Pharmacokinetics and safety of olopatadine hydrochloride 0.77% in healthy subjects with asymptomatic eyes: data from 2 independent clinical studies

Figures & data

Figure 1 Study design of (A) pharmacokinetic study and (B) safety study.

Notes: *PK sampling: 0 hour (pre-dose), 0.25, 0.5, 1, 2, 4, 8, and 12 hours. ^$PK sampling: 0 hour (trough–24 hours after 1st dose-trough). ^‡PK sampling: 0 hour (trough). ^ΦAll 3 subjects withdrew from the study with consent, and the withdrawal was not related to the treatment. ^#One subject was not included in the safety population because of randomization error and for not receiving the investigational product.
Abbreviations: IP, investigational product; PK, pharmacokinetics; TC, telephonic contact.

Table 1 Baseline characteristics and subject demographics

Characteristics	Pharmacokinetic study* (N=36)		Safety study** (N=499)
	Olopatadine 0.77% (n=24)	Vehicle (n=12)	Olopatadine 0.77% (n=330)	Vehicle (n=169)
Age (years)
Mean (SD)	42.0 (11.7)	42.8 (12.9)	32.4 (17.1)	31.5 (15.7)
2–17, n (%)	0	0	51 (15.5)	24 (14.2)
≥18, n (%)	24 (100.0)	12 (100.0)	279 (84.5)	145 (85.8)
Sex, n (%)
Female	10 (41.7)	7 (58.3)	214 (64.8)	111 (65.7)
Male	14 (58.3)	5 (41.7)	116 (35.2)	58 (34.3)
Race, n (%)
Asian	14 (58.3)	6 (50.0)	12 (3.6)	4 (2.4)
Black or African American	2 (8.3)	1 (8.3)	20 (6.1)	17 (10.1)
White	7 (29.2)	5 (41.7)	289 (87.6)	140 (82.8)
Multi-racial	1 (4.2)	0	4 (1.2)	3 (1.8)
Others#	0	0	5 (1.5)	5 (3.0)
Iris color, n (%)
Blue	1 (4.2)	0	86 (26.1)	29 (17.2)
Brown	21 (87.5)	11 (91.7)	169 (51.2)	93 (55.0)
Green	1 (4.2)	0	26 (7.9)	18 (10.7)
Hazel	1 (4.2)	1 (8.3)	45 (13.6)	29 (17.2)
Gray	0	0	4 (1.2)	0
Contact lens use, n (%)	NA	NA	51 (15.5)	24 (14.2)

Notes:

* Pharmacokinetic population included subjects who were exposed to any dose of the test article.

** Safety population included subjects who were exposed to the test article for the duration of 6 weeks.

# Native Hawaiian or other Pacific Islander (n=3), American Indian or Alaskan Native (n=1), others (n=6). Olopatadine 0.77%, olopatadine hydrochloride solution 0.77%; vehicle, olopatadine hydrochloride solution 0.77% vehicle.

Abbreviations: NA, not analyzed; SD, standard deviation.

Figure 2 Mean olopatadine 0.77% plasma concentration over time (A) and AUC_0–12 (B) following single-dose (Day 1) and multiple-dose (Day 7) exposure.

Notes: ^#n=9 at 8- and 12-hour time points due to study consent withdrawal. Data for Day 7 AUC_0–12 are from 19 subjects. AUC_0–12, area under the plasma concentration–time curve from 0 to 12 hours.

Table 2 Pharmacokinetic parameters following single- and multiple-dose exposures of olopatadine 0.77% (pharmacokinetics population)

Pharmacokinetic parameters	Single dose (Day 1) (n=24)	Multiple dose (Day 7) (n=22)
Cmax, ng/mL* (range)	1.65 (0.62–4.12)	1.45 (0.61–4.50)
Tmax, h** (range)	2.00 (0.25–4.02)	2.00 (0.25–8.00)
AUC0–12, ng⋅h/mL* (range)	9.04 (4.05–18.40)	8.78 (3.72–21.20)
t1/2, h# (range)	2.90 (2.05–5.78)	3.40 (2.13–7.77)

Notes:

* C_max and AUC_0–12 expressed as geometric means,

** T_max expressed as median,

# t_1/2 expressed as arithmetic mean. AUC_0–12, area under the plasma concentration–time curve from 0 to 12 hours; C_max, peak plasma concentration; T_max, time to reach maximum plasma concentration; t_1/2, elimination half-life.

Table 3 Summary of TEAEs regardless of study drug relationship by treatment (safety population)

AEs (MedDRA PT), n (%)	Olopatadine 0.77% (n=330)	Vehicle (n=169)
At least 1 TEAE, total	88 (26.7)	53 (31.4)
Most frequent TEAEs, ≥1%
Ocular AEs
Vision blurred	16 (4.8)	7 (4.1)
Dry eye	11 (3.3)	5 (3.0)
Abnormal sensation in the eye	7 (2.1)	7 (4.1)
Corneal staining*	8 (2.4)	7 (4.1)
Conjunctival staining*	6 (1.8)	1 (0.6)
Eye pruritus	5 (1.5)	2 (1.2)
Eye irritation	1 (0.3)	5 (3.0)
Conjunctival hemorrhage	0	2 (1.2)
Non-ocular AEs
Diarrhea	0	2 (1.2)
Headache	5 (1.5)	3 (1.8)
Dysgeusia	8 (2.4)	0
Upper respiratory tract infection	6 (1.8)	3 (1.8)
Nasopharyngitis	6 (1.8)	3 (1.8)
Gastroenteritis viral	0	2 (1.2)
Ligament sprain	1 (0.3)	2 (1.2)
Cough	1 (0.3)	2 (1.2)

Notes:

* All of the adverse drug reactions of corneal staining and conjunctival staining were reported by one investigator who conducted fluorescein staining at some post-dose visits. Fluorescein staining was not a protocol required procedure and was not conducted at baseline (screening visits) for any subjects. Olopatadine 0.77%, olopatadine hydrochloride solution 0.77%; vehicle, olopatadine hydrochloride solution 0.77% vehicle.

Abbreviations: AE, adverse event; MedDRA, medical dictionary for the regulatory activities; PT, preferred term; TEAE, treatment-emergent adverse event.

Table 4 Summary of TEAEs in the selected age subgroups occurring at an incidence of ≥1% by treatment

AEs (MedDRA PT), n (%)	Olopatadine 0.77% (n=330)		Vehicle (n=169)
	2–17 years (n=51)	≥18 years (n=279)	2–17 years (n=24)	≥18 years (n=145)
Ocular AEs
Vision blurred	0	16 (5.7)	0	7 (4.8)
Dry eye	0	11 (3.9)	0	5 (3.4)
Abnormal sensation in the eye	2 (3.9)	5 (1.8)	0	7 (4.8)
Corneal staining*	1 (2.0)	7 (2.6)	0	7 (4.8)
Conjunctival staining*	2 (3.9)	4 (1.5)	1 (4.2)	0
Eye pruritus	1 (2.0)	4 (1.4)	0	2 (1.4)
Eye pain	0	3 (1.1)	0	0
Eye irritation	0	1 (0.3)	1 (4.2)	4 (2.7)
Chalazion	0	0	1 (4.2)	0
Ocular hyperemia	0	3 (1.1)	0	1 (0.7)
Conjunctival hemorrhage	0	0	0	2 (1.4)
Non-ocular AEs
Headache	1 (2.0)	4 (1.4)	0	3 (2.1)
Diarrhea	0	0	0	2 (1.4)
Nausea	1 (2.0)	0	0	1 (0.7)
Tongue discoloration	1 (2.0)	0	0	0
Vomiting	1 (2.0)	0	0	0
Dysgeusia	0	8 (2.9)	0	0
Upper respiratory tract infection	3 (5.8)	3 (1.1)	0	3 (2.1)
Nasopharyngitis	0	6 (2.2)	0	3 (2.1)
Urinary tract infection	1 (2.0)	2 (0.7)	0	1 (0.7)
Pharyngitis streptococcal	1 (2.0)	0	0	0
Gastroenteritis viral	0	0	0	2 (1.4)
Influenza	1 (2.0)	2 (0.7)	0	1 (0.7)
Pyrexia	2 (3.9)	0	1 (4.2)	0
Sinus congestion	0	2 (0.7)	1 (4.2)	0
Skin discoloration	1 (2.0)	0	0	0
Ligament sprain	0	1 (0.3)	0	2 (1.4)
Ligament injury	0	0	1 (4.2)	0

Notes:

* All of the adverse drug reactions of corneal staining and conjunctival staining were reported by one investigator who conducted fluorescein staining at some post-dose visits. Fluorescein staining was not a protocol required procedure and was not conducted at baseline (screening visits) for any subjects. Olopatadine 0.77%, olopatadine hydrochloride solution 0.77%; vehicle, olopatadine hydrochloride solution 0.77% vehicle.

Abbreviations: AE, adverse event; MedDRA, medical dictionary for the regulatory activities; PT, preferred term; TEAE, treatment-emergent adverse event.

Table 5 Summary of safety parameters in the overall safety population and selected age subgroups at Week 6 or at the Early Exit visit by treatment

	Olopatadine 0.77%			Vehicle
	Overall (n=330)	2–17 years (n=51)	≥18 years (n=279)	Overall (n=169)	2–17 years (n=24)	≥18 years (n=145)
Mean change in BCVA (SD)	−0.5 (3.5)	0.3 (3.2)	−0.7 (3.5)	0.3 (4.2)	0.4 (2.6)	0.3 (4.4)
Slit-lamp findings, abnormal, n (%)
Eyelids
Baseline	3 (0.9)	0	3 (1.1)	1 (0.6)	0	1 (0.7)
Week 6	2 (0.6)	0	2 (0.7)	1 (0.6)	0	1 (0.7)
Conjunctiva
Baseline	4 (1.2)	0	4 (1.4)	0	0	0
Week 6	3 (0.9)	0	3 (1.1)	0	0	0
Cornea
Baseline	3 (0.9)	0	3 (1.1)	1 (0.6)	0	1 (0.7)
Week 6	1 (0.3)	0	1 (0.4)	1 (0.6)	0	1 (0.7)
Lens
Baseline	32 (9.7)	0	32 (11.5)	13 (7.7)	0	13 (9.0)
Week 6	32 (9.7)	0	32 (11.5)	13 (7.7)	0	13 (9.0)
Mean change in IOP (SD), mmHg	0.5 (2.3)	−0.1 (2.4)	0.5 (2.3)	−0.2 (2.1)	0.6 (1.2)	−0.2 (2.1)
Dilated fundus parameters, abnormal, n (%)
Vitreous
Baseline	0	0	8 (2.9)	3 (1.8)	0	3 (2.1)
Week 6	7 (2.1)	0	7 (2.5)	3 (1.8)	0	3 (2.1)
Peripheral retina
Baseline	2 (0.6)	0	2 (0.7)	2 (1.2)	0	2 (1.4)
Week 6	2 (0.6)	0	2 (0.7)	1 (0.6)	0	1 (0.7)
Macula
Baseline	1 (0.3)	0	1 (0.4)	1 (0.6)	0	1 (0.7)
Week 6	1 (0.3)	0	1 (0.4)	0	0	0
Choroid
Baseline	1 (0.3)	0	1 (0.4)	0	0	0
Week 6	1 (0.3)	0	1 (0.4)	0	0	0
Mean change in vital signs (SD)
Pulse, bpm	0.7 (9.0)	1.9 (14.2)	0.5 (7.9)	0.4 (8.8)	−3.3 (7.7)	1.0 (8.8)
Systolic BP, mmHg	−0.3 (8.5)	0.6 (6.6)	−0.4 (8.8)	−0.7 (9.4)	0.6 (6.0)	−0.9 (9.8)
Diastolic BP, mmHg	−0.6 (6.7)	1.8 (4.9)	−1.0 (6.8)	−1.2 (7.9)	−1.5 (6.2)	−1.1 (8.2)

Notes: None of the subjects had abnormal anterior chamber, iris, and optic nerve at baseline or Week 6 or at the Early Exit visit. Olopatadine 0.77%, olopatadine hydrochloride solution 0.77%; vehicle, olopatadine hydrochloride solution 0.77% vehicle.

Abbreviations: BCVA, best-corrected visual acuity; BP, blood pressure; bpm, beats per minute; IOP, intraocular pressure; SD, standard deviation.

Table S1 Pharmacokinetic parameters following single- and multiple-dose exposures of olopatadine 0.77% in Japanese and non-Japanese subjects

Parameters	Japanese (n=12)		Non-Japanese (n=12)
	Day 1	Day 7*	Day 1	Day 7
Cmax (ng/mL)**	1.75	1.65	2.07	1.63
Tmax (hours)#	2.00	2.00	2.00	1.50
AUC0–12 (ng⋅h/mL)**	9.25	9.35	10.55	9.97
t1/2 (hours)	2.79	3.03	3.01‡	3.61

Notes:

* n=10.

** Both C_max and AUC_0–12 are expressed as geometric means.

# T_max expressed as median.

‡ t_1/2 expressed as arithmetic mean with n=7 for Japanese subjects. AUC_0–12, area under the plasma concentration–time curve from 0 to 12 hours. C_max, peak plasma concentration; T_max, time to reach maximum plasma concentration; t_1/2, elimination half-life.

Table S2 Overall summary of treatment-related AEs occurring at an incidence of ≥1% by treatment (safety population)

AEs (MedDRA PT), n (%)	Olopatadine 0.77% (n=330)	Vehicle (n=169)
Total	53 (16.1)	31 (18.3)
Ocular AEs
Vision blurred	15 (4.5)	7 (4.1)
Dry eye	8 (2.4)	5 (3.0)
Abnormal sensation in the eye	7 (2.1)	7 (4.1)
Corneal staining*	8 (2.4)	7 (4.1)
Conjunctival staining*	6 (1.8)	1 (0.6)
Eye pruritus	2 (0.6)	1 (0.6)
Eye pain	3 (0.9)	0
Eye irritation	1 (0.3)	5 (3.0)
Ocular hyperemia	2 (0.6)	0
Conjunctival hemorrhage	0	0
Non-ocular AEs
Headache	3 (0.9)	1 (0.6)
Dysgeusia	8 (2.4)	0
Upper respiratory tract infection	0	0
Nasopharyngitis	0	0
Influenza	0	0
Pyrexia	0	0
Sinus congestion	0	0
Skin discoloration	1 (0.3)	0
Ligament sprain	0	0
Hypertension	0	0

Notes:

* All of the adverse drug reactions of corneal staining and conjunctival staining were reported by one investigator who conducted fluorescein staining at some post-dose visits. Fluorescein staining was not a protocol required procedure and was not conducted at baseline (screening visits) for any subjects. Olopatadine 0.77%, olopatadine hydrochloride solution 0.77%; vehicle, olopatadine hydrochloride solution 0.77% vehicle.

Abbreviations: AE, adverse event; MedDRA, medical dictionary for the regulatory activities; PT, preferred term.

Table S3 Summary of TEAEs in selected age subgroups occurring at an incidence of ≥1% by treatment (safety population)

AEs (MedDRA PT), n (%)	Olopatadine 0.77% (n=330)		Vehicle (n=169)
	2–17 years (n=51)	≥18 years (n=279)	2–17 years (n=24)	≥18 years (n=145)
Ocular AEs
Vision blurred	0	15 (5.4)	0	7 (4.8)
Dry eye	0	8 (2.9)	0	5 (3.4)
Abnormal sensation in the eye	2 (3.9)	5 (1.8)	0	7 (4.8)
Corneal staining*	1 (2.0)	7 (2.5)	0	7 (4.8)
Conjunctival staining*	2 (3.9)	4 (1.4)	1 (4.2)	0
Eye pruritus	1 (2.0)	1 (0.4)	0	1 (0.7)
Eye pain	0	3 (1.1)	0	0
Eye irritation	0	1 (0.4)	1 (4.2)	4 (2.8)
Ocular hyperemia	0	2 (0.7)	0	0
Foreign body sensation in eyes	1 (2.0)	1 (0.4)	0	0
Non-ocular AEs
Headache	0	3 (1.1)	0	1 (0.7)
Dysgeusia	0	8 (2.9)	0	0
Skin discoloration	1 (2.0)	0	0	0

Notes:

* All of the adverse drug reactions of corneal staining and conjunctival staining were reported by one investigator who conducted fluorescein staining at some post-dose visits. Fluorescein staining was not a protocol required procedure and was not conducted at baseline (screening visits) for any subjects. Olopatadine 0.77%, olopatadine hydrochloride solution 0.77%; vehicle, olopatadine hydrochloride solution 0.77% vehicle.

Abbreviations: AE, adverse event; MedDRA, medical dictionary for the regulatory activities; PT, preferred term; TEAE, treatment emergent adverse event.

Table S4 Comparison of mean human plasma pharmacokinetic parameters following topical ocular and oral single- and multiple-dose exposures of olopatadine

Pharmacokinetic parameters	Single-dose		Multiple-dose
	Olopatadine 0.77% (n=24)	10 mg olopatadine oral tablet (n=8)^Citation1	Olopatadine 0.77% (n=22)	10 mg olopatadine oral tablet (n=8)^Citation1
Cmax, ng/mL (SD)	1.88 (0.99)	131.10 (19.36)	1.64 (0.89)	146.82 (44.37)
Tmax, hours (SD)	1.74 (1.10)	1.44 (0.50)	2.08 (1.69)	1.56 (0.50)
AUC0–12, ng⋅h/mL (SD)	9.79 (4.02)	426 (68)	9.68 (4.42)*	479 (81.00)**
AUC0–∞, ng⋅h/mL (SD)	10.6 (4.32)	455 (61)	10.8 (4.83)*	ND
t1/2, hours (SD)	2.90 (0.98)	10.50 (1.38)	3.40 (1.20)	11.47 (2.95)

Notes:

* n=19.

** n=4. AUC_0–12, area under the plasma concentration–time curve from 0 to 12 hours; C_max, peak plasma concentration; T_max, time to reach maximum plasma concentration; t_1/2, elimination half-life.

Abbreviations: ND, not determined; SD, standard deviation.

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