Study of Comparative Bioavailability and Pharmacokinetics of ACM-001.1) and Pindolol in Healthy Volunteers (HV)

Actimed Therapeutics Ltd51 enrolled

Overview

The aim of this early phase two-part study was to compare the bioavailability (BA) pharmacokinetics (PK) and pharmacodynamics (PD) of racemic pindolol with the benzoate salt of the S-enantiomer of pindolol (ACM-001.1) and provide safety information. A total of 51 healthy male and female subjects were enrolled, and 48 healthy subjects completed the study. Part 1 consisted of two Groups to compare BA and PK, Group 1 received two treatment sequences of a single dose of ACM-001.1 versus racemic pindolol; Group 2 ran in parallel with Group 1 and assessed the PK of a single dose of racemic pindolol in a single period. Part 2 consisted of four groups, to evaluate the steady state PK and PD of ACM-001.1 with multiple ascending doses over 4 days.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

Cachexia

Interventions

Drug: ACM-001.1 immediate release tablets for oral use and matching placebo, and pindolol tablets for oral use. Subjects randomised to Regimen A received placebo tablets to match the tablet number received by subjects in Regimen B.

Part 1 Group 2 Regimen C (Pindolol)DRUG

Drug: Pindolol tablets for oral use.

Part 2 Group D (Pindolol)DRUG

Drug: Pindolol tablets for oral use. Subjects were dosed over a four day treatment period twice daily. Subjects receiving ACM-001.1 in regimens E, F and G also received placebo tablets to match the tablet number received by subjects receiving pindolol in Regimen D.

Part 2 Group E (ACM-001.1)DRUG

Drug: ACM-001.1 immediate release tablets for oral use and matching placebo. Subjects were dosed over a four day treatment period twice daily. Subjects receiving ACM-001.1 in regimens E, F and G also received placebo tablets to match the tablet number received by subjects receiving pindolol in Regimen D.

Part 2 Group F (ACM-001.1 )DRUG

Part 2 Group G (ACM-001.1)DRUG

Part 1 Group 1 Regimen B (Pindolol)DRUG

Drug: pindolol tablets for oral use. Subjects randomised to Regimen A received placebo tablets to match the tablet number received by subjects in Regimen B.

Part 1 Group 1 Regimen A (Placebo)OTHER

Placebo for oral use. Subjects randomised to Regimen A received placebo tablets to match the tablet number received by subjects in Regimen B.

Part 2 Group E (Placebo)OTHER

Placebo for oral use. Subjects were dosed over a four day treatment period twice daily. Subjects receiving ACM-001.1 in regimens E, F and G also received placebo tablets to match the tablet number received by subjects receiving pindolol in Regimen D.

Part 2 Group F (Placebo)OTHER

Part 2 Group G ( Placebo)OTHER

Eligibility

Sex: ALLMin age: 20 YearsMax age: 45 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Healthy males or non-pregnant, non-lactating healthy females * Aged 20 to 45 years inclusive at the time of signing informed consent * Body Mass Index (BMI) of 18.0 to 30.0 kg/m2 as measured at screening * Weight of 50 to 100 kg at screening Exclusion Criteria: * Subjects who had received any investigational medicinal product in a clinical research study within the 90 days prior to Day 1, * Subjects for whom pindolol was contraindicated: hypersensitivity to the active substance or to any of its listed excipients. * Evidence of current Severe Acute Respiratory Coronavirus 2 infection. * History of any drug or alcohol abuse in the past 2 years. * Females of childbearing potential who were pregnant or lactating. * History of clinically significant cardiovascular disease, Raynaud's disease or phenomenon, renal, hepatic, dermatological, chronic respiratory or gastrointestinal disease, neurological or psychiatric disorder. * Subjects who were found to have mean heart rate less than 50 bpm at rest or mean systolic blood pressure (BP) less than 100 mmHg or mean diastolic heart rate less than 50 mmHg. * Subjects who were taking, or had taken, any prescribed or over-the-counter drug or herbal remedies (other than paracetamol, hormonal replacement therapy/hormonal contraception). Pindolol should not be taken in conjunction with agents which inhibit calcium transport.

Locations (1)

Quotient Sciences Ltd

Ruddington, United Kingdom

Outcomes

Primary Outcomes

Part 1 Composite of PK parameters following single doses

Comparative bioavailability of S- pindolol and pindolol include: area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC\[0-infinite\].

Time frame: Up to 5 days

Part 1 PK parameters following single doses

Comparative bioavailability of S- pindolol and pindolol include:maximum observed concentration (Cmax)

Time frame: Up to 5 days

Part 1 PK parameters following single doses

Comparative bioavailability of S- pindolol and pindolol include:time of occurrence of Cmax (Tmax)

Time frame: Up to 5 days

PK parameters following single doses

Comparative PK parameters of S- pindolol and racemic pindolol include: area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC\[0-infinite\]).

Time frame: Up to 5 days

PK parameters following single doses

Comparative PK parameters of S- pindolol and racemic pindolol include: maximum observed concentration (Cmax)

Time frame: Up to 5 days

PK parameters following single doses

Comparative PK parameters of S- pindolol and racemic pindolol include: t time of occurrence of Cmax (Tmax)

Time frame: Up to 5 days

Stoichiometric dose relationship measured using PK parameters following single doses

PK parameters of S- pindolol and racemic pindolol include: area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC\[0-infinite\])

Time frame: Up to 5 days

Stoichiometric dose relationship measured using PK parameters following single doses

PK parameters of S- pindolol and racemic pindolol include: maximum observed concentration (Cmax).

Time frame: Up to 5 days

Part 2 Composite of PK parameters following multiple doses in plasma

PK parameters of S- pindolol/racemic pindolol:Area under the curve for interval between doses (tau) (AUC(0 tau);Area under the concentration-time curve from time zero (pre-dose) to last time of measurable concentration (AUC\[0-t\])

Time frame: Up to 6 days

Part 2 Composite of PK parameters following multiple doses in plasma

PK parameters of S- pindolol/racemic pindolol: Maximum observed concentration (Cmax),

Time frame: Up to 6 days

Part 2 Composite of PK parameters following multiple doses in plasma

PK parameters of S- pindolol/racemic pindolol: Time to first occurrence of Cmax from plasma concentration-time data(Tmax).

Time frame: Up to 6 days

Pharmacodynamics of ACM-001.1: Cardiovascular vital parameter- heart rate

Heart rate (beats per minute)

Time frame: Up to 6 days

Cardiovascular vital parameter- blood pressure

Systolic blood pressure (mmHG) and diastolic blood pressure (mmHG)

Time frame: Up to 6 days

Serum biomarker- DHEA/Cortisol

Dehydroepiandrosterone (DHEA)/Cortisol (ng/mL). Serum concentrations were determined using validated analytical method.

Time frame: Day 1 at pre-dose. Day 4 at pre-dose, 1.5 hours

Serum biomarker- Myostatin

Myostatin (pg/mL).Serum concentrations were determined using validated analytical method.