Evaluating MED2005 & Nitrostat Bioavailability
Ključne besede
Povzetek
Opis
GTN is a well‐established vasodilatory therapeutic agent with a long, documented history of use and comprehensive safety profile. In Europe, licensed indications for GTN include the treatment and prophylaxis of angina pectoris and the relief of pain associated with chronic anal fissure. Other indications for prescription only parenteral products include use during cardiac surgery and for emergency reduction of blood pressure.
GTN's vasodilatory action is thought to result from the release of nitric oxide (NO) in vascular smooth muscle. NO stimulates guanylate cyclase, the enzyme responsible for production of cGMP, whose action is to lower intracellular calcium resulting in smooth muscle relaxation and vasodilation.
In the case of erectile dysfunction, GTN works locally by penetrating the glans/penile skin and directly targeting penile blood vessels. Nitrates appear to have a direct, local effect on penile haemodynamics. The most likely mechanism for the erectile effect of nitrates involves nitrate induced dilation of the cavernous and helicine arteries, thereby increasing blood flow to the lacunar spaces, coupled with nitrate‐induced relaxation of trabecular smooth muscle.
Nitroglycerin (Nitrostat) is indicated for the acute relief of an attack or acute prophylaxis of angina pectoris due to coronary artery disease.
The principal pharmacological action of nitroglycerin is relaxation of vascular smooth muscle. Although venous effects predominate, nitroglycerin produces, in a dose-related manner, dilation of both arterial and venous beds. Dilation of postcapillary vessels, including large veins, promotes peripheral pooling of blood, decreases venous return to the heart, and reduces left ventricular end-diastolic pressure (preload). Nitroglycerin also produces arteriolar relaxation, thereby reducing peripheral vascular resistance and arterial pressure (afterload), and dilates large epicardial coronary arteries; however, the extent to which this latter effect contributes to the relief of exertional angina is unclear.
Nitroglycerin forms free radical nitric oxide (NO) which activates guanylate cyclase, resulting in an increase of guanosine 3'5' monophosphate (cyclic GMP) in smooth muscle and other tissues. These events lead to dephosphorylation of myosin light chains, which regulate the contractile state in smooth muscle, and result in vasodilatation.
Datumi
| Nazadnje preverjeno: | 06/30/2019 |
| Prvič predloženo: | 01/23/2018 |
| Predviden vpis oddan: | 07/01/2019 |
| Prvič objavljeno: | 07/04/2019 |
| Zadnja posodobitev oddana: | 07/01/2019 |
| Zadnja posodobitev objavljena: | 07/04/2019 |
| Dejanski datum začetka študija: | 11/14/2017 |
| Predvideni datum primarnega zaključka: | 04/15/2018 |
| Predvideni datum zaključka študije: | 04/15/2018 |
Stanje ali bolezen
Intervencija / zdravljenje
Drug: MED2005
Drug: Nitrostat 0.6Mg Sublingual Tablet
Drug: Nitro Pohl
Faza
Skupine rok
| Roka | Intervencija / zdravljenje |
|---|---|
| Experimental: MED2005 (0.6 mg) MED2005 (0.2% GTN) gel to be used topically in Part 1 of the study | |
| Experimental: MED2005 (1.2 mg) MED2005 (0.4% GTN) gel to be used topically in Part 1 of the study | |
| Experimental: MED2005 (1.8 mg) MED2005 (0.6% GTN) gel to be used topically in Part 1 of the study | |
| Active Comparator: Nitrostat (1.8 mg) - Treatment Period 1 3 x 0.6 mg tablets will be required to make up the 1.8 mg dose to be used orally in Part 1 of the study but to be dosed in two treatment periods | |
| Active Comparator: Nitrostat (1.8 mg) - Treatment Period 2 3 x 0.6 mg tablets will be required to make up the 1.8 mg dose to be used orally in Part 1 of the study but to be dosed in two treatment periods | |
| Experimental: MED2005 (2.4 mg)- Part 1 MED2005 (0.8% GTN) gel to be used topically in Part 1 of the study | |
| Active Comparator: Intravenous (I.V.) dose of GTN (0.3 mg) GTN solution for infusion (1 mg/ml) to be used intravenously in Part 2 of the study | |
| Experimental: MED2005 (2.4 mg)- Part 2 MED2005 (0.8% GTN) gel to be used topically in Part 2 of the study |
Merila upravičenosti
| Starost, primerna za študij | 18 Years Za 18 Years |
| Spol, upravičen do študija | Male |
| Sprejema zdrave prostovoljce | Da |
| Merila | Inclusion Criteria: 1. Healthy male subjects between 18 and 50 years of age, inclusive (at screening). 2. A BMI of 18.5-30 kg/m2 (inclusive). 3. No clinical significant abnormal serum biochemistry, haematology and urine examination values as defined by the Investigator. 4. A negative urinary drugs of abuse screen. A positive alcohol test may be repeated on admission at the discretion of the Investigator. 5. Negative HIV and Hepatitis B and C results. 6. No clinically significant abnormalities in 12-lead ECG as defined by the Investigator. 7. No clinically significant deviation outside the normal ranges for blood pressure and heart rate measurements as defined by the Investigator (please refer to appendix 1 for normal ranges). 8. Subjects (unless anatomically sterile (documented evidence) or where abstaining from sexual intercourse is in line with the preferred and usual lifestyle of the subject) and sexual partners must use 2 effective contraception methods during the trial and for 3 months after the last dose, for example: - Oral contraceptive + condom. - Intra-uterine device (IUD) + condom. - Diaphragm with spermicide + condom. 9. Subjects must be available to complete all periods of the study and the follow-up visit. 10. Subjects must satisfy the PI / designee about their fitness to participate in the study. 11. Subjects must be able to read and understand the informed consent form and must provide written informed consent to participate in the study. Exclusion Criteria: 1. A clinically significant history of gastrointestinal disorder likely to influence IMP absorption (Part 1 only). 2. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements within 28 days (or 5 half-lives (whichever is longer) prior to the first dose of IMP, unless in the opinion of the Investigator and Sponsor's Responsible Physician the medication will not interfere with the study procedures or compose subject safety. 3. Evidence of renal, hepatic, central nervous system, respiratory, cardiovascular or metabolic dysfunction. 4. A clinically significant history of drug or alcohol abuse within 2 years before the first dose of IMP. 5. A clinically significant history of previous allergy/sensitivity to GTN, other nitrates and/or any of the excipients in either the test of reference products. 6. Recent history of using PDE5 inhibitors or alkyl nitrates (e.g. poppers). 7. A history of frequent tension headaches or vascular headaches or migraine. 8. A history of increased intra-cranial pressure or spinal cord injury. 9. A history of severe psychological disorders. 10. A presence of scarring/piercings/tattoos at the site of MED2005 administration (penis) (or any other features that the Investigator considers may influence IMP absorption). 11. Subjects (if uncircumcised) who are not able to retract foreskin of penis easily without any discomfort. 12. Any obvious sensitivity/local tolerability issues at the site of medication application. 13. Inability to communicate well with the investigator (i.e. language problems, poor mental development or impaired cerebral function). 14. Participation in a New Chemical Entity or marketed drug clinical study within the previous 3 months or, five half-lives of study drug, whichever is the longer period. (NB. the three month washout period between trials is defined as the period of time elapsed between the last dose of the previous study and the first dose of the next study). 15. Subjects who smoke (or ex-smokers) who have smoked or used nicotine-containing products (including snuff, chewing tobacco, cigars, pipes or nicotine replacement products) within four months prior to first dose. 16. Donation or receipt of ≥ 450 mL of blood within 3 months before the first dose of IMP. 17. Donation of sperm from the first dose and for at least 3 months after the last dose of IMP. |
Izid
Primarni izidni ukrepi
1. To demonstrate similar or lower bioavailability of GTN when administered as a gel via MED2005 compared to Nitrostat (which will administrated as a sublingual tablet) in terms of AUC0-t (Part 1) [22 days]
2. To demonstrate similar or lower bioavailability of GTN when administered as a gel via MED2005 compared to Nitrostat (which will administrated as a sublingual tablet) in terms of AUC0-inf (Part1) [22 days]
3. To demonstrate similar or lower bioavailability of GTN when administered as a gel via MED2005 compared to Nitrostat (which will administrated as a sublingual tablet) in terms of Cmax (part1) [22 days]
Ukrepi sekundarnega rezultata
1. The pharmacokinetics of GTN metabolite 1,2-GDN will be evaluated following the administration of MED2005 compared with Nitrostat (Part 1). [22 days]
2. Adverse events (AEs) coded using Medical Dictionary for Regulatory Activities (MedDRA) version 20.0 or higher [46 days]
3. GTN absorption (to quantify the amount of GTN remaining on the glans penis post application) [10 days]
4. GTN absorption (to quantify a figure of 100% GTN being absorbed) [10 days]
5. The pharmacokinetics of GTN metabolite1,3-GDN will be evaluated following the administration of MED2005 compared with Nitrostat (Part 1). [22 days]
