First-in-human study to assess the pharmacokinetics, tolerability, and safety of single-dose oxybutynin hydrochloride administered via a microprocessor-controlled intravaginal ring

Figures & data

Figure 1. Illustration of the MedRing vaginal ring device.

Table 1. Subject demographics and baseline characteristics.

Subject number	Age (years)	Race	Hormonal status	Height (cm)	Weight (kg)	BMI^a (kg/m^2)
1	33	Hispanic	Premenopausal	162.5	60.0	22.7
2	31	White	Premenopausal	170.6	67.3	23.0
3	21	Mixed^b	Premenopausal	176.9	88.9	28.4
4	21	White	Premenopausal	174.0	67.2	22.2
5	68	White	Postmenopausal	168.6	87.3	30.7
6	69	White	Postmenopausal	167.7	59.7	21.2
7	67	White	Postmenopausal	165.2	69.5	25.3
8	57	White	Postmenopausal	177.0	58.8	18.8

^a BMI – body mass index.

^b Mixed – white and black mixed race.

Table 2. Summary of the pharmacokinetic parameters of oxybutynin and N-desethyloxybutynin after a single intravaginal dose of 3 mg oxybutynin hydrochloride using the MedRing vaginal ring device.

Parameter	Unit	N	Mean	SD	CV%	GeoMean	GeoCV%	Median	Min.	Max.
Oxybutynin AUC extrapolated	%	6	24.4	13.5	55.3	20.4	84.8	26.2	5.5	45.2
Oxybutynin AUC8h	h ng/mL	8	21.4	9.7	45.3	18.5	73.5	22.6	4.5	34.7
Oxybutynin AUCinf	h ng/mL	6	34.9	17.4	50.0	29.9	78.7	35.3	8.2	59.8
Oxybutynin CL/F	L/h	6	117.0	108.0	93.0	91.2	78.7	79.0	45.2	334.0
Oxybutynin Cmax	ng/mL	8	5.4	2.7	51.0	4.5	77.1	5.6	1.2	9.3
Oxybutynin dose normalized AUCinf	h ng/mL/mg	6	12.8	6.4	50.0	11.0	78.7	13.0	3.0	22.0
Oxybutynin dose normalized Cmax	ng/mL/mg	8	2.0	1.0	51.0	1.7	77.1	2.1	0.4	3.4
Oxybutynin t1/2	h	6	8.5	3.5	41.4	7.9	44.2	8.6	4.7	14.3
Oxybutynin tlag	h	8						0.0	0.0	0.25
Oxybutynin tmax	h	8						2.0	1.0	5.0
Oxybutynin Vz/F	L	6	1391	1294	93.0	1042	92.0	749.0	496.0	3830
N-desethyloxybutynin AUC extrapolated	%	7	28.7	16.9	59.1	23.5	87.2	24.9	6.0	52.2
N-desethyloxybutynin AUC8h	h ng/mL	8	20.7	13.5	65.3	16.4	95.5	18.7	3.3	45.2
N-desethyloxybutynin AUCinf	h ng/mL	7	51.1	43.1	84.2	34.9	141.6	31.5	5.2	119.0
N-desethyloxybutynin Cmax	ng/mL	8	3.9	2.5	63.2	3.1	98.4	3.6	0.6	8.1
N-desethyloxybutynin t1/2	h	7	7.7	5.9	76.7	6.38	69.4	5.1	2.9	20.3
N-desethyloxybutynin tlag	h	8						0.4	0.0	0.5
N-desethyloxybutynin tmax	h	8						4.0	3.0	5.0
Ratio AUC22hN-desethyloxybutynin/oxybutynin		4	1.4	0.7	51.9	1.2	50.4	1.1	0.8	2.4
Ratio AUC8hN-desethyloxybutynin/oxybutynin		8	0.9	0.4	42.5	0.9	34.7	0.8	0.7	1.9
Ratio AUCinf N-desethyloxybutynin/oxybutynin		6	1.3	0.7	57.9	1.1	58.0	0.9	0.6	2.4
Ratio CmaxN-desethyloxybutynin/oxybutynin		8	0.7	0.3	40.4	0.7	37.1	0.7	0.5	1.4

AUC, area under the curve; AUC_8h, area under the curve – time from 0 h to 8 h; AUC_22h, area under the curve – time from 0 h to 22 h; AUC_inf, area under the curve – time from 0 h to infinity; CL/F, apparent total clearance following extravascular administration; C_max, maximum concentration; CV, coefficient of variation; GeoMean, geometric mean; GeoCV, geometric coefficient of variation; Max., maximum; Min., minimum; SD, standard deviation; t_1/2, terminal elimination half-life; t_max, time to attain C_max; t_lag, absorption half-time; V_z/F, apparent volume of distribution during the terminal elimination phase after extravascular administration.

Figure 2. Individual pharmacokinetic profiles of oxybutynin (A) and N-desethyloxybutynin (B) up to 22 h after intravaginal dosing with 3 mg oxybutynin hydrochloride.

Figure 3. Mean (±SD) pharmacokinetic profiles of oxybutynin and N-desethyloxybutynin, 2 h and 6 h (A and B) after removal of MedRing and based on hormonal status (premenopause and postmenopause; C and D) after targeted intravaginal dosing with 3 mg oxybutynin hydrochloride.

Table 3. Treatment-emergent adverse events reported during the study.

	Oxybutynin 100 mg (n = 8)
	Event n	Subject n (%)
All events	11	5 (62.5)
Eye disorders
Blurry vision	1	1 (12.5)
Gastrointestinal disorders
Dry mouth	1	1 (12.5)
Lip dry	1	1 (12.5)
Nausea	1	1 (12.5)
General and administration conditions
Fatigue	2	2 (25.0)
Feeling hot	1	1 (12.5)
Nervous system disorders (headache)	4	3 (37.5)

Table 4. MedRing tolerability assessments through dichotomous questions asked by the physician or the nurse during the study day.

Tolerability question	No (%)	Yes (%)
Was the placement of MedRing uncomfortable?	8 (100%)	0 (0%)
Can you feel the presence of MedRing?	7 (88%)	1 (13%)
Is the presence of MedRing uncomfortable?	8 (100%)	0 (0%)
Can you feel the administration of the medication?	7 (88%)	1 (13%)
Was the removal of MedRing uncomfortable?	8 (100%)	0 (0%)
Did you experience any form of irritation following insertion (2 to 6 hr of wear) and/or removal of MedRing?	8 (100%)	0 (0%)

Data availability

The datasets generated during and/or analyzed during the study are available from the corresponding author on reasonable request.