• Open Access

Evaluation of 2 Trilostane Protocols for the Treatment of Canine Pituitary-Dependent Hyperadrenocorticism: Twice Daily versus Once Daily

Authors

  • C. Arenas,

    Corresponding author
    1. Department of Small Animal Medicine and Surgery Clinical Sciences, School of Veterinary Medicine, Complutense University of Madrid, Madrid, Spain
    • Corresponding author: C. Arenas, Department of Small Animal Medicine and Surgery Clinical Sciences, School of Veterinary Medicine, Complutense University of Madrid, Avda. Puerta de Hierro s/n 28040, Madrid, Spain; e-mail: caroarenas10@hotmail.com.

    Search for more papers by this author
  • C. Melián,

    1. Clínica Veterinaria Atlántico, Las Palmas Gran Canaria, Spain
    Search for more papers by this author
  • M.D. Pérez-Alenza

    1. Department of Small Animal Medicine and Surgery Clinical Sciences, School of Veterinary Medicine, Complutense University of Madrid, Madrid, Spain
    Search for more papers by this author

  • Part of this paper has been presented at the ECVIM congress, 2012, Maastricht.

Abstract

Background

Trilostane is the drug of choice to treat pituitary-dependent hyperadrenocorticism (PDH) in dogs, but there is still controversy about which protocol best controls the clinical signs and results of adrenal functioning test.

Objectives

To compare the efficacy of twice daily (BID) versus once daily (SID) trilostane administration and to compare the safety of both protocols in the treatment of dogs with PDH.

Animals

Thirty-two client-owned dogs diagnosed with PDH between 2008 and 2010 and treated with trilostane either BID or SID.

Methods

In this prospective randomized study, 2 trilostane protocols were evaluated on the basis of the owner′s perception of clinical signs, on the results of laboratory tests, and on the results of the ACTH stimulation test in dogs with PDH. Dogs were followed up for a period of 1 year.

Results

During the study, more dogs in the BID group had complete clinical recovery than in the SID group. However, there was no significant difference in the mean post-ACTH cortisol concentration between groups. Basal cortisol concentration at 6 months was higher in animals treated SID compared with animals treated BID. Mean total daily doses of trilostane used to control PDH, as well as adverse effects observed in the course of the study, in both groups were not statistically different.

Conclusion and Clinical Importance

Adverse effects were mild using either protocol of treatment. Using trilostane BID might increase the number of dogs with a good clinical response compared with using trilostane SID.

Abbreviations
3β-HSD

3β-hydroxysteroid dehydrogenase

ACTH

adrenocorticotropic hormone

BID

twice daily

CBC

complete blood cell count

HAC

hyperadrenocorticism

LDDST

low-dose dexamethasone suppression test

PDH

pituitary-dependent hyperadrenocorticism

SID

once daily

UCCR

urinary-corticoid : creatinine ratio

Hyperadrenocorticism (HAC) is a common endocrine disease caused by excessive secretion of ACTH in approximately 85% of cases, usually by a pituitary corticotroph adenoma, and known as pituitary-dependent hyperadrenocorticism (PDH). The remaining 15% have adrenal-dependent hyperadrenocorticism (ADH) caused by a cortisol-secreting adrenocortical tumor.[1]

Trilostane has become the treatment of choice for dogs with PDH in the last decade. This drug is a competitive inhibitor of the 3β-hydroxysteroid dehydrogenase-isomerase enzyme system (3β-HSD). The effectiveness of treatment is evaluated on the basis of resolution of clinical signs and results of adrenocortical function tests. Most authors use trilostane once daily (SID) following the protocol described by Neiger and collaborators in 2002.[2-5] However, trilostane does not suppress basal circulating and post-ACTH cortisol concentrations for 24 hours.1,[[6]] Twice daily (BID) trilostane administration was first described in 2006,[7] demonstrating similar efficacy as the SID protocol, and since that time, the BID protocol has been used by other authors.[6, 8]

Despite these studies, there still is no consensus about frequency of administration or about the dose of trilostane that best controls clinical signs while minimizing risk of adverse effects and gives acceptable results on the ACTH stimulation test in dogs with PDH.

The aims of this study were to compare the efficacy of twice versus SID trilostane administration and to compare the safety of both protocols in the treatment of dogs with PDH.

Materials and Methods

Clinical Cases

In this prospective study, 32 client-owned dogs were diagnosed with PDH at the Veterinary Teaching Hospital (University Complutense) of Madrid and at the Clínica Veterinaria Atlántico (Las Palmas de Gran Canaria). Suspicion of HAC was made on the basis of the history and physical examination findings and on results of routine laboratory tests. The diagnosis was confirmed by adrenal function tests: ACTH stimulation test, low-dose dexamethasone suppression test (LDDST), and urinary-corticoid : creatinine ratio (UCCR) as described.[1] Dogs were alternately assigned to 1 of the 2 treatment groups. One group received trilostane twice daily (BID group) and 1 group received trilostane once daily (SID group).

Diagnostic Tests

A complete blood cell count (CBC), urinalysis, biochemical profile, and ACTH stimulation test were performed in all dogs. In addition in some cases, an LDDST (n = 3) or an UCCR (n = 14) also were performed. The diagnosis was confirmed if the ACTH stimulation test or the LDDST was supportive of HAC in a dog with compatible clinical signs. For the ACTH stimulation test, cortisol concentrations were determined before and 1 hour after IM administration of 250 μg synthetic tetracosactide.2 The diagnosis was considered compatible with HAC when the post-ACTH cortisol concentration was ≥20 μg/dL. To perform the LDDST, blood samples were collected before and 4 and 8 hours after administration of 0.01 mg/kg IV dexamethasone.3 A cortisol concentration >1.4 μg/dL in the sample collected at 8 hours was considered consistent with HAC. For the UCCR, owners collected a first morning urine sample at home as described.[9] Serum cortisol concentration was determined by means of an automated chemiluminescence system, validated for use in the dog.4 The UCCR was determined on 2 consecutive urine samples, and diagnosis of hypercortisolism was considered by finding an increased UCCR (>60 × 10−6).

In all cases, the differentiation of PDH was based on the ultrasonographic appearance of the adrenal glands and, additionally in some cases, on the results of the LDDST. Mild bilateral enlargement of the adrenal glands (maximal diameter >7.5 mm) was considered indicative of PDH.[1] Dogs with cortisol suppression (<1.4 μg/dL or <50% of basal cortisol concentration) at 4 hours (LDDST) were considered to have PDH.

Treatment and Follow-up

Dogs were alternately allocated into 2 groups: 16 animals were treated with trilostane every 12 hours. The initial dosage ranged between 1.25 and 2.75 mg/kg/12 hours. The remaining 16 animals were treated SID with trilostane at an initial dosage ranging from 1.0 to 6.6 mg/kg/24 hours.

Owners were requested to bring their dogs for follow-up evaluation at 7 days, 1, 3, 6, and 12 months after treatment began. All dogs in the BID treatment group completed the study; 2 dogs from the SID group were changed to BID treatment at 3 and 6 months and were excluded from the study when treatment was modified. At each re-evaluation time, some of the owners did not present their dogs for re-evaluation. At each evaluation, owners were questioned about clinical response, which was categorized as no response, partial response, or complete response. Dogs with partial response showed improvement of clinical signs, but not complete resolution of clinical signs and there was persistence of at least one of the following signs: polydipsia, polyuria, or polyphagia. The owners also were asked about the presence of any potential adverse effects such as anorexia, vomiting, diarrhea, or weakness regardless of whether these signs could be attributable to the medication. All dogs were examined and a CBC, serum biochemical profile, and ACTH stimulation test were performed. The ACTH stimulation test was performed in the BID group at 7 days between 4 and 6 hours after administration of trilostane. In the remainder of the evaluations for animals in BID group (1 month to 1 year), as well as in all of the evaluations in animals in SID group, the ACTH stimulation test was carried out between 8 and 12 hours after administration of trilostane as previously described.[7] Performing ACTH at this time on animals treated BID allowed determination if there was a low concentration of cortisol a few hours before the next administration of the medication. The range of post-ACTH cortisol concentrations considered indicative of good cortisol control was 2.0–5.0 μg/dL (test performed 4–6 hours after trilostane administration) and 2.0–9.0 μg/dL (test performed 8–12 hours post trilostane).[7] The trilostane dosage was adjusted individually based on clinical signs and post-ACTH cortisol concentrations. The dosage of trilostane was unchanged in dogs with partial or complete response and an ACTH stimulation test within the upper limit of the reference range. The dosage was increased in dogs with no response or partial response and with a post-ACTH cortisol concentration above the reference range. The dosage of trilostane was decreased in dogs with a low post-ACTH cortisol concentration (<2.0 μg/dL) regardless of the presence or absence of adverse effects.

Statistical Analyses

Results were analyzed by a statistical software package.5 The population characteristics of both groups were compared by a chi-squared test for categorical data, and population attributes treated as continuous data were compared by a Levene t-test. Linear correlations were calculated by Spearman′s nonparametric correlations. Differences were considered significant at values of P ≤ .05.

Results

Clinical Cases

Thirty-two dogs with PDH were included in the study. The age at diagnosis ranged from 5 to 15 years (mean ± SD: 10.9 ± 2.3; median, 11.0) and the body weight ranged from 2.3 to 37.6 kg (12.6 ± 9.6; median, 9.2). In the BID group, 9 dogs weighed <10 kg; 5 weighted 10–20 kg; 1 dog weighed 20–30 kg, and 1 weighed >30 kg. In the SID group, 10 dogs weighed <10 kg; 3 dogs weighed 10–20 kg, and 3 dogs weighed >30 kg. Sixteen dogs were female (9 intact, 7 spayed) and 16 were male (12 intact, 4 neutered). The most frequently represented breeds were mixed breed (41%; n = 13), Yorkshire Terrier (19%; n = 6), Poodle (13%; n = 4), and Beagle (6%; n = 2). There was 1 Boxer, Chihuahua, Cocker Spaniel, Fox Terrier, Golden Retriever, Scottish Terrier, and Gos d′ Atura, respectively. There were no statistical differences in age (P = .074), sex (P = 1.000), or body weight (P = .973) between the groups.

The most common clinical signs were polyuria, polydipsia, polyphagia, alopecia, and abdominal distension. In the BID group, 75% (n = 12) of the dogs presented with polyuria and polydipsia, 81.3% (n = 13) with polyphagia, 62.5% (n = 10) with alopecia, and 56.3% (n = 9) with abdominal distension. In the SID group 93.8% (n = 15) of the dogs presented with polyuria and polydipsia, 87.5% (n = 14) with polyphagia, 68.8% (n = 11) with alopecia, and 62.5% (n = 10) with abdominal distension. There were no statistical differences between groups regarding the presence of polyuria and polydipsia (P = .333), polyphagia (P = 1.000), alopecia (P = 1.000), and abdominal distension (P = 1.000). Lethargy was observed in 4 dogs in the BID group and 7 dogs in the SID group (P = .458), and weakness in 5 dogs in each group (P = 1.000). In the BID group, PDH was diagnosed between 1 and 3 months after the initial development of clinical signs in 6 dogs (37.5%), between 3 and 6 months in 5 dogs (31.3%), between 6 and 12 months in 3 dogs (18.7%), and after 1 year in 2 dogs (12.5%). In the SID group, PDH was diagnosed between 1 and 3 months after the initial development of clinical signs in 5 dogs (31.3%), between 3 and 6 months in 4 dogs (25%), and between 6 and 12 months, and after 1 year in 6 dogs (37.5%) and 1 dog, respectively (6.2%). No differences were observed regarding the time from initial development of clinical signs until diagnosis of the disease (P = .800).

Diagnostic Tests

The hematological and biochemical test results at diagnosis were similar in both the SID and BID groups and there were no statistical differences in any of the variables tested.

The mean ± SD (range) of basal cortisol concentrations in the BID group was 6.4 ± 3.9 μg/dL (1.4–15.6) and in the SID group was 6.9 ± 2.4 μg/dL (2.4–10.0). There was no statistical difference between groups (P = .509). The mean ± SD (range) of post-ACTH cortisol concentrations in the BID group was 32.7 ± 12.4 μg/dL (10.1–60.7) and in the SID group was 29.8 ± 13.2 μg/dL (10.8–58.4). There was no statistical difference between groups (P = .459). The mean ± SD (range) UCCR in the 16 dogs in the BID group was 270 ± 278 (56–875) and in the SID group was 480 ± 509 (159–1500). Differences between groups were not significant (P = .365).

Treatment and Follow-up

One-Week Evaluation

In the BID group (n = 13), 7 dogs had complete clinical response; 3 dogs had partial response; and 3 had no clinical response.

Seven dogs had post-ACTH cortisol concentrations above the reference range (>5.0 μg/dL). In one of these dogs, the owner stopped trilostane treatment 2 days before the ACTH stimulation test because of mild adverse effects. One dog had a post-ACTH cortisol concentration below the reference range (2.0 μg/dL). The mean (±SD) basal cortisol concentration was 3.1 ± 1.4 μg/dL (range 0.6–5.7 μg/dL), and the mean post-ACTH cortisol concentration was 8.6 ± 6.8 μg/dL (range 1.5–23.0). The dosage of trilostane was increased in 3 dogs with no response and ACTH stimulation test results above the range and decreased in 2 dogs (the one that developed mild adverse effects 2 days before re-evaluation and another one with a low post-ACTH cortisol concentration).

In the SID group (n = 15), 4 dogs had complete clinical response; 6 had partial clinical response; and 5 had no clinical response. Six dogs had post-ACTH cortisol concentrations above the reference range (9.0 μg/dL). One animal had a post-ACTH cortisol concentration below the reference range. The mean (±SD) basal cortisol concentration was 3.9 ± 2.5 μg/dL (range, 0.61–7.8 μg/dL), and the mean post-ACTH cortisol concentration was 10.36 ± 5.6 μg/dL (range 1.2–18.5). The dosage of trilostane was increased in 5 dogs with no clinical response and a post-ACTH cortisol concentration above the reference range. Among the 6 dogs with partial response, in 1 dog, the post-ACTH concentration was slightly higher than the reference range and in the others was within the reference range. In these dogs, the dosage of trilostane was not modified.

Differences in clinical response (P = .153), mean basal cortisol (P = .317), and post-ACTH cortisol (P = .488) between groups were not statistically significant. Changes in the ACTH stimulation test results during the study are shown in Figures 1 and 2.

Figure 1.

Box and whisker plots of basal cortisol concentrations before and during trilostane treatment in both groups. The top end of the box represents the 75th percentile of the data, and the bottom end of the box represents the 25th percentile. The horizontal line between the boxes is the median. The whiskers on the top and bottom of the boxes indicate 10th and 90th percentiles. Circles indicate outliers and asterisks represent extreme outliers. The line across the graphic represents the lowest reference value for basal cortisol concentration.

Figure 2.

Box and whisker plots of post-ACTH cortisol concentrations before and during trilostane treatment in both groups. The top end of the box represents the 75th percentile of the data, and the bottom end of the box represents the 25th percentile. The horizontal line between the boxes is the median. The whiskers on the top and bottom of the boxes indicate the 10th and 90th percentiles.

One-Month Evaluation

In the BID group (n = 11), 8 dogs had complete clinical response; 2 dogs had partial response; and 1 dog showed no clinical response. One dog had decreased appetite. Four dogs had an exaggerated response to ACTH. The mean (±SD) basal cortisol concentration was 3.7 ± 2.1 μg/dL (range 1.2–8.2 μg/dL), and the mean post-ACTH cortisol concentration was 8.6 ± 4.8 μg/dL (range 3.6–18.6). The dosage of trilostane was increased in 2 dogs and in 1, the dosage was decreased (with decreased appetite, but normal ACTH stimulation tests).

In the SID group (n = 13), 5 dogs had complete clinical response; 3 dogs had partial response; and 5 dogs had no clinical response. Eight dogs had a post-ACTH concentration above the reference range (5 of them had persistence of clinical signs). The mean (±SD) basal cortisol concentration was 4.3 ± 1.9 μg/dL (range 1.8–7.3 μg/dL), and the mean post-ACTH cortisol concentration was 12.1 ± 5.8 μg/dL (range 6.1–25.1). The dosage of trilostane was increased in 6 dogs (5 dogs with persistence of clinical signs and ACTH stimulation test results above the reference range and another dog without clinical signs, but an exaggerated ACTH stimulation test result).

Differences in persistence of clinical signs (P = .101), mean basal cortisol concentrations (P = .587), and the mean post-ACTH cortisol concentrations (P = .177) between groups were not statistically significant.

Three-Month Evaluation

In the BID group (n = 15), 8 dogs had complete clinical response; 6 had partial response; and 1 had no clinical response. A low post-ACTH cortisol concentration was observed in 6 dogs (2 of them also had clinical signs consistent with hypocortisolism). The mean (±SD) basal cortisol concentration was 3.6 ± 1.7 μg/dL (range 1.3–6.2 μg/dL), and the mean post-ACTH cortisol concentration was 8.3 ± 4.4 μg/dL (range 2.4–19.8). The dosage of trilostane was increased in 3 dogs (2 with clinical signs and high post-ACTH cortisol concentrations and another with high post-ACTH cortisol concentrations) and decreased in another with low post-ACTH cortisol concentration.

In the SID group (n = 14), 5 dogs had complete clinical response; 8 had partial response; and 1 had no clinical response. Five dogs had an increased post-ACTH cortisol concentration (all of them had signs of HAC). The mean (±SD) basal cortisol concentration was 4.4 ± 1.5 μg/dL (range 1.8–6.3 μg/dL), and the mean post-ACTH cortisol concentration was 10.3 ± 2.2 μg/dL (range 7.92–13.9). The dosage of trilostane was increased in 5 dogs with clinical signs and increased post-ACTH cortisol concentrations and decreased in 1. One dog with clinical signs and a high dosage of trilostane was changed to BID treatment.

Differences in persistence of clinical signs (P = .374), mean basal cortisol concentrations (P = .265), and the mean post-ACTH cortisol concentrations (P = .226) between groups were not statistically significant.

Six-Month Evaluation

In the BID group (n = 16), 11 dogs had complete clinical response; 3 had partial response; and 1 had no clinical response. Seven dogs had increased post-ACTH cortisol concentrations (one of them with clinical signs). The mean (±SD) basal cortisol concentration was 3.3 ± 1.6 μg/dL (range 1.5–7.5 μg/dL), and the mean post-ACTH cortisol concentration was 8.9 ± 4.9 μg/dL (range 3.2–20.2). The dosage of trilostane was increased in 4 dogs (2 with clinical signs and increased post-ACTH cortisol concentrations and another 2 with increased post-ACTH cortisol concentrations) and decreased in 1 dog.

In the SID group (n = 12), 5 dogs had complete clinical response, 5 partial response, and 2 no clinical response. The ACTH stimulation test results were above the reference range in 3 dogs (all of them with persistence of clinical signs). The mean (±SD) basal cortisol concentration was 5.0 ± 2.0 μg/dL (range 3.1–10.0 μg/dL), and the mean post-ACTH cortisol concentration was 8.8 ± 4.9 μg/dL (range 4.7–21.8). The dosage of trilostane was increased in 2 dogs with inadequate clinical and endocrine control of the disease. One dog was changed to BID treatment because of partial clinical response despite receiving a high dosage of trilostane.

The mean basal cortisol concentration was significantly higher for dogs in the SID group compared with dogs in the BID group (P = .023). The differences observed regarding the persistence of clinical signs (P = .136) and mean post-ACTH cortisol concentration (P = .956) between the groups were not statistically significant.

One-Year Evaluation

In the BID group (n = 12), all dogs had complete clinical response. Three dogs had post-ACTH cortisol concentrations above the reference range. One dog had a post-ACTH cortisol concentration below the reference range. The mean (±SD) basal cortisol concentration was 2.5 ± 1.5 μg/dL (range 0.9–5.7 μg/dL), and the mean post-ACTH cortisol concentration was 7.6 ± 7.2 μg/dL (range 1.6–25.3). The dosage of trilostane was increased in the dog with an exaggerated response to ACTH despite no clinical signs and decreased in another.

In the SID group (n = 8), 4 dogs had complete clinical response, and 2 dogs each had partial and no clinical response. None of the dogs had post-ACTH cortisol concentrations >9.0 μg/dL. One dog had a post-ACTH cortisol concentration below the reference range (2.0 μg/dL). The mean (±SD) basal cortisol concentration was 2.2 ± 0.7 μg/dL (range 1.1– 3.0 μg/dL), and the mean post-ACTH cortisol concentration was 4.2 ± 2.2 μg/dL (range 0.8–7.7). The dosage of trilostane was decreased in 1 dog.

Clinical signs persisted in a significantly higher proportion of dogs (P = .004) in the SID group. Differences in the mean basal cortisol (P = .716) and post-ACTH cortisol concentrations (P = .243) between the groups were not statistically different.

Dosage of Trilostane

The initial dosage of trilostane for dogs in the BID group ranged from 2.5 to 5.5 mg/kg/day, with a mean ± SD of 3.6 ± 0.8 mg/kg/day (1.8 mg/kg/12 hours) and for dogs in the SID group ranged from 1.0 to 6.6 mg/kg/day, with a mean of 2.9 ± 1.3 mg/kg/day. Differences were not statistically significant (P = .070). The mean dosage of trilostane during the study for dogs in the BID group was 3.8 ± 0.8 mg/kg/day (range 2.8–5.9 mg/kg/day) and for dogs in the SID group was 3.7 ± 2.1 mg/kg/day (range 1.0–8.5 mg/kg/day). The dosage of trilostane at the end of the study in dogs in the BID group ranged from 2.8 to 8.9 mg/kg/day (mean, 4.7 ± 1.9) and for dogs in SID group ranged between 1.0 and 11.5 mg/kg/day (mean, 4.6 ± 3.5). The differences were not significant (P = .933). Although mean dosages of trilostane were similar in both groups, dogs in the SID group were more likely to need higher dosages (>5 mg/kg/day) as shown in Table 1.

Table 1. Mean dosages (mg/kg/day) of trilostane in both groups during the study. The number of dogs with a high dosage of trilostane and the body weight of these dogs are also shown.
 BIDSID
  1. BID, twice daily; SID, once daily.

Basal
Mean dosage (mg/kg/day) ± SD (range) (P = .070)3.7 ± 0.8 (2.5–5.5)2.9 ± 1.3 (1–6.6)
Number of dogs and body weight (kg) with trilostane dosage >5 mg/kg/dayn = 1 (8.0)n = 1 (4.5)
One week
Mean dosage (mg/kg/day) ± SD (range) (P = .103)3.6 ± 0.8 (2.5–5.5)2.9 ± 1.4 (1–6.6)
Number of dogs and body weight (kg) with trilostane dosage >5 mg/kg/dayn = 1 (8.0)n = 1 (4.5)
One month
Mean dosage (mg/kg/day) ± SD (range) (P = .777)3.5 ± 0.9 (2.7–6.3)3.4 ± 1.9 (1–7)
Number of dogs and body weight (kg) with trilostane dosage >5 mg/kg/dayn = 1 (7.3)n = 4 (6.4; 19.5; 2.7; 4.6)
Three months
Mean dosage (mg/kg/day) ± SD (range) (P = .513)3.7 ± 0.9 (2.7–6)4.2 ± 2.9 (1–11.2)
Number of dogs and body weight (kg) with trilostane dosage >5 mg/kg/dayn = 1 (7.3)n = 6 (6.6; 31.4; 19.5; 2.7;2.4; 4.6)
Six months
Mean dosage (mg/kg/day) ± SD (range) (P = .204)4.0 ± 1.2 (1.8–6.3)5.5 ± 3.5 (1–12.5)
Number of dogs and body weight (kg) with trilostane dosage >5 mg/kg/dayn = 3 (7.6; 10.2; 15.8)n = 5 (6.6; 31.2; 19.8; 2.5; 2.4)
One year
Mean dosage (mg/kg/day) ± SD (range) (P = .942)4.7 ± 1.9 (2.8-8.9)4.6 ± 3.5 (1–11.5)
Number of dogs and body weight (kg) with trilostane dosage >5 mg/kg/dayn = 2 (7.8; 13.8)n = 2 (6.7; 31.0)

In both groups, the initial dosage of trilostane was modified. In only 5 dogs (31.3%) in BID group and in 4 (25%) dogs in the SID group, the trilostane dosage was not modified during the follow-up period. The dosage of trilostane was increased in 5 dogs in the BID group to achieve good control of the disease and in 6 dogs, the dosage was increased, but also decreased during the study. Of dogs in the SID group, 9 needed an increase in the dosage; it was decreased in 2 and both increased and decreased in 1 dog.

The statistical analyses determined that, independently of the treatment protocol used, the mean dosage of trilostane needed to achieve control of HAC was correlated with the post-ACTH cortisol concentration at diagnosis. Animals with the highest post-ACTH cortisol concentration at diagnosis needed higher doses to control the disease (P = .006; coef 0.472). Dogs with a post-ACTH cortisol concentration at diagnosis >35 μg/dL were most likely to need a mean dosage of trilostane >4.5 mg/kg/day to control the disease (P = .013).

Adverse Effects

Adverse effects were observed in 40% (n = 7) of dogs in the BID group and in 37.5% (n = 6) of dogs in the SID group. In both groups, all of the adverse effects were mild. No moderate or severe adverse effects were observed. The most frequent adverse effects were transient decreased appetite (n = 2; BID n = 1; SID n = 1), lethargy (BID n = 1), weakness (SID n = 3), vomiting (n = 7; BID n = 5; SID n = 2), and diarrhea (n = 2; BID n = 1; SID n = 1). There were no statistical differences (P = .886) in adverse effects between groups.

Discussion

Although trilostane is considered the treatment of choice for PDH in dogs, there currently is no consensus on the ideal trilostane protocol including the ideal starting dosage, frequency of administration, and monitoring (ACTH stimulation test timing and target range for post-ACTH cortisol concentration).

In this study, we evaluated the response to 2 different trilostane protocols; we established related criteria, which consisted of owner perception of clinical signs combined with results of the ACTH stimulation test.

The results of this study indicate that both protocols of trilostane administration are safe and effective for the resolution of clinical signs and endocrine abnormalities observed in dogs with PDH. This efficacy also has been observed by other authors.[2-4, 6, 7] However, there are some differences that should be considered before selecting either protocol.

There currently is no agreement on the ideal timing to perform the ACTH stimulation test during monitoring of trilostane treatment. The manufacturer recommends administering trilostane SID and performing an ACTH stimulation test 4–6 hours post pill to evaluate maximal trilostane effect. However, other authors recommend testing 2–4 hours after SID trilostane administration.[10] In our study, we evaluated 2 groups of dogs receiving trilostane either SID or BID, and the ACTH stimulation test was performed 8–12 hours after trilostane administration, as has been described in a previous study with trilostane administered BID.[7] Another study evaluated the pre- and post-ACTH cortisol concentration at 2 different times after trilostane administration in 22 dogs with good control of HAC.[8] The mean (±SD) post-ACTH cortisol 9-hour posttrilostane administration (8.1 ± 3.4 μg/dL) was significantly higher than the mean 3-hour post-ACTH cortisol concentration (2.6 ± 1.3 μg/dL) in the same dogs. This observation shows that a 9-hour postpill time point cannot be used to evaluate peak trilostane action, but may provide information about the expected post-ACTH cortisol concentration when well-controlled dogs on trilostane are tested 9 hours post pill. Considering the mean (±SD) post-ACTH cortisol concentration 9 hours post trilostane in the dogs of the previously mentioned study (8.1 ± 3.4 μg/dL), in general, we can expect dogs with good control of HAC to be in a range of approximately 2–14 μg/dL when tested 9 hours post pill. In this study, dogs were tested at a similar time (8–12 hours post pill). By testing at this time, trilostane action is evaluated knowing that it is not the peak action time and therefore the ideal range for post-ACTH cortisol concentration during monitoring will be higher. Most dogs with good clinical control of the disease will have a post-ACTH cortisol concentration in the range of 2–9 μg/dL and some will have good control in a range as high as 2–14 μg/dL. Therefore, testing 8–12 hours post pill can be useful to evaluate efficacy of trilostane, but it also can be useful as a precautionary measure by assuring that the dog is not at risk of hypocortisolemia just before the next trilostane administration. This will be more important when trilostane is administered BID because the action of 2 administrations may overlap for a few hours.

There are some variations in the recommended ideal range of cortisol concentration for monitoring HAC in dogs receiving trilostane SID. The upper limit for post-ACTH cortisol concentration at peak action established by the manufacturer is 5.4 μg/dL, whereas other authors recommend 4.3 μg/dL for dogs receiving trilostane every 24 hours.[10, 11] Other authors who use trilostane BID established an arbitrary but safe post-ACTH cortisol concentration <7.5 μg/dL, performing the test at peak action (3–4 hours post pill).[6] Because of the relatively short-lasting effect of trilostane, ACTH stimulation test results vary considerably with the time of testing relative to dosing.[11] As such, when performing the test after the peak action (8–12 hours post pill), the upper limit of the ideal range should be higher (9–14 μg/dL).

In this study, the results of the ACTH stimulation test were similar in both groups. However, clinical signs seem to be better controlled when trilostane is given BID. Trilostane decreases basal cortisol concentration for a few hours and the post-ACTH cortisol concentration for a period of 2–13 hours. Also, post-ACTH cortisol concentration 9 hours post trilostane administration is significantly higher than post-ACTH cortisol concentration 3 hours post trilostane.1,[6] In dogs treated with trilostane BID, there are fewer hours every day in which cortisol is not suppressed. Chronic excess of cortisol may be responsible for the higher persistence of clinical signs observed in animals treated SID, and these dogs may be exposed more to the long-term complications of hypercortisolism. These effects of chronic excess of cortisol have been observed in humans and without appropriate treatment, Cushing′s disease is associated with increased morbidity and mortality.[12]

The onset of clinical signs associated with increased ACTH concentrations and cortisol hypersecretion typically is insidious, with many disabling effects. A primary goal in the treatment of this disease is to resolve signs associated with HAC as perceived by the owners. However, owner expectations appear to change during treatment, reporting a response early in the course of treatment, but being more critical in assessment as treatment progresses.[8] Trilostane is a drug that decreases cortisol concentrations from first administration, resulting in a rapid resolution of most of the bothersome clinical signs, thus initially owners tend to be satisfied with treatment. As time goes by, and clinical signs are less apparent than initially, owners become more critical of the treatment, which could be the reason why, as time passes, animals in the BID group seemed to be better controlled than those in the SID group. The short action of trilostane might be responsible for the persistence of some of the clinical signs and unsatisfactory clinical control in dogs receiving trilostane SID.

The range of dosages used to achieve good control of the disease varied widely in both groups. However, more dogs in the SID group needed higher dosages to control the disease, and dogs with the highest dosages were located in the SID group. Some of these dogs needed as much as twice as much trilostane as initially required to control the disease.

In this study, dogs that needed higher dosages of trilostane to achieve good control of the disease were those with the highest post-ACTH cortisol concentrations at diagnosis, as has been observed by other authors.[11] These dogs may have larger adrenal cortisol reserves and could require higher dosages of trilostane to decrease their cortisol production. It also has been noticed that animals with chronic exposure to steroids need higher dosages of glucocorticoids than animals without previous exposure to steroids to maintain a determined plasma cortisol concentration.[13, 14] This is probably because they have accelerated plasma clearance of steroids caused by higher renal excretion.[15] This also could happen with trilostane, a steroid analog, and animals that have greater adrenal reserve may need a higher dosage of trilostane to maintain an adequate plasma concentration of the drug or they might need an increase in the frequency of administration, rather than an increase in the dosage, to maintain the plasma concentration of trilostane. Animals with greater adrenal cortisol reserve also may have a higher proportion of steroid precursors that could compete with trilostane for the active action site of 3β-HSD, and thus need, higher dosages, or an increase in the frequency of dosing, to displace the precursors from trilostane′s site of action.

Other authors have shown that body weight is related to dosage requirements of trilostane, and dogs weighing >30 kg might require smaller amounts of trilostane than dogs weighing less than 30 kg.[16] In our study, distribution of dogs between groups was similar, and the proportion of dogs in each category of body weight was comparable. Moreover, there were more animals in the SID group weighing >30 kg than in the BID group.

Finally, adverse effects were similar in both groups, and none of the animals developed moderate or severe clinical signs of hypocortisolism. This could be attributable to the lower dosages used in this study (approximately 3 mg/kg/day) compared with other studies (approximately 6 mg/kg/day).[2, 3, 7] Using lower dosages of trilostane might help prevent hypocortisolism and the higher mortality observed in older studies. However, other factors can influence the presence of moderate-to-severe adverse effects. These adverse effects may occur after years of treatment and if the duration of a study is relatively short (ie, 1 year or less) it may miss some of the adverse effects. In 1 study, trilostane was well tolerated by 30 dogs during the 1-year follow-up, but 4 of them developed hypoadrenocorticism after completion of the survey.[2, 3, 7] In another study, persistent hypocortisolemia occurred in 5 of 44 dogs from 1 to 3.5 years after trilostane administration.[2, 3, 7]

As this is a clinical study, some of the dogs were not returned for all of the re-evaluations, which may have influenced the results of the statistical analysis and could be a limitation of this study. If all dogs had been returned for all re-evaluations, the results may have better clarified which protocol is best for the treatment of HAC.

In conclusion, using trilostane BID compared with SID might increase the number of dogs with a good clinical response. On the other hand, results of adrenal function tests were similar in both groups throughout the study. A higher proportion of dogs in the SID group needed higher dosages of trilostane to control the disease, and dogs with the highest dosages were in the SID group. Adverse effects were mild with either protocol of treatment, probably because of the moderate dosages of trilostane used, which likely decreased the development of severe adverse effects.

Acknowledgment

The authors thank Dr Pedro Cuesta for the statistical support. The study was not supported by a grant or other financial resource.

Conflict of Interest Declaration: Authors disclose no conflict of interest.

Footnotes

  1. 1

    Neiger R, Hurley KJ. 24 hour cortisol values in dogs with HAC on trilostane. British Small Animal Veterinary Association (BSAVA) Congress, Birmingham, Reino Unido 2001.

  2. 2

    Nuvacthen depot; Novartis Farmaceútica, Barcelona, Spain[17]

  3. 3

    Caliercortin; Calier Laboratories, Barcelona, Spain

  4. 4

    ACS: 180; Chiron Diagnostics, Walpole, MA

  5. 5

    SPSS 17.0 for Windows; SPSS Inc, Chicago, IL

Ancillary