Drug exposure and clinical effect of transdermal mirtazapine in healthy young cats: a pilot study

Abstract

Objectives The objective of this study was to measure drug exposure and clinical effects after administration of transdermal mirtazapine (TMZ) in healthy cats. Methods Phase I: seven healthy research cats received (1) 3.75 mg and 7.5 mg TMZ once aurally with 48 h serum sampling (serum samples were obtained via the jugular catheter at 0, 0.5, 1, 2, 5, 9, 12, 24, 36 and 48 h); (2) 7.5 mg TMZ and placebo daily aurally for 6 days then 48 h serum sampling; (3) 1.88 mg mirtazapine orally once with serum sampling at 1, 4 and 8 h. Phase II: 20 client-owned cats were enrolled in a randomized, double-blind, placebo-controlled, three-way crossover clinical effect study. Treatments consisted of 6 days of aural 7.5 mg TMZ or placebo gel at home, and 1.88 mg mirtazapine orally once in the clinic. Owners documented appetite, rate of food ingestion, begging activity and vocalization daily at home. On day 6, food consumed, activity and vocalization were documented in hospital, and trough and peak serum mirtazapine levels were obtained. Serum mirtazapine and gel concentrations were measured using liquid chromatography/tandem mass spectrometry. Results Phase I: administration of TMZ achieved measureable serum mirtazapine concentrations. Area under the curve_0-48 of multidose 7.5 mg TMZ was significantly higher than single-dose 1.88 mg oral mirtazapine (OMZ) ( P = 0.02). Phase II: client-owned cats administered TMZ had a significant increase in appetite ( P = 0.003), rate of food ingestion ( P = 0.002), activity ( P = 0.002), begging ( P = 0.002) and vocalization ( P = 0.002) at home. In hospital there was a significant increase in food ingested with both TMZ and OMZ compared with placebo ( P <0.05). Gel concentrations ranged from 87%-119% of target dose. Conclusions and relevance TMZ 7.5 mg daily achieves measureable serum concentrations and produces significant appetite stimulation despite variance in compounded gel concentrations, but side effects denote a lower dose is indicated.

Figure 1

Serum mirtazapine concentration curve (± SD) after administration of single-dose 3.75 mg transdermal mirtazapine (TMZ), single-dose 7.5 mg TMZ, single-dose 1.88 mg oral mirtazapine (OMZ) and multiple-dose 7.5 mg TMZ to healthy research cats. Serum concentrations after administration of TMZ were relatively consistent over at least a 48 h period in comparison with OMZ, which shows an initial spike in drug concentration followed by a typical drug concentration curve

Figure 2

Comparative calculated serum mirtazapine exposure over 48 h after single-dose 3.75 mg transdermal mirtazapine (TMZ), single-dose 7.5 mg TMZ, single-dose 1.88 mg oral mirtazapine (OMZ) and multidose 7.5 mg TMZ in healthy research cats. The area under the curve (AUC)_0–48 of multidose 7.5 mg TMZ was significantly higher than single-dose 1.88 mg OMZ (P = 0.02), and approached being significantly higher than single-dose 7.5 mg TMZ (P = 0.06).There was no significant difference in AUC_0–48 between administration of single-dose 3.75 mg TMZ, single-dose 7.5 mg TMZ and single-dose 1.88 mg OMZ

Figure 3

Appetite score based on daily owner assessment after administering 7.5 mg transdermal mirtazapine (TMZ) or placebo daily for 5 days in a blinded crossover design. There is a statistically significant difference in appetite score between TMZ and placebo (*P = 0.003; n = 18)

Figure 4

Rate of food ingestion score based on daily owner assessment after administering 7.5 mg transdermal mirtazapine (TMZ) or placebo daily for 5 days in a blinded crossover design. There is a statistically significant difference in rate of food ingestion score between TMZ and placebo (*P = 0.002; n = 19)

Figure 5

Begging score based on daily owner assessment after administering 7.5 mg transdermal mirtazapine (TMZ) or placebo daily for 5 days in a blinded crossover design. There is a statistically significant difference in begging score between TMZ and placebo (*P = 0.002; n = 17)

Figure 6

Vocalization score based on daily owner assessment after administering 7.5 mg transdermal mirtazapine (TMZ) or placebo daily for 5 days in a blinded crossover design. There is a statistically significant difference in vocalization score between TMZ and placebo (*P = 0.002; n = 17)

Figure 7

Comparison of percent food ingested when client-owned cats were observed in the hospital environment after 6 days of transdermal mirtazapine (TMZ) or transdermal placebo and a single oral mirtazapine dose (OMZ). There was a statistically significant difference in percent food ingested between placebo and TMZ, and placebo and OMZ (*P <0.05)

Figure 8

Trough and peak serum mirtazapine concentrations compared between the healthy research cat multidose 7.5 mg drug exposure study and the client-owned cat multidose 7.5 mg clinical effect study; client-owned cats had significantly higher peak (*P = 0.02) and trough (*P = 0.02) serum mirtazapine levels