of any surgical or medical condition which might interfere with the absorption, distribution, metabolism or excretion of the study drug. * Previous history of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions. * Documented history of chronic liver or gall bladder disease. * Documented history of hemolytic anemia. * Veins unsuitable for intravenous puncture on either arm (e.g., veins that are difficult to locate, access, or puncture, veins with a tendency to rupture during or after puncture). * Previous exposure to the study medication. * Treatment with another investigational drug within 3 months prior to screening or participation in more than four investigational drug studies within the 12 months prior to screening. * Subject in the exclusion period of a previous clinical study. * Subject who had received more than 4,500 Euros as indemnities for his participation in a biomedical research within the 12 last months, including the indemnities for the present study. * History or clinical evidence of alcoholism or drug abuse within the 3-year period prior to screening. * Excessive caffeine consumption, defined as 800 mg or more per day at screening. * Smoking within 3 months prior to screening and inability to refrain from smoking during the course of the study. * Previous treatment with any prescribed or over-the-counter medications (including herbal medicines such as St. John's Wort) within 2 weeks prior to first study drug administration. * Loss of 250 mL or more of blood within 3 months prior to screening. * Positive results from the hepatitis (hepatitis B and C) serology, except for vaccinated subjects. * Positive results from human immunodeficiency virus serology at screening. * Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol. * Legal incapacity or limited legal capacity at screening.

Locations (1)

OPTIMED Clinical Research

Gières, France

Outcomes

Primary Outcomes

Change in systolic blood pressure from baseline up to end of study

Blood pressure (systolic and diastolic) and pulse rate will be measured using an automatic oscillometric device, always on the dominant/same arm (i.e., dominant arm right = writing with right hand). Measurements should be recorded from the subject in the supine position after having rested for a 5-minute period.

Time frame: 4 days

Change in diastolic blood pressure from baseline up to end of study

Time frame: 4 days

Change in pulse rate from baseline up to end of study

Time frame: 4 days

Change in body weight from baseline up to end of study

Body weight will be measured using the same weighing scale for all subjects and throughout the study. The weighing scale should have a precision of at least 0.5 kg.

Time frame: 4 days

Change in heart rate from baseline up to end of study

Heart rate will be measured using a standard 12-lead electrocardiogram recorded at rest with the subject in the supine position for a 5-minute period. Electrocardiograms will be performed immediately prior to dosing and at 1, 2, 4, 6, 8, 12, 24, 48, and 96 hours post dosing.

Time frame: 4 days

Change in PQ/PR interval from baseline up to end of study

Data from ClinicalTrials.gov

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Secondary Outcomes

Maximum plasma concentration (Cmax) of ACT-451840

Time frame: 4 days

Time to maximum plasma concentration (tmax) of ACT-451840

Time frame: 4 days

Area under the plasma concentration-time curve (AUC(0-t)) of ACT-451840

Blood samples for pharmacokinetic analysis will be taken immediately prior to dosing with ACT-451840 and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 24, 36, 48, 72, and 96 hours after dosing. AUC(0-t) will be calculated as the area under the plasma concentration-time profile from time zero to time t of the last measured concentration above the limit of quantification.

Time frame: 4 days

Area under the plasma concentration-time curve (AUC(0-infinity)) of ACT-451840

Blood samples for pharmacokinetic analysis will be taken immediately prior to dosing with ACT-451840 and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 24, 36, 48, 72, and 96 hours after dosing. AUC(0-infinity) will be calculated by combining AUC(0-t) and AUC(extra). AUC(extra) represents an extrapolated value obtained by Ct/λz, where Ct is the last plasma concentration measured above the limit of quantification and λz represents the terminal elimination rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal elimination phase.

Time frame: 4 days

Plasma half life (t1/2) of ACT-451840

Time frame: 4 days

Dose proportionality of single doses of ACT-451840

Blood samples for pharmacokinetic analysis will be taken immediately prior to dosing with ACT-451840 and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 24, 36, 48, 72, and 96 hours after dosing. Dose proportionality will be explored by the power model as described by Gough et al \[1995\]. The power model will be applied to the loge AUC0-∞ and Cmax data. A point estimate and 90% Confidence Interval (CI) will be produced for the population mean slope. Approximate dose proportionality will be concluded if the 90% CI for the slope is completely contained in the range (1+log(0.5))/log(r), 1+log(2)/log(r) where r = high dose/low dose.

Time frame: 4 days

Percentage of administered ACT-451840 excreted unchanged in urine

A baseline urine sample will be collected from each subject in the selected dose group after admission on Day -1. On Day 1, subjects will be instructed to empty their bladder immediately prior to study drug intake. Thereafter, all urine produced will be collected during the 4 days following study drug intake until the morning of Day 5. On Day 1, urine will be collected at three consecutive 8-hour intervals, from 0-8 hours, 8-16 hours, and 16-24 hours. On Days 2, 3, and 4 urine will be collected in 24-hours intervals.

Time frame: 4 days

Anti-malarial half-maximal inhibitory concentration (IC50) of ACT-451840

Blood (2.5 mL) will be collected by direct venipuncture or via an intravenous catheter placed in an antecubital vein in the arm into 3.5 mL vacutainer serum separation tubes. The anti-malarial IC50 of ACT-451840 will be determined using a bioassay and ACT-451840 IC50 concentrations will be estimated based on the measured antimalarial activity.

Time frame: 4 days