Bioequivalence of diclofenac sodium 2% and 1.5% topical solutions relative to oral diclofenac sodium in healthy volunteers

Figures & data

Table 1. Study designs.

Characteristic	Study 1 (MNK15310250)	Study 2 (COV05100070)	Study 3 (COV05100175)
Country	USA	USA	USA
Participants	Healthy volunteers aged 18–55 years with BMI 19–≤30 kg/m^2 (n = 32)	Healthy volunteers aged 18–55 years with BMI 19–≤29 kg/m^2 (n = 30)	Healthy volunteers aged 18–55 years with BMI 19–≤30 kg/m^2 (n = 32)
Study design	Phase 1, single-center, randomized, open-label, multiple-dose, 2-period	Phase 1, single-center, randomized, open-label, multiple-dose, 3-period	Phase 1, single-center, randomized, open-label, multiple-dose, 2-period
Objectives	Compare BA and PK of topical diclofenac 2% vs 1.5% solutions	Compare BA and PK of topical diclofenac 2% vs 1.5% solutions, and oral diclofenac	Compare BA and PK of topical diclofenac 2% vs 1.5% solutions
Treatment groups	Diclofenac 2% solution (40.4 mg/2 mL to each knee BID; total = 162 mg/day) for 7.5 days	Diclofenac 2% solution (40.4 mg/2 mL to each knee BID; total = 162 mg/day) for 7.5 days	Diclofenac 2% solution (40.4 mg/2 mL to each knee BID; total = 162 mg/day) for 7.5 days
	Diclofenac 1.5% solution (40 drops [19.3 mg/1.2 mL] to each knee QID; total = 154 mg/day) for 7.5 days	Diclofenac 1.5% solution (40 drops [19.3 mg/1.2 mL] to each knee QID; total = 154 mg/day) for 7.5 days	Diclofenac 1.5% solution (40 drops [19.3 mg/1.2 mL] to each knee QID; total = 154 mg/day) for 7.5 days
		Oral diclofenac 75 mg SR tablet BID for 7.5 days
Washout period	15 days	21 days	21 days
Analytical method (range)	LC-MS/MS (0.100 to 100 ng/mL diclofenac)	LC-MS/MS (0.100 to 100 ng/mL diclofenac)	LC-MS/MS (0.100 to 100 ng/mL diclofenac)
Measures of exposure	Cmax, AUC0–12	Cmax, AUC0–24	Cmax, AUC0–24

Abbreviations: AUC = Area under the plasma concentration-time curve; AUC_0–12 = AUC from 0 to 12 hours after study drug administration; AUC_0–24 = AUC from 0 to 24 hours after study drug administration; BA = Bioavailability; BID = Twice daily; BMI = Body mass index; C_max = Maximum observed plasma concentration; LC-MS/MS = Liquid chromatography/tandem mass spectrometry; PK = Pharmacokinetics; QID = Four times daily; SR = Sustained release.

Table 2. Subject demographics.

	Study 1 (MNK15310250)		Study 2 (COV05100070)		Study 3 (COV05100175)
Characteristics	All Subjects Dosed (n = 32)	Completers (n = 30)	All Subjects Dosed (n = 30)	Completers (n = 22)	All Subjects Dosed (n = 32)	Completers (n = 29)
Mean age (SD), years	33.8 (8.7)	34.1 (8.9)	38.9 (9.4)	40.1 (8.8)	40.6 (8.2)	41.0 (8.5)
Gender, n (%)
Female	13 (40.6)	11 (36.7)	14 (46.7)	11 (50.0)	19 (59.4)	16 (55.2)
Male	19 (59.4)	19 (63.3)	16 (53.3)	11 (50.0)	13 (40.6)	13 (44.8)
Race, n (%)
White	22 (68.8)	20 (66.7)	28 (93.3)	20 (90.9)	31 (96.9)	28 (96.6)
Black/African American	9 (28.1)	9 (30.0)	2 (6.7)	2 (9.1)	1 (3.1)	1 (3.5)
Asian	1 (3.1)	1 (3.3)	0	0	0	0
Hispanic/Latino ethnicity	12 (37.5)	10 (33.3)	30 (100)	22 (100)	32 (100)	29 (100)
Mean body mass index (SD), kg/m^2	25.4 (2.8)	25.3 (2.8)	25.5 (2.0)	25.4 (2.0)	26.4 (2.4)	26.6 (2.4)

Abbreviation: SD = Standard deviation.

Figure 1. Flow diagram of subject disposition: Panel (A) Study 1, Panel (B) Study 2, and Panel (C) Study 3. Note that five subjects were excluded from the pharmacokinetic (PK) analysis in Study 1 because predose diclofenac concentrations were >5% of maximum observed plasma concentration; thus, 25 subjects were included in the PK analysis.

Table 3. Summary of diclofenac pharmacokinetic parameters on Day 1 and Day 8 of dosing with topical diclofenac 2% solution (40 mg/knee) BID and topical diclofenac 1.5% solution (19.3 mg/knee) QID in Study 1. Only data from study completers are shown.

Parameter, Mean (SD)	Topical Diclofenac 2% Solution BID (n = 25)	Topical Diclofenac 1.5% Solution QID (n = 25)
Day 1
Tmax h^a	8 (5.83, 11.95)	5.83 (4, 5.98)
Cmax, ng/mL	12.16 (7.66)	2.30 (2.02)
AUC0–12, ng · h/mL	77.27 (49.89)	27.46 (23.97)
Steady state (Day 8)
Tmaxss h^a	6.50 (0.00, 12.00)	0.00 (0.00, 5.83)
Cmaxss, ng/mL	25.24 (12.95)	17.04 (11.28)
Cminss, ng/mL	9.94 (6.16)	8.83 (5.56)
Cavgss, ng/mL	17.05 (9.25)	11.47 (7.64)
AUCss0–12, ng · h/mL	204.58 (111.02)	141.49 (92.47)
DFL	93.41 (24.38)	72.21 (22.79)
Swing	3.58 (9.46)	0.99 (0.53)
Kel, 1/h^b	0.0295 (0.0072)	0.0240 (0.0057)
t½, h^b	24.84 (5.98)	31.15 (10.98)
Geometric LSM AUC0–12, ng · h/mL	61.61	20.51
Geometric LSM ratio (90% CI)^c	300.41 (235.8, 382.8), p < 0.001
CV, %	52.1
Geometric LSM AUCss0–12, ng · h/mL	175.07	120.17
Geometric LSM ratio (90% CI)^c	145.68 (125.35, 176.35), p = 0.003
CV, %	40.1

^aT_max and T_maxss values are presented as median (range).

^bCalculated over Days 8–15.

^cLSM ratios were calculated as diclofenac 2%/diclofenac 1.5%.

Abbreviations: AUC = Area under the plasma concentration-time curve; BID = Twice daily; C_avg = Average plasma concentration during the dosing interval; C_max = Maximum observed plasma concentration; C_min = Minimum observed plasma concentration; CI = Confidence interval; CV = Coefficient of variability; DFL = Degree of fluctuation; K_el = Apparent first-order elimination rate constant; LSM = Least squares mean; QID = Four times daily; SD = Standard deviation; SS = Steady state; t_1/2 = Terminal elimination half-life; T_max = Time to C_max.

Table 4. Summary of diclofenac pharmacokinetic parameters on Day 1 and Day 8 of dosing with topical diclofenac 2% solution (40.4 mg/knee) BID and topical diclofenac 1.5% solution (19.3 mg/knee) QID in Studies 2 and 3. Only data from study completers are shown.

Parameter, Mean (SD)	Study 2 (COV05100070) (n = 22)			Study 3 (COV05100175) (n = 29)
	Topical Diclofenac 2% Solution BID	Topical Diclofenac 1.5% Solution QID	Oral Diclofenac 75 mg SR BID	Topical Diclofenac 2% Solution BID	Topical Diclofenac 1.5% Solution QID
Day 1
Cmax, ng/mL	15.63 (13.23)	3.17 (3.24)	1271.10 (1117.99)	15.53 (12.98)	4.86 (4.12)
AUC0–24, ng · h/mL	190.82 (160.32)	25.25 (25.55)	4917.33 (3567.08)	199.07 (172.96)	46.83 (49.91)
Steady state (Day 8)
Cmaxss, ng/mL	19.53 (10.31)	18.07 (8.99)	1348.41 (1073.83)	19.99 (10.15)	14.61 (9.25)
AUCss0–24, ng · h/mL	315.47 (158.70)	353.78 (174.93)	4426.01 (2793.74)	322.57 (167.81)	251.24 (152.64)
Kel, 1/h	0.02 (0.01)	0.02 (0.01)	0.18 (0.05)	0.03 (0.01)	0.03 (0.01)
t1/2, h	35.24 (9.01)	36.17 (9.98)	5.88 (9.24)	25.43 (8.71)	29.96 (11.77)
Geometric LSM AUC0–24, ng · h/mL	4.95	2.80	7.99	4.95	3.41
LSM ratio (90% CI)^a	857.67 (428.47, 1716.81), p < 0.0001			464.07 (355.13, 606.42), p < 0.0001
LSM ratio (90% CI)^b	4.81 (2.40, 9.62), p < 0.0001
CV, %^c	227.7			65.5
Geometric LSM AUCss0–24, ng · h/mL	5.67	5.73	8.23	5.64	5.38
LSM ratio (90% CI)^a	94.20 (73.79, 120.25), p = 0.6824			128.86 (106.06, 156.58), p = 0.0352
LSM ratio (90% CI)^b	7.75 (6.07, 9.90), p < 0.0001
CV, %^c	50.3			45.7

^aLSM ratios were calculated as diclofenac 2%/diclofenac 1.5%.

^bLSM ratios were calculated as diclofenac 2%/oral diclofenac.

^cIncludes all treatments.

Abbreviations: AUC = Area under the plasma concentration-time curve; BID = Twice daily; C_max = Maximum observed plasma concentration; CI = Confidence interval; CV = Coefficient of variability; K_el = Apparent first-order elimination rate constant; LSM = Least squares mean; QID = Four times daily; SD = Standard deviation; SR = Sustained release tablet; SS = Steady state; t_1/2 = Terminal elimination half-life.

Figure 2. Mean concentration of diclofenac in plasma on Day 1 (A) and Day 8 (B) after topical application of diclofenac sodium 2% and 1.5% solutions. Pooled analysis of data from subjects who completed treatment in two trials.

Table 5. Summary of diclofenac pharmacokinetic parameters on Day 1 and Day 8 of dosing with topical diclofenac 2% solution (40.4 mg/knee) BID and topical diclofenac 1.5% solution (19.3 mg/knee) QID. Combined results of data from Studies 2 and 3. Only data from study completers are shown.

Parameter, Mean (SD)	Topical Diclofenac 2% Solution BID (n = 51)	Topical Diclofenac 1.5% Solution QID (n = 51)
Day 1
Cmax, ng/mL	15.57 (12.96)	4.14 (3.83)
AUCss0–24, ng · h/mL	195.51 (166.03)	37.52 (42.26)
Steady state (Day 8)
Cmaxss, ng/mL	19.79 (10.12)	16.10 (9.21)^a
AUCss0–24, ng · h/mL	319.51 (162.36)	295.47 (168.91)^b
Kel, 1/h	0.0264 (0.0104)	0.0236 (0.0071)^c
t½, h	29.72 (10.04)	32.53 (11.38)^d

^ap = 0.06.

^bp = 0.47.

^cp = 0.12.

^dp = 0.19.

Abbreviations: AUC = Area under the plasma concentration-time curve; BID = Twice daily; C_max = Maximum observed plasma concentration; K_el = Apparent first-order elimination rate constant; QID = Four times daily; SD = Standard deviation; SS = Steady state; t_1/2 = Terminal elimination half-life.

Figure 3. Mean plasma concentration profile of diclofenac after topical application of diclofenac sodium 2% and 1.5% solutions and oral diclofenac 75 mg in Study 2 from 0 to 24 hours (Day 1, A), 24 to 168 hours (Days 2 to 7, B) and 168 to 192 hours (Day 8, C).

Table 6. Safety and tolerability of topical diclofenac 2% solution applied BID and topical diclofenac 1.5% solution applied QID for 7.5 days in three studies

Adverse Events, n (%)	Study 1 (MNK15310250)		Study 2 (COV05100070)		Study 3 (COV05100175)
	Diclofenac 2% BID (n = 32)	Diclofenac 1.5% QID (n = 30)	Diclofenac 2% BID (n = 22)	Diclofenac 1.5% QID (n = 27)	Diclofenac 2% BID (n = 32)	Diclofenac 1.5% QID (n = 31)
Subjects with ≥ 1 TEAE	21 (65.6)	14 (46.7)	8 (36.4)	14 (51.9)	25 (78.1)	18 (58.1)
TEAEs experienced by ≥ 5% of subjects
Application site dryness	12 (37.5)	6 (20.0)	5 (22.7)	8 (29.6)	15 (46.9)	11 (35.5)
Application site pain	4 (12.5)	1 (3.3)	0	0	0	0
Application site pruritus	5 (15.6)	1 (3.3)	0	0	4 (12.5)	3 (9.7)
Application site exfoliation	1 (3.1)	3 (10.0)	0	0	0	0
Application site erythema	2 (6.3)	0	0	0	4 (12.5)	2 (6.5)
Application site rash	2 (6.3)	0	0	0	0	0
Nasopharyngitis	2 (6.3)	0	0	0	0	0
Excoriation	3 (9.4)	0	0	0	0	0
Constipation	0	0	3 (13.6)	5 (18.5)	5 (15.6)	2 (6.5)

Abbreviations: BID = Twice daily; QID = Four times daily; TEAE = Treatment-emergent adverse event.