Primary* To evaluate the pharmacokinetics of oxybutynin and its main hepatic metabolite N-desethyloxybutynin after pulsed intra-vaginal delivery of a single dose of oxybutyninSecondary* To assess the safety and tolerability of the intra-vaginal…
ID
Source
Brief title
Condition
- Bladder and bladder neck disorders (excl calculi)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
PK parameters by non-compartmental analysis of the plasma concentration-time
data:
* AUCinf, AUClast, Cmax, tmax, t1/2, tlag, CL/F, Vz/F
* Dose-normalized PK parameters: AUCinf, AUClast, Cmax
Secondary outcome
* Treatment-emergent (serious) adverse events ((S)AEs) throughout the study at
every study visit
* Anticholinergic side effect (pupil size, salivary flow, visual near point
acuity and pulse rate) per assessment schedule
* Concomitant medication throughout the study at every study visit
* Vital signs (Pulse Rate (bpm), Systolic blood pressure (mmHg), Diastolic
blood pressure (mmHg)) as per assessment schedule
* Physical examination including in speculum examination per assessment
schedule
Background summary
Controlled release technologies, including sustained release of oral
medication, implants and transdermal drug delivery, have been developed to
mimic physiological concentrations and endogenous substance profiles. However,
there is still a need to develop novel controlled release technologies. The
intra-vaginal delivery route may facilitate such novel technology as it offers
several advantages over more commonly used systemic drug delivery routes. It is
a non-invasive route of administration, features a suitable residence time for
long-term treatment and could be used for placement of medical devices designed
for pulsatile drug delivery.
Currently, no intravaginal controlled delivery method is available to achieve
temporary peak concentration at pre-determined time intervals. Therefore, the
vaginal MedRing was designed. The MedRing contains a drug formulation
reservoir, a miniature peristaltic pump, a miniature electronic circuit board
that controls the device, and a battery. The system can wirelessly connect to
an external device (smartphone, tablet or laptop computer) from which drug
delivery can be programmed and which receives data (volume delivered,
temperature) from the ring.
The competitive muscarine receptor antagonist oxybutynin alleviates symptoms of
an overactive bladder/urge incontinence, and is often administered orally.
Oxybutynin is subject to an extensive first pass effect, resulting in the
formation of the active metabolite N-desethyloxybutynin with systemic,
anticholinergic side effects. An intravaginal route of administration of
oxybutynin has potential advantages compared to oral administration. By this
route it bypasses the first-pass effect and may have local efficacy. In
contrast to intra-vaginal devices in which oxybutynin is released
continuously[1], the MedRing is developed to administer the compound pulsatile
and on-demand. Oxybutynin *on demand* could be of potential use in the
treatment of overactive bladder/urge incontinence. Other potential indications
are the treatment of post-menopausal or aromatase inhibitor-induced hot
flashes.
In this study we will investigate the feasibility of pulsed intra-vaginal
delivery via the LiGalli MedRing and explore systemic exposure after a single
dose of oxybutynin.
Study objective
Primary
* To evaluate the pharmacokinetics of oxybutynin and its main hepatic
metabolite N-desethyloxybutynin after pulsed intra-vaginal delivery of a single
dose of oxybutynin
Secondary
* To assess the safety and tolerability of the intra-vaginal delivery of
oxybutynin via the MedRing device in healthy females
Study design
This is an open-label single dose study to assess the pharmacokinetics and
safety/tolerability of oxybutynin after a single pulsed intra-vaginal delivery
in healthy pre- and post-menopausal females. After a single oxybutynin
intra-vaginal dose, PK and safety data will be collected and reviewed for a
total period of 24 hours post-dose. Safety data will be collected by telephone
7 (+/- 2 days) after the dose administration.
Intervention
All subjects will receive a single-dose oxybutynin intra-vaginally.
Study burden and risks
Oxybutynin
Oxybutynin has been on the market for several years as a competitive
acetylcholine antagonist of the postganglionic muscarine receptors. It can be
administered orally in a dose of 2.5 mg 3dd, up to 20 mg 4dd oral, via
transdermal patches, or vesicular lavage.
For this study, a single dose up to 6 mg oxybutynin HCl (dissolved in 50%
propylene glycol / 50% water for injection) will be administered
intra-vaginally in a concentration of 100 mg/mL (for dosing rationale, see
Section 1.4.5.).
There is extensive experience with oxybutynin in clinical practice with oral,
intravesical and dermal administrations. In general, the systemic exposure of
oxybutynin in humans is considered safe. Common side effects are caused by the
anti-cholinergic mode of action of the drug: obstipation, nausea, dry mouth,
dizziness, fatigue, and, rarely, confusion. A large part of the side effects
are thought to be mediated by the main metabolite N-desethyloxybutynin. With an
intra-vaginal route of administration these side effects may be less
pronounced.
Data on local side effects are scarce. In earlier studies with intra-vaginally
administered oxybutynin, no local side effects where observed. The higher
concentrated solution of oxybutynin used in this study could theoretically lead
to irritation. However, only a single dose with a small volume is administered
and if irritation complaints should occur, the extent of irritation should be
investigated by an experienced physician. Furthermore, the vagina may be
irrigated after removal of the MedRing in case of tolerability issues during
the clinical phase.
MedRing intra-vaginal ring
Pre-dose, the MedRing will be instructed to release the intended dose of
oxybutynin solution at 37 degrees Celsius (in case of 6 mg, it will be 60 ul)
to be pipetted using a capillary to check for correct output of the ring prior
to placement. This output will subsequently be measured and dissolved in a
*calibration reservoir* to enable determination of the calibration
concentration. The ring will be inserted intra-vaginally by the physician and
the subject will be subsequently monitored. The ring will stay in place for 6
hours. Thereafter, it will be removed by the physician under the same
conditions as during insertion. After removal, the ring is cleaned and will be
post-calibrated in a similar fashion to the pre-calibration process.
Koninginnegracht 33
The Hague 2514 AC
NL
Koninginnegracht 33
The Hague 2514 AC
NL
Listed location countries
Age
Inclusion criteria
Eligible subjects must meet all of the following inclusion criteria at
screening:
1. Willing to give written informed consent and willing and able to comply with
the study protocol;
2. Female subjects of child bearing potential (women of child bearing
potential, WOCBP) aged between 18 and 45 years (inclusive)
OR
Female postmenopausal subjects aged between 50 and 69 years (inclusive);
Postmenopausal status is defined as age * 50 years and having > 12 months
amenorrhoea in the absence of hormonal therapy that may cause amenorrhoea.
3. Subject is in good general health, according to the investigator*s judgement
based on vital signs, medical history, physical examination, and laboratory
tests performed.
4. Body mass index between 18-32 kg*m2 (inclusive) and with a minimum body
weight of 50 kg at screening
5. Ability to communicate well with the investigator in the Dutch language and
willing to comply with the study restrictions
6. Using contraceptives of second generation containing ethinylestradiol and
progesterone derivate (WOCBP subjects only). This includes a hormone-containing
IUD (e.g. Mirena), second generation oral contraceptive pill, hormonal
contraception using parenteral medroxyprogesteron or subcutaneous etonogestrel.
Exclusion criteria
Eligible subjects must meet none of the following exclusion criteria at
screening:
1. (A history of) any clinically significant medical condition or
abnormalities, as judged by the investigator, in physical examination,
laboratory test results (including chemistry panel with hepatic and renal
panels, complete blood count, and urine dipstick) or electrocardiography (ECG).
In the case of uncertain or questionable results, tests performed during
screening may be repeated to confirm eligibility or judged by the investigator
to be clinically irrelevant for healthy subjects.
2. Being a virgin.
3. History of sexual abuse/violence.
4. First day of last withdrawal bleeding <10 days before Day 0
5. Plan to discontinue oral contraceptive during study period.
6. Positive pregnancy test at screening or at baseline prior to IMP
administration and/or lactating.
7. Having given birth vaginally or by caesarean section 6 months prior to
screening
8. Having had sexual intercourse or objects inserted vaginally that could
potentially lacerate or damage the vaginal wall 24 hours prior to dosing.
9. Positive screening test for Hepatitis B/C and/or Human Immunodeficiency
Virus (HIV) test at screening
10. Positive screening PCR test for Chlamydia trachomatis or gonorrhea at
screening
11. Medical history of intra- and/or transvaginal operations that in the
opinion of the investigator may interfere with placement or stability of the
MedRing or absorption of the IMP. Exceptions may include endometrial curettage
for e.g. miscarriage or abortion or LIS-excision of the cervix for CIN if
performed > 3 months prior to screening.
12. High risk for sexual transmitted diseases (STD) (a. 3 or more different
sexual contacts in last 6 months, and/or b. is a sex worker or visits them
and/or c. has a partner with an STD risk as described (a. and/or b.), and/or d.
partner is a male who has sex with male).
13. Any confirmed significant allergic reactions (urticaria or anaphylaxis)
against oxybutynin, or multiple drug allergies (non-active hay fever is
acceptable).
14. Participation in any marketed or investigational drug or device study
within 3 months or 5 half-lives (whichever is longer) prior to first dosing.
15. Use of any prescription medication and any other substance that in the
opinion of the investigators may influence the outcome of the study within 21
days prior to study drug administrations, or less than five half-lives
(whichever is longer, and during the course of the study). Exceptions are the
incidental use of OTC medications paracetamol (up to 4 g/day) and ibuprofen (up
to 1 g/day) which are allowed within two days of clinical assessments
16. Use of alcohol during the 24 hours prior to screening and/or an
unwillingness to abstain from alcohol consumption during the stay at the
clinical unit, and for at least 24 hours prior to each study visit;
17. Positive urine drug screen or alcohol test at screening and/or at study
days.
18. Intake of grapefruit or grapefruit juice within 5 days of IMP
administration, and/or unwillingness to abstain from the consumption of these
products from 5 days prior to IMP administration until the last study visit;
19. Loss or donation of blood over 500 mL within four months prior to screening.
20. Any other condition that in the opinion of the investigator would
complicate or compromise the study or the well-being of the subject.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-005044-30-NL |
| CCMO | NL75627.056.20 |
| OMON | NL-OMON20539 |