Phase I study in healthy volunteers of both sexes Other
Conditions
Interventions
The study consists of:
1. Screening (to be performed within 4 weeks prior to the 1st PK study session), for the evaluation of the volunteer's eligibility.
2. Three PK study sessions, each one separate
no blinding technique will be used. Each randomised subject will be allocated to a sequence (Sequence A, Sequence B or Sequence C) of treatment administrations in the three study periods (Periods 1, 2
Sponsors
Menarini Group (Italy)
Eligibility
Sex/Gender
All
Age
18 Years to 60 Years
Inclusion criteria
Inclusion criteria: 1. Properly executed written informed consent form (ICF) 2. Healthy males and females aged 18 to 60 years, inclusive, at Screening 3. BMI between 18.5 and 30 kg/m2, inclusive, and weight of at least 50 kg at Screening 4. Normal metabolizers for CYP2D6 based on the genotype 5. Negative pregnancy test for women of childbearing potential 6. Females of child-bearing potential must be using at least one of the following reliable methods of contraception: 6.1. Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit 6.2. A non-hormonal intrauterine device (IUD) or female condom with spermicide or contraceptive sponge with spermicide or diaphragm with spermicide or cervical cap with spermicide for at least 2 months before the screening visit 6.3. A male sexual partner who agrees to use a male condom with spermicide 6.4. A sterile sexual partner 6.5. True abstinence. True (long-term) heterosexual abstinence, defined as refraining from heterosexual intercourse when this is in line with the preferred and usual lifestyle of the subject, while periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), lactational amenorrhea and withdrawal are not acceptable 7. Women of non-child-bearing potential or in post-menopausal status defined as such when there is either: 7.1. 12 months of spontaneous amenorrhea or 7.2. 6 months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL or 7.3. 6 weeks documented postsurgical bilateral oophorectomy with or without hysterectomy will be admitted 8. Male participants with a partner of childbearing potential must agree to use a barrier method (condom with spermicidal cream) when sexually active while participating in the study, unless they are sterile 9. Non-smokers/non-users of nicotine-containing products and non-users of Vapo e-cigarettes (defined as a non-smoker/non-user during the last three months before Screening) 10. Considered by the Investigator to be in good health for participation in this study, i.e. absence of clinically significant diseases or clinically significant abnormal laboratory values, as per medical history review, physical examination, vital signs, electrocardiograms (ECG) tracing, and clinical laboratory findings 11. Systolic blood pressure (SBP) =90 mmHg and diastolic blood pressure (DBP) =60 mmHg; Pulse Rate (PR) =50 bpm 12. Willing and able to comply with all study requirements, schedules and procedures
Exclusion criteria
Exclusion criteria: 1. History of allergy, photoallergy or phototoxicity, idiosyncrasy or hypersensitivity to the study drugs, or any of the excipients of the study drug products (lactose monohydrate included). 2. History or clinical evidence of cardiovascular, respiratory, renal, hepatic, endocrine, metabolic, gastrointestinal, haematological, bleeding disorders, neurological or psychiatric pathology or other chronic diseases that, in the opinion of the investigator, could jeopardize or would compromise the participant’s ability to participate in this study. 3. History of angioedema (hereditary, idiopathic or secondary to treatment with ACE inhibitors or angiotensin II receptor antagonists). 4. History of orthostatic hypotension (orthostatic hypotension is defined as a drop of at least 20 mmHg in SBP or a drop of at least 10 mmHg in DBP within two to five minutes of standing, or if standing causes at least moderate symptoms, i.e. light-headedness, visual blurring, dizziness, generalized weakness, fatigue, cognitive slowing, leg buckling, coat-hanger ache, and gradual or sudden loss of consciousness). 5. Any condition which might interfere with the absorption, distribution, metabolism or excretion of the drugs, according to the Investigator’s judgement. 6. Surgery within the previous 6 months, blood loss > 450 mL within the previous 3 months before treatment start (i.e., first dosing) or active bleedings (except menstruations). 7. Having donated blood or received a transfusion of any blood products within 3 months and/or having donated plasma within 7 days before Screening. 8. Positive serology to Human Immunodeficiency Virus (HIV) I and II, Hepatitis B Virus (HBV) (i.e. positive for HBsAg or HBcAb) or Hepatitis C Virus (HCV). 9. History of drug, alcohol [>1 drink/day for females and >2 drinks/day for males, defined according to the USDA Dietary Guidelines 2020-2025], caffeine abuse (>5 cups coffee/tea/day). 10. Use of caffeine- or xanthine-containing products (e.g. tea, coffee, cola, chocolate) and not suitable to abstain from such products consumption 48 h before dosing with study treatments and for the 72 hours of each PK study session. 11. Abnormal diets (3500 kcal/day) or substantial changes in eating habits in the 4 weeks before this study; vegetarians 12. Positive result of drugs of abuse on urine screening test for cocaine and metabolites (COC 300), amphetamine (AMP 500), methamphetamine (MET 500), marijuana (including cannabinoids THC) (THC 50), opiates (including heroin morphine and metabolites) (MOP 300), methylenedioxymethamphetamine ecstasy (MDMA 500), methadone (MTD 300), or positive result in alcohol salivary test or cotinine urine test. 13. Females of childbearing potential who are not using any of the highly effective contraceptive methods (see inclusion criterion 6). 14. Breastfeeding and pregnant females as per positive ß-HCG (Beta-subunit Of Human Chorionic Gonadotropin) results at Screening and at Admission (first residence in the Unit before first dosing). 15. Taking any pharmacological treatment, within 21 days or 5 half-lives of the product, whichever is longer, prior to dosing (except for symptomatic short-term paracetamol use, up to 1.5 g/day, and hormonal contraception as per inclusion criterion 6). 16. Intake of any herbal product/preparation or food supplement in the last 14 days prior to the dosing. 17. Receiving concomitant treatment with other investigational medicinal product (IMP) or who have received the last d
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Area Under the plasma concentration-time Curve (AUC) from time zero to the last quantifiable time point (AUC(0-t)) and maximum plasma concentration (Cmax) of NEB and RAM when administered as FDC tablet (Test) and as EC tablets (Reference). The concentrations of NEB and RAM in plasma samples are determined using a fully validated liquid chromatography-tandem mass spectrometry (LC/MS/MS) method by the analytical laboratory Anapharm, Spain at different timepoints from baseline up to 72 h post-dose | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Relevant secondary standard pharmacokinetic parameters of NEB and RAM such as AUC from time zero to infinity (AUC(0-8)), AUC from time zero to 72h (AUC(0-72)) for NEB only, plasma terminal half-life (t1/2), terminal elimination rate constant (?z), residual area (%AUCextrap) and time to maximum plasma concentration (tmax) when NEB and RAM are administered as Test and Reference formulations. The concentrations of NEB and RAM in plasma samples are determined using a fully validated liquid chromatography-tandem mass spectrometry (LC/MS/MS) method by the analytical laboratory Anapharm, Spain at different timepoints from baseline up to 72 h post-dose 2. Safety and tolerability of the study treatments are evaluated by collecting the adverse events during the whole study, by measuring vital signs (blood pressure and heart rate) and registering an ECG at screening, baseline, during the study and at the final visit, by performing a physical examination at screening, baseline and final visit, and by performing laboratory tests on blood and urine at the screening and final visits. | — |
Countries
Switzerland
Contacts
Public ContactDaniela Menichini
Outcome results
None listed