To compare the pharmacokinetics of sublingual testosterone cyclodextrin followed by buspirone as an encapsulated tablet with administration of testosterone and buspirone as one tablet designed to release the components in a specific time-frame.
ID
Source
Brief title
Condition
- Sexual dysfunctions, disturbances and gender identity disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Cmax of total testosterone (F2 >= 75% of Cmax F1);
• Cmax of free testosterone ( F2 >= 75% of Cmax F1);
• Cmax of buspirone (F2 >= 75% of Cmax F1);
• AUC0-1590 of total testosterone (F2 >= 75% of AUC0-1590 F1);
• AUC0-1590 of free testosterone (F2 >= 75% of AUC0-1590 F1);
• AUC0-infinity of buspirone (F2 >= 75% of AUC0-infinity F1);
Secondary outcome
To investigate the time frame in which the mint flavored testosterone coating
is dissolved.
Background summary
Lybridos (0.5 mg testosterone + 10 mg buspirone) is under development by
Emotional Brain BV as an on-demand treatment for (the subset of) women with
hypoactive sexual desire disorder (HSDD) characterized by maladaptive activity
of sexual inhibitory systems. Lybridos is intended for use on a per need (i.e.,
not continuous) basis before proposed sexual activity. The cause of maladaptive
activity of sexual inhibitory systems is not well elucidated, but both
physiological and psychological factors are believed to be involved. Thus a
combined treatment targeting the motivational sensitivity for sexual stimuli
(testosterone) and enhancing a potential genital sexual response by decreasing
possible inhibitory factors (buspirone) may increase genital arousal, as well
as the frequency and quality of sexual encounters.
Our previous studies have shown that women with HSDD can be subdivided on the
base of their pre-attentional bias for sexual stimuli (1,2). Although these
women may be diagnosed with Female Sexual Dysfunction (FSD) according to the
Diagnostic and Statistical Manual of Mental disorders, fourth edition (text
revision) (DSM IV-TR), they appear to process sexual stimuli differently.
When women with low sensitivity for sexual cues receive testosterone,
alterations in pre-attentional bias for sexual stimuli occur, which could be an
important condition for the induction of sexual motivation and sexual desire.
Several studies have demonstrated that for women suffering from HSDD whose low
initial sensitivity to sexual cues was boosted by sublingual testosterone, the
combination of testosterone and a PDE-5 inhibitor (Lybrido) induced higher
levels of vaginal blood flow when exposed to sexual stimuli (1,2), coupled with
subjective reports of more intense genital sensations and sexual lust (1). It
was also shown that neither testosterone nor a PDE-5 inhibitor produced these
effects in women with HSDD when administered separately (1,2). In these same
studies, subjects who did show an increased pre-attentional bias for sexual
stimuli before testosterone administration, showed a decrease in
pre-attentional bias after testosterone administration. Since these women
showed no increase in vaginal blood flow or subjective reports of genital
sensations in any of the drug conditions, and because most of them had a
history of negative sexual experiences, it was hypothesized that this group
suffered from maladaptive activity of sexual inhibitory systems. Acute 5HT1a
agonism decreases serotonergic activity (3,4), an important mediator of
inhibitory mechanisms (5). It was postulated that these individuals might
benefit from the inhibition of these inhibitory mechanisms through acute 5HT1a
agonism, especially in conjunction with testosterone-induced intensified sexual
stimulation. In a study investigating the efficacy of the combination of
testosterone and a PDE-5 inhibitor and of the combination of testosterone and a
5HT1a agonist it was indeed shown that women with HSDD who did not respond to
the combination of testosterone and a PDE-5 inhibitor, responded positively to
the combination of testosterone and a 5HT1a agonist (Lybridos), as measured by
event logs and week diaries pertaining to their sexual activities at home
(Tuiten et al., 2011 in preparation).
Sublingually administered testosterone (0.5mg) has been shown to have a delay
in effect of about 4 hours on subjective and peripheral sexual arousal (6,7) in
sexually functional women, but not in women with HSDD (1,2). If this central
effect of testosterone administration is coupled with the use of buspirone, an
increase in subjective and peripheral sexual arousal may be observed in women
with HSDD. However, the peak effect of buspirone must coincide with the peak
effect of the 4 hour delay effect of testosterone. So for buspirone (Tmax
approx. 60 minutes), one would have to administer the sublingual testosterone
first, and after 2-3 hours the buspirone.
In the above reviewed clinical studies, 0.5 mg testosterone was administered
sublingually as a solution, followed 2.5 hours later by a 10 mg buspirone
tablet, thus creating overlapping peaks in effect of testosterone and
buspirone. Because compliance to this method of administration requires
accurate and thorough instructions, Emotional Brain has recently developed a
combination tablet that will deliver testosterone (0.5 mg) sublingually and,
2.5 hours later, 10 mg buspirone hydrochloride. This will allow women with HSDD
to take just one single preparation 3-6 hours before anticipated sexual
activity.
This new developed drug product is a menthol flavored white tablet of 9 mm in
diameter employing two routes of administration; sublingual and oral. First, 90
seconds sublingual administration which is then followed by the swallowing of
the intact remainder of the tablet. The quickly dissolving outer coating will
deliver testosterone (0.5 mg) sublingually, and the time-delayed release core
will deliver buspirone (10 mg) 2.5 hours later. The outer coating comprises
testosterone and a menthol flavor, so when the menthol flavor is gone
(estimated to be around 30 sec), the testosterone is fully dissolved and
maximally available for absorption via the mucosal membranes. The buspirone
hydrochloride tablets as used in previous studies is an immediate release
compound. Thus, the present time-delayed-release core containing the buspirone
has been designed to release the buspirone all at once, 2 * hours after oral
administration (buspirone dump should fall in the specified window of 2-3
hours). This method of release is accomplished through the use of a polymer
coating of ethylcellulose which slowly permeates water in a pH independent
manner. The buspirone core swells due to the water absorption and this increase
in size leads to the rupture of the polymer coating, dumping all of the
buspirone at once, after approximately 2 * hours. This combination tablet has
thus been designed to mimic the pharmacokinetic (and thus also the
pharmacodynamic) properties of the separate administration of the testosterone
solution and the buspirone tablet 2 * hours later.
The present study is part of the ongoing drug development program for Lybridos.
This research proposal describes a pharmacokinetic study of which the main goal
is to compare the pharmacokinetics of testosterone and buspirone following
administration of a sublingual solution of testosterone with an encapsulated
tablet, versus the newly developed combination product.
The purpose of this study is not to determine bioequivalence, but to explore
the pharmacokinetic profiles of both administration methods.
Study objective
To compare the pharmacokinetics of sublingual testosterone cyclodextrin
followed by buspirone as an encapsulated tablet with administration of
testosterone and buspirone as one tablet designed to release the components in
a specific time-frame.
Study design
Randomized, crossover, controlled pharmacokinetic study with 2 pharmaceutical
formulations containing testosterone and buspirone; wash-out between treatments
will be at least 7 days. Blood sampling for pharmacokinetic measurements will
be performed at predetermined time points.
Intervention
Two interventions will be performed on all participants:
1. Testosterone (0.5 mg) cyclodextrin administered sublingually as a solution,
followed 2.5 hours later by an encapsulated tablet containing 10 mg buspirone
HCl.
2. A fixed-combination tablet consisting of an inner-core component of 10 mg
buspirone HCl, and a polymeric coating of 0.5 mg testosterone; this formula is
designed to release the inner-core buspirone at about 2.5 hours after tablet
intake. After this time delay of 2.5 hours, the buspirone is released
immediately, rather than being released in a sustained mode. The coated
buspirone core tablet is film-coated with an additional, immediately
dissolving, polymeric, testosterone coating that releases 0.5 mg testosterone
sublingually within 90 seconds. The tablets need to be in the mouth
sublingually for 90 seconds after which the tablet is swallowed as a whole,
without chewing or disrupting the dosage form.
Study burden and risks
The main adverse reactions to exogenous androgens given chronically in
physiological to slightly supraphysiological concentrations are androgenic side
effects, primarily hirsutism and acne. We consider it to be highly unlikely
that testosterone administration in the doses and frequency to be used in this
study will give rise to any serious health risks. In our previous studies, no
serious health risks/adverse reactions were observed. Within 15 minutes of
testosterone (0.5 mg, sublingually) intake plasma testosterone concentration
increased 10-fold, and returned to baseline levels within 150 minutes.(Tuiten
et al., 2000, van Rooij et al., in preparation). Testosterone is administered
over two admission periods with a 7 day wash-out between the admission periods.
The dosing regime regarding testosterone is therefore considered to be safe.
The combined use of sublingual testosterone and buspirone is considered safe
because buspirone efficacy is not influenced when testosterone is given
concomitantly. Moreover, the dose of buspirone in one dose of Lybridos is at
most two thirds of the starting daily dose and less than a half (2/5) of the
lightest weekly dose of buspirone prescribed for use as an anxiolytic drug. A
previous home study (EB70) showed that Lybridos is well tolerated on long term,
see the Investigator*s Brochure for Lybridos for additional information.
Data on the effect of buspirone and testosterone on oral contraceptives is
lacking. For this reason, participants on oral contraceptives will be
instructed to use a second anti-conception method (double barrier). All
participants will be instructed not to become pregnant during the study.
Clinically relevant abnormalities in ECG and chemistry may be noticed, in which
case a medical specialist may be asked for advice, upon decision of the
research team. If the specialist confirms that medical treatment is necessary,
the participant*s GP physician will be informed. This procedure is mandatory
and explained to the subject in the Informed Consent form.
Louis Armstrongweg 78
1311 RL
NL
Louis Armstrongweg 78
1311 RL
NL
Listed location countries
Age
Inclusion criteria
1. Provision of written informed consent
2. Female 18-35 years of age (inclusive)
3. Healthy based on medical history, physical examination, laboratory values and vital signs
4. Body mass index (BMI) >= 18 kg/m2 and <= 30 kg/m2
5. Venous access sufficient to allow blood sampling as per protocol
Exclusion criteria
Cardiovascular conditions
1. Any underlying cardiovascular condition, including unstable angina pectoris
2. Systolic blood pressure >= 140 mmHg and/or diastolic blood pressure >= 90 mmHg.
3. Systolic blood pressure < 90 mmHg and/or diastolic blood pressure <50 mmHg;Gynecological and obstetric conditions
4. Use of oral contraceptive containing anti-androgens (e.g. Crypteron acetate) or (anti) androgenic progesteron (drospirone, dienogest, chlormadinone acetate and norgestrel)
5. Use of oral contraceptive containing 50 µg estrogen or more
6. Pregnancy or intention to become pregnant during this study (Note: An urine pregnancy test will be performed in all women prior to the administration of study medications.)
7. Lactating or delivery in the previous 6 months
8. Unexplained gynecological complaints, such as clinically relevant abnormal uterine bleeding patterns
9. Subjects with a perimenopausal hormonal status (follicle-stimulating hormone>30);Other medical conditions
10. Liver- and/or renal insufficiency
11. Current clinically relevant endocrine disease
12. Current clinically relevant neurological disease which, in the opinion of investigator, would compromise the validity of study results, or which could form a contraindication for buspirone and/or testosterone use
13. (A history of) hormone-dependant malignancy;Psychological/psychiatric factors
14. A substance abuse disorder that, in the opinion of the investigator, is likely to affect the subject's ability to complete the study or precludes the subject*s participation in the study; mild or moderate alcohol consumption is allowed but must be stopped 24 hours before the admission period. Recreational drug use is not allowed beginning 3 weeks before the start of the admission period until follow up. Smokers are not allowed to participate.;Concomitant medication
15. Subjects who are taking CYP3A4-inhibitors (eg, ritonavir, ketoconazol, itraconazol claritromycine, erytromycine and saquinavir)
16. Subjects who are taking CYP3A4-inducers (eg, fenytoïne, fenobarbital, st Johns Wort, rifampicine)
17. Use of serotonergic drugs (eg, trazodon, fluvoxamine)
18. Use of testosterone therapy within 6 months before study entry
19. Use of any other medication that interferes with study medication (eg, monoamine oxidase (MAO) inhibitors (includes classic MAO inhibitors and linezolid), calcium channel blockers (eg, diltiazem and verapamil), use of corticosteroids);Drug/food interaction
20. Consumption of grapefruit or grapefruit-containing foods throughout the duration of the study;General
21. Illiteracy, unwillingness, or inability to follow study procedures
22. Any other clinically significant abnormality or condition which, in the opinion of investigator, might interfere with the participant*s ability to provide informed consent or comply with study instructions, compromise the validity of study results, or be a contraindication for buspirone and/or testosterone use.
23. 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
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-003700-20-NL |
| CCMO | NL37775.056.12 |