A Randomized, Open-Label, Bioequivalence Study of Lidocaine Topical System 1.8% and Lidocaine Patch 5% in Healthy Subjects

Figures & data

Table 1 Characteristics of Lidocaine Topical System 1.8% and Lidocaine Patch 5%

Attribute	Lidocaine Topical System 1.8% (ZTlido^®)^Citation9	Lidocaine Patch 5% (Lidoderm^®)^Citation12
Formulation	Nonaqueous polymer matrix	Aqueous polymer matrix
Lidocaine content	36 mg (18 mg per gram adhesive)	700 mg (50 mg per gram adhesive)
Size	10 cm × 14 cm	10 cm × 14 cm
Thickness	0.08 cm	0.16 cm*
Weight	2 g adhesive	14 g adhesive
Bioavailability	~48%	3% ± 2%

Note: *Approximate thickness based on product utilized in studies.

Table 2 Demographics and Baseline Characteristics (Study 1)

	<65 Years (n=54)	≥65 Years (n=4)	All Subjects (N=58)
Age (years)
Mean (SD)	36.8 (9.9)	68.5 (4.4)	39.0 (12.5)
Median	37.0	66.5	39.5
Minimum, maximum	20, 55	66, 75	20, 75
Gender, n (%)
Male	20 (37.0)	2 (50.0)	22 (37.9)
Female	34 (63.0)	2 (50.0)	36 (62.1)
Ethnicity, n (%)
Hispanic or Latino	21 (38.9)	0	21 (36.2)
Non-Hispanic or Latino	33 (61.1)	4 (100.0)	37 (63.8)
Race, n (%)
White	28 (51.9)	2 (50.0)	30 (51.7)
Black or African American	23 (42.6)	2 (50.0)	25 (43.1)
American Indian or Alaska Native	1 (1.9)	0	1 (1.7)
Asian	1 (1.9)	0	1 (1.7)
Other	1 (1.9)	0	1 (1.7)

Abbreviation: SD, standard deviation.

Table 3 Demographics and Baseline Characteristics (Study 2)

	Sequence 1 [Lidocaine Topical System 1.8% → Lidocaine Patch 5%] (n=28)	Sequence 2 [Lidocaine Patch 5% → Lidocaine Topical System 1.8%] (n=26)	Overall (N=54)
Age (years)
Mean (SD)	41.3 (10.8)	40.8 (9.9)	41.1 (10.3)
Median	41.0	45.0	42.5
Minimum, maximum	20, 58	25, 59	20, 59
Gender, n (%)
Male	20 (71.4)	19 (73.1)	39 (72.2)
Female	8 (28.6)	7 (26.9)	15 (27.8)
Ethnicity, n (%)
Hispanic or Latino	6 (21.4)	5 (19.2)	11 (20.4)
Non-Hispanic or Latino	22 (78.6)	21 (80.8)	43 (79.6)
Race, n (%)
White	15 (53.6)	13 (50.0)	28 (51.9)
Black or African American	12 (42.9)	13 (50.0)	25 (46.3)
American Indian or Alaska Native	1 (3.6)	0 (0.0)	1 (1.9)

Abbreviation: SD, standard deviation.

Table 4 Pharmacokinetic Parameter Estimates of Lidocaine in Plasma (per Protocol Population) (Studies 1 and 2)

Pharmacokinetic Parameter	Lidocaine Topical System, 1.8%	Lidocaine Patch, 5%	Lidocaine (0.7 mg/kg) IV
Study 1
Number of Subjects	56	56	56
Cmax (ng/mL)	80.5 (25.53)	75.4 (30.0)	1778.39 (2555.09)
AUC0-t (ng·h/mL) [±SD]	1160.3 (394.5)	1121.0 (453.1)	1981.94 (1660.51)
AUC0-inf (ng·h/mL) [±SD]	1207.4 (387.6)	1183.4 (437.4)	1998.56 (1667.92)
Tmax (hour) [range]^a	14.0 (9.0, 20.0)	12.7 (9.1, 24.0)	0.13 (0.1, 4.0)
T½ (hour) [±SD]	5.6 (1.7)	6.3 (1.8)	2.92 (0.52)
ke (hr^−1) [±SD]	0.13 (0.03)	0.12 (0.03)	0.24 (0.04)
Study 2
Number of Subjects	54	54
Cmax (ng/mL)	75.1 (28.0)	86.6 (42.3)
AUC0-t (ng·h/mL) [±SD]	1242.9 (432.5)	1420.8 (586.0)
AUC0-inf (ng·h/mL) [±SD]	1253.7 (432.5)	1435.5 (588.9)
Tmax (hour) [range]^a	13.9 (4.0, 18.0)	11.0 (4.0, 17.9)
T½ (hour) [±SD]	5.4 (1.0)	6.2 (1.6)
ke (hr^−1) [±SD]	0.13 (0.03)	0.12 (0.03)

Note: ^aMedian value.

Abbreviations: C_max, maximum plasma drug concentration; AUC_0-t, area under the curve from time 0 to the time of the last measurable concentration; SD, standard deviation; AUC_0-inf, area under the plasma concentration-time curve from time 0 to infinity; T_max, time point at which the maximum plasma concentration was observed; T_½, elimination half-life; K_e, elimination rate constant; IV, intravenous.

Figure 1 Mean lidocaine plasma concentrations versus time profiles for IV lidocaine 0.7 mg/kg, semilog scale (N = 56) (Study 1). Time = 0 is pre-dose measurement.

Abbreviation: IV, intravenous.

Figure 2 Mean lidocaine plasma concentrations versus time profiles for lidocaine topical system 1.8% (N = 56) and lidocaine patch 5%, semilog scale (N = 54) (Study 1). Time = 0 is pre-dose measurement.

Table 5 Analysis of Bioequivalence (Study 1)

	n	Ratio of Geometric Means	90% CI
Cmax (ng/mL)	56	111.22	103.82, 119.15
AUC0-t (ng·h/mL)	56	106.41	99.85, 113.41
AUC0-inf (ng·h/mL)	54	104.57	98.84, 110.63

Abbreviations: C_max, maximum plasma drug concentration; AUC_0-t, area under the curve from time 0 to the time of the last measurable concentration; AUC_0-inf, area under the plasma concentration-time curve from time 0 to infinity; CI, confidence interval.

Table 6 Analysis of Bioequivalence (Study 2)

	n	Ratio of Geometric Means	90% CI
Cmax (ng/mL)	54	90.7	85.0, 96.8
AUC0-t (ng·h/mL)	54	89.1	84.9, 93.5
AUC0-inf (ng·h/mL)	53	88.6	84.4, 93.0

Note: Log-transformed quantities are analyzed in a mixed effects analysis of variance model, with treatment, sequence, and period as fixed effects and subject within sequence as a random effect.

Abbreviations: C_max, maximum plasma drug concentration; AUC_0-t, area under the curve from time 0 to the time of the last measurable concentration; AUC_0-inf, area under the plasma concentration-time curve from time 0 to infinity; CI, confidence interval.

Figure 3 Mean lidocaine plasma concentrations versus time profiles for lidocaine topical system 1.8% and lidocaine patch 5% (Study 2).

Table 7 Summary of Apparent Dose Absorbed (Studies 1 and 2)

Product	Study 1		Study 2
	AnalysisIVClearance		AnalysisIVResidual
	Dose Absorbed/3 Products (mg) (SD)	Fraction of Applied Dose Absorbed (%)	Dose Absorbed/3 Products (mg) (SD)	Fraction of Applied Dose Absorbed (%)
Lidocaine topical system 1.8%	43.99 ± 17.62	41 ± 16	47.9 ± 8.8	44 ± 8
Lidocaine patch 5%	43.74 ± 18.22	2 ± 1	–	–

Abbreviations: IV, intravenous; SD, standard deviation.

Table 8 Summary of Adhesion (Study 2)

Parameter	Lidocaine Topical System 1.8%	Lidocaine Patch 5%
Subjects with <50% adherence for at least one patch (%)
2 hours	0	2 (3.8)
6 hours	0	5 (9.4)
9 hours	0	7 (13.2)
12 hours	0	8 (15.1)
Number of patches completely detached (%)
2 hours	0	1 (0.6)
6 hours	0	2 (1.3)
9 hours	0	3 (1.9)
12 hours	0	5 (3.1)
Mean (90% CI) adherence score at 12 hours	0.22 (0.08, 0.36)	0.86 (0.72, 1.00)
P value (1-sample t-test, test vs reference)	<0.001

Abbreviation: CI, confidence interval.

Table 9 Summary of Irritation Analysis (Study 2)

	Lidocaine Topical System 1.8% (N=54)	Lidocaine Patch 5% (N=54)
Subjects’ maximum irritation score across all 3 patches (%)
0	34 (63.0)	30 (55.6)
1	18 (33.3)	24 (44.4)
2	2 (3.7)	0
Subjects by sum of irritation scores for all patches (%)*
0	34 (63.0)	30 (55.6)
1–2	3 (5.6)	1 (1.9)
3–4	15 (27.8)	23 (42.6)
5–6	2 (3.7)	0
Mean (90% CI) sum of irritation scores	1.15 (0.91, 1.38)	1.31 (1.08, 1.55)
P value (1-sample t-test, test vs reference)	0.406

Notes: *The mean sums of irritation scores are for the three patches per subject (ie, total score for all three patches) for lidocaine topical system 1.8% and lidocaine patch 5% at 12 hours following application. Irritation Scale: 0=No evidence of irritation; 1=Minimal erythema, barely perceptible; 2=Definite erythema, readily visible, or minimal edema, or minimal popular response; 3=Erythema and papules; 4=Definite edema; 5=Erythema, edema, and papules; 6=Vesicular eruption; 7=Strong reaction spreading beyond test site.

Abbreviation: CI, confidence interval.

Table 10 Overall Summary of Adverse Events (Study 1)

System Organ Class	Preferred Term	0.7 mg/kg Lidocaine IV (N=58)	Lidocaine Topical System 1.8% (N=56)	Lidocaine Patch 5.0% (N=57)
Subjects with any AE, n (%)		5 (8.6%) NR=5 (8.6%) R=0	2 (3.6%) NR=0 R=2 (3.6%)	6 (10.5%) NR=4 (7.0%) R=2 (3.5%)
Blood, lymphatic disorders, n (%)	Anemia	0	0	2 (3.5%) NR=1 (1.8%) R=1 (1.8%)
Gastrointestinal disorders, n (%)	Abdominal discomfort	0	0	1 (1.8%) NR=1 (1.8%) R=0
	Abdominal pain	0	1 (1.8%) NR=0 R=1 (1.8%)	0
	Nausea	0	0	1 (1.8%) NR=1 (1.8%) R=0
Injury, poisoning, and procedural complications, n (%)	Sunburn	1 (1.7%) NR=1 (1.7%) R=0	0	0
Laboratory evaluations, n (%)	Elevated alanine transaminase	0	0	1 (1.8%) NR=0 R=1 (1.8%)
Nervous system disorders, n (%)	Dizziness	1 (1.7%) NR=1 (1.7%) R=0	1 (1.8%) NR=0 R=1 (1.8%)	0
	Headache	1 (1.7%) NR=1 (1.7%) R=0	1 (1.8%) NR=0 R=1 (1.8%)	2 (3.5%) NR=2 (3.5%) R=0
Skin and subcutaneous disorders, n (%)	Hyperhidrosis	1 (1.7%) NR=1 (1.7%) R=0	0	0
	Pruritus	0	0	1 (1.8%) NR=1 (1.8%) R=0
	Urticaria	1 (1.7%) NR=1 (1.7%) R=0	1 (1.8%) NR=0 R=1 (1.8%)	0

Notes: Counts reflect numbers of subjects reporting one or more AEs that map to the MedDRA preferred term. TEAEs included definitely related, probably related, and possibly related. AEs were analyzed based on the last treatment subjects were on prior to AE occurrence. Denominator for percentages was number of subjects exposed to the given treatment.

Abbreviations: AE, adverse event; IV, intravenous; MedDRA, Medical Dictionary for Regulatory Activities; NR, not related; R, related; TEAE, treatment-emergent adverse event.

Table 11 Overall Summary of Adverse Events (Safety Population) (Study 2)

System Organ Class	Preferred Term (Verbatim)	Lidocaine Topical System 1.8% (N=54)	Lidocaine Patch 5% (N=54)	Overall (N=54)
Subjects with any AE, n (%)		1 (1.9%)	1 (1.9%)	2 (3.7%)
Nervous system disorders, n (%)	Syncope	0	1 (1.9%) Mild, notrelated	1 (1.9%)
Skin and subcutaneous tissue disorders, n (%)	Acne	1 (1.9%) Mild, not related	0	1 (1.9%)

Abbreviation: AE, adverse event.

ZTLIDO®. (Lidocaine Topical System): [Prescribing Information]. San Diego, CA, USA: Scilex Pharmaceuticals; 2018.

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LIDODERM®. (Lidocaine Patch 5%): [Prescribing Information]. Malvern, PA, USA: Endo Pharmaceuticals; 2018.

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