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Picato

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Picato

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of action by which Picato® gel induces cell death in treating AK lesions is unknown.

Pharmacodynamics

The pharmacodynamics of Picato® gel is unknown.

Pharmacokinetics

Absorption

The systemic exposure to Picato® gel, 0.05% was assessed in two studies in a total of 16 subjects with AK, following application of approximately 1 g of Picato® gel, 0.05% to an area of 100 cm² of the dorsal forearm once daily for two consecutive days. In these studies, the blood levels of ingenol mebutate and two of its metabolites (acyl isomers of ingenol mebutate) were measured. Blood levels of ingenol mebutate and the two metabolites were below the lower limit of quantification (0.1 ng/mL) in all the blood samples of the subjects evaluated.

Drug Interactions

In vitro studies demonstrated that [3H]-ingenol mebutate undergoes extensive metabolism in human hepatocytes.

In vitro studies to assess the potential of ingenol mebutate to inhibit or induce human cytochrome P450 (CYP) enzymes demonstrated that ingenol mebutate does not inhibit CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 or induce CYP 1A2, 2C9, and 3A4. The estimated expected systemic exposure ( < 0.1 ng/mL) following topical application of Picato® gel, 0.05% to AK subjects in the pharmacokinetic studies described above is negligible compared to the concentrations of ingenol mebutate evaluated in the in vitro studies.

Clinical Studies

Actinic Keratosis of the Face and Scalp

In two double-blind, vehicle-controlled, clinical trials, 547 adult subjects with AK on the face or scalp were randomized to treatment with either Picato® gel, 0.015% or vehicle gel for 3 consecutive days, followed by an 8 week follow-up period. The studies enrolled subjects with 4 to 8 clinically typical, visible, discrete AK lesions within a 25 cm² contiguous treatment area. Hypertrophic and hyperkeratotic lesions were excluded from treatment. On each scheduled dosing day, the study gel was applied to the entire treatment area. A total of 536 subjects (98%) completed these studies. Study subjects ranged from 34 to 89 years of age (mean 64 years) and 94% had Fitzpatrick skin type I, II, or III. Approximately 85% of subjects were male, and all Picato® -treated subjects were Caucasian.

Efficacy was assessed at Day 57. Complete clearance rate was defined as the proportion of subjects with no (zero) clinically visible AK lesions in the treatment area. Partial clearance rate was defined as the proportion of subjects with 75% or greater reduction in the number of AK lesions at baseline in the selected treatment area.

Table 5 : presents the efficacy results for each trial. Table 5 Number and Percent of Subjects Achieving Complete and Partial Clearance at Day 57 in Each Trial

  Study 1 Study 2
Picato® gel, 0.015%
(N=135 )
Vehicle
(N=134 )
Picato® gel, 0.015%
(N=142)
Vehicle
(N=136)
Complete Clearance Rate 50 (37%) 3 (2%) 67 (47%) 7 (5%)
Partial Clearance Rate ( ≥ 75%) 81 (60%) 9 (7%) 96 (68%) 11 (8%)

Table 6 : presents the response rates by anatomical location for each trial. Table 6 Number and Percent of Subjects Achieving Complete Clearance at Day 57 by Anatomical Location and by Trial

  Study 1 Study 2
Picato® gel, 0.015%
(N=135 )
Vehicle
(N=134 )
Picato® gel, 0.015%
(N=142)
Vehicle
(N=136)
Scalp 4/26 (15%) 0/25 (0%) 9/31 (29%) 1/25 (4%)
Face 46/109 (42%) 3/109 (2%) 58/111 (52%) 6/111 (5%)

Subjects who achieved complete clearance at Day 57 in Study 1 and Study 2 entered a 12-month follow-up period. Based on 108 Picato® gel-treated subjects who achieved complete clearance in Study 1 and Study 2, the recurrence rate at 12 months was 54% where recurrence was defined as the percentage of subjects with any identified AK lesion in the previously treated area who achieved complete clearance at Day 57.

Actinic Keratosis of the Trunk and Extremities

In two double-blind, vehicle-controlled clinical trials, 458 adult subjects with AK on the trunk or extremities were randomized to treatment with either Picato® gel, 0.05% or vehicle gel for 2 consecutive days, followed by an 8 week follow-up period. The studies enrolled subjects with 4 to 8 clinically typical, visible, discrete AK lesions within a 25 cm² contiguous treatment area. Hypertrophic and hyperkeratotic lesions were excluded from treatment. On each scheduled dosing day, the study gel was applied to the entire treatment area. A total of 447 subjects (98%) completed these studies. Study subjects ranged from 34 to 89 years of age (mean 66 years) and 94% had Fitzpatrick skin type I, II, or III. Approximately 62% of subjects were male, and all Picato® -treated subjects were Caucasian.

Efficacy was assessed at Day 57. Complete clearance rate was defined as the proportion of subjects with no (zero) clinically visible AK lesions in the treatment area. The partial clearance rate was defined as the proportion of subjects with 75% or greater reduction in the number of AK lesions at baseline in the selected treatment area. Table 7 presents the efficacy results for each study.

Table 7 : Number and Percent of Subjects Achieving Complete and Partial Clearance at Day 57 in Each Trial

  Study 3 Study 4
Picato® gel, 0.05%
(N=126 )
Vehicle
(N=129 )
Picato® gel, 0.05%
(N=100)
Vehicle
(N=103)
Complete Clearance Rate 35 (28%) 6 (5%) 42 (42%) 5 (5%)
Partial Clearance Rate ( ≥ 75%) 56 (44 %) 9 (7 %) 55 (55 %) 7 (7 %)

Table 8 presents the response rates by anatomical location for each study.

Table 8 : Number and Percent of Subjects Achieving Complete Clearance at Day 57 by Anatomical Location and by Trial

  Study 3 Study 4
Picato® gel, 0.05%
(N=126)
Vehicle
(N=129)
Picato® gel, 0.05%
(N=100)
Vehicle
(N=103)
Arm 22/84 (26 %) 4/82 (5 %) 27/59 (46 %) 3/67 (5 %)
Back of Hand 4/25 (16 %) 0/29 (0%) 6/28 (21 %) 0/27 (0 %)
Chest 8/9 (89 %) 1/8 (13 %) 3/5 (60 %) 1/3 (33 %)
Othera 1/8 (13 %) 1/10 (10 %) 6/8 (75 %) 1/6 (17 %)
aOther includes shoulder, back, leg.

Subjects who achieved complete clearance at Day 57 in Study 4 entered a 12-month follow-up period. Based on 38 Picato® gel-treated subjects who achieved complete clearance in Study 4, the recurrence rate at 12 months was 50% where recurrence was defined as the percentage of subjects with any identified AK lesion in the previously treated area who achieved complete clearance at Day 57.

Last reviewed on RxList: 2/6/2012
This monograph has been modified to include the generic and brand name in many instances.

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