Transdermal Asenapine in Schizophrenia: A Systematic Review

Figures & data

Table 1 Summary of the Most Relevant Studies Examining Transdermal Asenapine

Author	Title	Summary	Results
Citrome et al 2019^Citation3	HP-3070 Asenapine Transdermal System in Adults with Schizophrenia Categorical Response and Clinical Relevance as Assessed in a Phase 3 RCT	Citrome et al 2019 evaluated the efficacy and tolerability of this formulation in a Phase 3, randomized, double-blind, fixed dose, placebo-controlled inpatient study conducted in 59 centers worldwide. The study took place in a period of 6 weeks with a 30 day follow-up including 616 adults with schizophrenia, with a total of 489 participants completing the full length of the trial. Patients were divided evenly among three groups: (1) High dose treatment (7.6mg/24hrs), (2) Low dose treatment (3.8mg/24hrs), and (3) Placebo. The primary endpoint was change from baseline in the sum of all participants’ PANSS score to Week 6. CGI-S is another widely used medical instrument that consists of a 7-point scale requiring a clinician to determine the extent of illness severity improvement relative to baseline (7= extremely ill) (Leucht et al 2019). The key secondary endpoint was the change from baseline in sum of CGI-S scores at Week 6. Primary safety outcomes included the overall treatment emergent adverse events (SAEs), deaths, and dermal side-effects.	High dose: PANSS=29.6% responders NNT=10 (95% CI 6–39) CGI=43.3% responders NNT=11 (not significant) Low dose: PANSS=30.8% responders, NNT=9 (95% CI 5–27) CGI=49.8% responders NNT=7 (95% CI 4–16)
Mohr et al 2018^Citation4	Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene.	This in vivo study placed one patch on 4 Goettingen minipigs each (3 drug-containing and 1 placebo) and determined the blood plasma concentrations of ASP [ng/mL] at 4 hour intervals for a total period of 96 hours. The area under the curve was reported for each 24 hour period. Secondary outcome measures included Draize score and histopathological studies to assess skin toxicity.	Cmax (ng/mL)= 5.0 AUC24 (ng*h/mL)= 78.2 AUC96 (ng*h/mL)= 262.4 Draize score= 1/1/1/0
Mohr et al 2019^Citation5	Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer.		Cmax (ng/mL)= 6.7 AUC24 (ng*h/mL)= 100.9 AUC96 (ng*h/mL)= 422.8
Mohr et al 2018^Citation6	Transdermal therapeutic system containing asenapine.	In addition to measuring skin permeability with an identical study design as the experiments described above, an in vivo clinical study was performed in 16 human participants to determine the pharmacokinetics of this formulation. This was a Phase I clinical trial that aimed at comparing the relative bioavailability of two different transdermal patch formulations of ASP against that of sublingual tablets. The study comprised of three periods of several days where participants were administered one of the given treatments: Period 1= 5mg sublingual tablet b.i.d, Period 2= transdermal formulation 1, and Period 3= transdermal formulation 2). Blood plasma concentrations of ASP as well as key metabolites (eg N-desmethyl-ASP and ASP-glucuronide) were measured at specified time points after administration. The key secondary outcome measure was adverse events of each treatment which was quantified by a numerical grading system determined by physicians in the study.	Cmax (ng/mL)= 4.4–6.8 AUC24 (ng*h/mL)= 64.4–109.5 AUC96 (ng*h/mL)= 317.9–439.3 Draize score at 84 and 96 h = 1/1/1/0 Patch: Cmax (ng/mL)= 2.93 ± 1.14 AUC48 (ng*h/mL)= 95.06 ± 37.20 AUC84 (ng*h/mL)= 152.36 ± 48.81 tlag (h)= 4.27 ± 1.00 Sublingual tablet: Cmax (ng/mL)= 4.71 ± 1.68 AUC84 (ng*h/mL)= 178.44 ± 63.59 tlag (h)= 0.5
Shreya et al 2016^Citation7	Nano-transfersomal formulations for transdermal delivery of asenapine maleate: in vitro and in vivo performance evaluations.	Tested the ability of artificial liposomes designed to mimic cell vesicles, known as nano-transfersomes, to deliver ASP percutaneously. Chemical enhancers were also screened for their ability to further increase skin permeability to the nano-carrier system. Transfersomes were prepared with soy phosphatidylcholine (SPC) and sodium deoxycholate (SDC) via thin film hydration method and incorporated into a carbopol gel base. The formulation was optimized by testing the effect of sonification amplitude, amount of drug, SPC:SDC ratios on particle size, polydispersity index, zeta potential, and entrapment efficiency of the nano-particle transfersomes. Pharmacokinetic data was determined in two groups of Wistar rats (n= 6): Group 1 receiving a pill formulation administered orally, and Group 2 receiving the optimized transfersome gel formulation. ASP plasma concentrations were measured at various time intervals for 24 hours after drug administration. The nano-carrier transdermal formulation showed significantly different pharmacokinetic parameters compared to oral administration.	Transdermal route: Cmax (ng/mL)= 426.78 ± 26.16 tmax (h)= 2.33 ± 0.82 AUC∞ (ng*h/mL) = 7517.4 ± 278.86 Oral route: Cmax (ng/mL)= 368.2 ± 17.78 tmax (h)= 1.17 ± 0.41 AUC∞ (ng*h/mL) = 5764.1 ± 201.95
Solomon, 2010^Citation8	Transdermal Compositions of Asenapine for the Treatment of Psychiatric Disorders.	In vitro preliminary investigations were conducted using human skin and a Franz cell in order to compare the epidermal permeation between a number of transdermal formulations that include non-film forming spray, gel, patch, cream, spray-on (non-occlusive), and spray-on (occlusive). The gel composition provided the highest maximum permeation level; this was followed by the occlusive spray-on composition, the cream, and fourthly the non-occlusive spray-on formulation. In vivo pharmacokinetic studies were then performed using three pigs in order to study the transdermal absorption of asenapine. A dose of 50 μg of the spray formulation (approx. one spray) was administered to each subject and asenapine concentrations were measured periodically via blood sampling for 24 hours.	Gel: Cumulative amount of permeation (μg/cm2)= 44.5 ± 11.60 Tmax (minutes)= 10–20
Suzuki et al 2017^Citation9	n/a	Suzuki et al 2017, 2018 aimed to develop a transdermal patch of ASP that (1) is capable of achieving a therapeutically effective level of plasma concentration of ASP which is higher than ever achieved in previous studies and (2) is capable of sufficiently suppressing the plasma concentration of N-desmethyl ASP (the metabolite responsible for dermal side-effects). This formulation was comprised of a support layer, an ASP adhesive agent layer containing isopropyl palmitate as a transdermal absorption enhancer, and an adhesive base agent. Sodium diacetate was additionally added to the adhesive agent layer in order to further increase the skin permeability of ASP constantly over time. Suzuki et al 2017 applied the patch (area of 8 cm^2) to the upper arm of 18 healthy adult male participants. Blood plasma concentrations of free ASP and N-desmethyl ASP were measured every 4 hours for a period between 2 hours after application and 120 hours. An area under plasma concentration-time curve (AUC2-120 [pg*hr/mL]) was calculated for both free ASP and its metabolite, N-desmethyl ASP.	Free asenapine: AUC2-120 (pg*h/mL) = 33,981 Asenapine metabolite: AUC2-120 (pg*h/mL)= 5,432
Suzuki et al 2018^Citation10	n/a	Suzuki et al 2018 used a similar study design and patch formulation to determine data on pharmacokinetics and efficacy. Primary efficacy endpoints used were dopamine D2 receptor occupancy and total PANSS score. Pharmacokinetic parameters were calculated by measuring blood plasma concentrations of free ASP and N-dimethyl ASP every 4 hours over a period of 120 hours after applying a single patch (N= 40 adult human participants, M= 20, F= 20). D2 receptor occupancy was determined by administering a single patch containing a dose of 4.5mg/10cm^2, 9.0mg/20cm^2, or 18.0mg/40cm^2 on healthy adult participants (N= 5) for seven days (new patch applied each day). Position emission topography (PET) scan data was used to quantify receptor occupancy in the caudate and putamen. Lastly, Suzuki et al 2018 determined clinical efficacy by administering a single patch (dose level of 9.0mg/20cm^2 or 18.0mg/40cm^2) daily for 6 weeks in 204 patients diagnosed with schizophrenia. The PANSS total score was obtained at baseline and Day 42 of the study. According to this data, a statistically significant difference in PANSS score was found for this formulation of transdermal ASP.	Free asenapine: Cmax (ng/mL)= 2.02–2.46 tmax (h)= 16 AUC∞ (ng*h/mL) = 63.2–73.2 Asenapine metabolite: Cmax (ng/mL)= 20% or less of Cmax of free asenapine AUC∞ (ng*h/mL) = 22% or less of AUC∞ of free asenapine D2 occupancy caudate 4.5 mg dose: 45.5% 9.0 mg dose: 57.1% 18 mg dose: 55.2% D2 occupancy putamen 4.5 mg dose: 37.5% 9.0 mg dose: 51.6% 18 mg dose: 51.1% PANSS score was reported to be statically significant in both 9 mg (p<0.001) and 18mg (p= 0.006) groups at the 6 week endpoint.

Figure 1 The chemical structure of asenapine. (image courtesy PubChem).

Table 2 The Inhibitory Constant of Asenapine and Potential Neurotransmitters

Receptor	Ki (nM)	Comment
Dopamine
D3	0.42
D4	1.1
D2A (long form)	1.3
D2B (short form)	1.4
Serotonin
5HT2C	0.03
5HT2A	0.07
5HT7	0.11
5HT2B	0.18
5HT6	0.25
5HT5A	1.6
5HT1A	2.5	Partial agonist with 25% intrinsic activity^Citation30
5HT1B	2.7
Norepinephrine
α2B	0.33
ααA	1.2
α2A	1.2
α2C	1.2
Histamine
H1	1.0
H2	6.2
Acetylcholine
M1	8128	Essentially no activity at this receptor

Notes: Since dosing is based on circa 70% D2 receptor occupancy, and Ki above 2.0 [not bolded] means that there is no meaningful activity at that receptor at clinically relevant doses; unless otherwise noted, the activity of asenapine is inhibitory.^28,29

Figure 2 Change in PANSS score in subjects with acute schizophrenia and baseline score of 97.4 (placebo), 97.0 (low dose), and 95.6 (high dose). Data From Citrome et al’s study.⁵³

Figure 3 Response rates over time in in subjects with acute schizophrenia treated with low-dose transdermal asenapine (3.8 mg/24 hours), high-dose transdermal asenapine (7.6 mg/24 hours), and placebo. Only week 6 is significantly higher than placebo for both doses (P < 0.05). Data from Citrome et al’s study.³

Table 3 Treatment-Emergent Adverse Effects (TEAE) That Occurred in the Phase 3 Trial of Transdermal Asenapine at a Rate of 5% of More in Subjects Receiving at Least One Dose

TEAE	High-Dose [n (%)] (Total n =204)	Low-Dose [n (%)] (Total n=204)	Placebo [n (%)] (Total n=206)
Headache	19 (9.3)	18 (8.8)	13 (6.3)
Extrapyramidal disorder	19 (9.3)	13 (6.4)	3 (1.5)
Akathisia	9 (4.4)	8 (3.9)	5 (2.4)
Insomnia	14 (6.9)	15 (7.4)	23 (11.2)
Anxiety	11 (5.4)	10 (4.9)	13 (6.3)
Application site erythema	20 (9.8)	19 (9.3)	3 (1.5)
Application site pruritus	8 (3.9)	10 (4.9)	4 (1.9)
Application site irritation	0 (0.0)	4 (2.0)	1 (0.5)
Constipation	9 (4.4)	11 (5.4)	9 (4.4)
Weight increased	12 (5.9)	8 (3.9)	4 (1.9)

Note: Application site reactions are included even though they occurred at a rate lower than 5%.⁵²

Citrome L, Walling D, Zeni C, Komaroff M, Park A Efficacy and safety of an asenapine transdermal system (HP-3070) for treatment of adults with schizophrenia: a Phase 3 randomized, placebo-controlled, inpatient study. Presented at: Psych Congress 2019; October 3-6, 2019; San Diego, CA. Poster 122.

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Citrome L, Walling D, Zeni C, Komaroff M, Park A Efficacy and safety of an asenapine transdermal system (Asenapine Transdermal System, HP-3070) in the treatment of adults with schizophrenia: a Phase 3 randomized, double-blind, placebo-controlled, 6-week inpatient study. Presented at the 57th Annual Meeting of the American College of Neuropsychopharmacology, December 9–13, 2018, Hollywood, Florida

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