Primary objective1. To determine the effect of food on the pharmacokinetics of sildenafil administered as the Lybrido formulation2. To determine whether >90% of the testosterone content is released after maximally 90 seconds after sublingual…
ID
Source
Brief title
Condition
- Sexual dysfunctions, disturbances and gender identity disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Pharmacokinetic
90% CI ratio for both AUCinf and Cmax
Secondary outcome
Pharmacokinetic
Difference in Tmax and tlag
and
- Area under the concentration time curve (AUC)
- Peak exposure (Cmax)
- Time to peak exposure (Tmax)
- Lag time (tlag)
- Terminal elimination half-life (t*)
Residual testosterone per tablet and rupture test analysis after:
A. 30 sec sublingual administration
B. 60 sec sublingual administration
C. 90 sec sublingual administration
D. 120 sec sublingual administration
Safety
E. Nature, frequency and severity of adverse events
F. Vital signs and 12-lead ECG
G. Safety laboratory tests (urinalysis, hematology, biochemistry)
Background summary
Background
Sexual dysfunction
In many mammalian species, female sex steroids are necessary for the expression
of female sexual behavior. In most animals, copulation is limited to the
period of ovulation. Humans (as well as higher primates), however, show sexual
intercourse also outside the periovulatory period. Testosterone is clearly
involved in female sexual behavior. A complete loss, decreased libido, or
absence of desire for sexual activity is common after bilateral oophorectomy,
adrenalectomy, and after natural menopause, while substitution with
testosterone has been shown to improve sexual motivation and performance.
The 3 (transitional and overlapping) phases of the human sexual response can
each be disrupted, leading to low sexual desire, sexual arousal problems, and
hampered orgasm. The phases are regulated by relatively independent
neurotransmitter functions, and dysfunctions may be amenable to
psychopharmacological treatment. Traditionally, motivated behaviors have been
divided into appetitive and consummatory components. Activities aimed at
obtaining reward and satisfactions belong to the appetitive component. The
fundamental appetitive motivational process is an intrinsic brain function and
is especially related to the predictive value of stimuli for reward.
Processing of motivationally relevant information (i.e., stimuli predicting
reward) causes an increase in activity of the meso-accumbens dopaminergic
system (i.e., dopamine neurons of the ventral tegmental area [VTA] innervating
the nucleus accumbens). The activity of this system is increased during
flexible approach behavior when anticipating reward related to copulation.
Increasing activity in these dopaminergic pathways facilitates sexual
motivation, in particular anticipatory sexual behavior.
Anticipating sexual reward will produce arousal of the genitals, in which at
least 2 key neurotransmitters are involved: acetylcholine and nitric oxide
(NO). Acetylcholine and NO both promote erections in men and lubrication and
swelling in women. Orgasm, the consummatory phase of human sexual response, is
facilitated by descending spinal noradrenergic fibers and innervation of the
genitals, and inhibited by descending spinal serotonergic fibers.
Study objective
Primary objective
1. To determine the effect of food on the pharmacokinetics of sildenafil
administered as the Lybrido formulation
2. To determine whether >90% of the testosterone content is released after
maximally 90 seconds after sublingual dosing
Secondary objective
1. To evaluate the safety and tolerability of a single dose of Lybrido under
fasted and fed conditions
Study design
This will be a randomized, open-label balanced two-period, two-treatment,
two-sequence crossover study in healthy female subjects to evaluate the effect
of food on the pharmacokinetics (PK) of sildenafil after a single dose of
Lybrido. In addition, safety and tolerability of Lybrido administered after
fed and fasted conditions will be evaluated. Furthermore, in vivo confirmation
of testosterone release and dissolution time of will be assessed.
All subjects will complete a screening visit. Prior to the day of dosing,
eligible subjects will stay overnight (O/N) (at least 10 hours) in an
environment controlled for fasting conditions.
The subjects will be randomized to one of the following treatments:
H. Lybrido under fed conditions
I. Lybrido under fasted conditions
On the day of dosing, subjects in treatment A will take a high fat, high
calorie meal (50% of the caloric intake of 800-1000 kcal) on site. The drug is
administered 30 minutes after the start of the food intake and the meal should
be completed within this 30 minutes time frame. No intake of water is allowed
the hour prior to and 1 hour post administration of the drug. Drug will be
taken with 240 mL water and subject will abstain from food intake the following
4 hours. The food intake will be standardized for all patients during 12 hours
post dose.
For subjects in treatment B, administration of the drug is taken with 240 mL
water. No intake of water is allowed the hour prior to and 1 hour post
administration of the drug. Next 4 hours, the subject will abstain from food
intake. The food intake will be standardized for all patients during 12 hours
post dose.
Both periods will be separated by a washout period of at least 1 week between
the dosing of the 1st period and dosing of the 2nd period.
After the last blood sample on day 2, the subjects will hold another Lybrido
tablet sublingually for a defined time (30, 60, 90 or 120 seconds) after which
the tablet is not swallowed but accurately collected in a tube for further
analysis of testosterone content.
Intervention
NA
Study burden and risks
NA
Louis Armstrongweg 78
Almere 1311 RL
NL
Louis Armstrongweg 78
Almere 1311 RL
NL
Listed location countries
Age
Inclusion criteria
1. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study;
2. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures;
3. Females between 18 and 55 years of age (both inclusive);
4. Healthy based on medical history, physical examination, electrocardiogram, laboratory values and vital signs;
5. Body mass index (BMI) >=18 kg/m2 and <= 30 kg/m2;
6. Venous access sufficient to allow blood sampling as per protocol;
Exclusion criteria
Cardiovascular conditions;
1. History of myocardial infarction, stroke, transient ischemic attack, or life-threatening arrhythmia within the prior 6 months;
2. Uncontrolled atrial fibrillation/flutter at screening or other significant abnormality as observed on electrocardiogram (ECG);
3. Systolic blood pressure >= 140 mmHg and/or diastolic blood pressure >= 90 mmHg;
4. Systolic blood pressure < 90 mmHg and/or diastolic blood pressure< 50 mmHg;
5. Use of oral contraceptives containing anti-androgens (e.g. crypteron acetate) or anti (androgenic) progestogens (drosperidone, dienogest, chlormadinone acetate and norgestrel);6. Use of any hormone replacement therapy (HRT) containing more than 50 µg/day of estrogen;
7. Pregnancy (note: an urine pregnancy test will be performed in all women prior to the administration of study medication);
8. Lactating or delivery in the previous 6 months;
9. Perimenopausal status (cycle shortening/irregular menstrual bleeding in the last 12 consecutive months and/or occurrence of vasomotor symptoms (e.g. hot flashes, night contraceptive sweating) in combination with elevated FSH levels (>40 IU/L) for women age 40 onwards; in women with a history of hysterectomy, perimenopausality can be assessed by FSH levels (>40 IU/L) and/or vasomotor symptoms);
10. Liver and/or renal insufficiency;
11. Current clinically relevant endocrine disease;
12. Positive serology for HIV, Hepatitis B (surface antigen), and/or Hepatitis C;
13. Substance abuse disorder;
14. Use of nitrates or nitric oxide donor compounds;
15. Subjects who are taking potent CYP3A4 inhibitors or inducers;
16. Use of serotonergic drugs (e.g. Trazodon, fluvoxamide);17. Use of testosterone therapy within 6 months before study entry;
18. Use of any medication that interferes with study medication (e.g. monoamine oxidase (MAO) inhibitors, calcium channel blockers);
19. Illiteracy, unwillingness or inability to follow study procedures;
20. Participation in any other clinical drug study in the previous 3 months;
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-001944-38-NL |
| CCMO | NL49313.056.14 |
| OMON | NL-OMON25592 |