Capromorelin

Overview

Capromorelin (development codes CP-424,391, AT-002, RQ-5) is a potent, orally active, non-peptide agonist of the growth hormone secretagogue receptor type 1a (GHS-R1a), the endogenous receptor for the appetite-regulating and GH-releasing hormone ghrelin [1][9][10]. Discovered by Pfizer Global Research and Development in the late 1990s as part of a medicinal chemistry program focused on pyrazolinone-piperidine dipeptide scaffolds, capromorelin was designed to mimic ghrelin's dual actions of stimulating appetite via hypothalamic orexigenic pathways and promoting pulsatile growth hormone release from pituitary somatotrophs [1][11].

Capromorelin is a peptidomimetic compound with the molecular formula C28H35N5O4 and a molecular weight of 505.62 g/mol (free base) [1]. It is typically formulated as the tartrate salt (MW 655.70 g/mol; CAS 193273-69-7) for pharmaceutical use. The compound features a pyrazolinone-piperidine core structure that confers oral bioavailability (approximately 44% in dogs) while maintaining potent GHS-R1a binding affinity (Ki = 7 nM at the human receptor) [1][5][7].

Originally developed for the treatment of musculoskeletal frailty in elderly adults, capromorelin advanced through Phase II human clinical trials at Pfizer before development was discontinued [3][16]. The compound was subsequently repurposed for veterinary medicine by Aratana Therapeutics (later acquired by Elanco Animal Health in 2019), leading to two landmark FDA veterinary approvals: Entyce (capromorelin oral solution) for appetite stimulation in dogs (May 2016) and Elura (capromorelin oral solution) for management of weight loss in cats with chronic kidney disease (October 2020) [4][18][19]. Capromorelin is the first and only ghrelin receptor agonist approved for therapeutic veterinary use in both dogs and cats.

Type

Non-peptide GHS-R1a agonist (ghrelin mimetic / peptidomimetic)

Molecular Formula

C28H35N5O4

Molecular Weight

505.62 g/mol (free base); 655.70 g/mol (tartrate salt)

CAS Number

193273-66-4 (free base); 193273-69-7 (tartrate salt)

Half-life

~1.2 hours (dogs); short in humans

Oral Bioavailability

~44% (dogs)

Routes Studied

Oral administration

FDA Status (Human)

Not approved; human development discontinued

FDA Status (Veterinary)

Approved for dogs (Entyce, 2016) and cats (Elura, 2020)

WADA Status

Prohibited under S2 (peptide hormones, growth factors)

Mechanism of Action

Capromorelin exerts its pharmacological effects through direct agonism of the growth hormone secretagogue receptor type 1a (GHS-R1a), the same G protein-coupled receptor activated by the endogenous 28-amino acid acylated peptide hormone ghrelin [1][9][10].

Receptor Binding and Signal Transduction: Upon binding GHS-R1a, capromorelin activates the Gq/11-coupled phospholipase C (PLC)/inositol trisphosphate (IP3)/calcium signaling cascade [9][11]. In anterior pituitary somatotroph cells, this triggers calcium release from intracellular stores, driving exocytosis of growth hormone-containing secretory granules. In preclinical assays, capromorelin bound the human GHS-R1a with a Ki of 7 nM and stimulated GH release from rat pituitary cell cultures with an EC50 of 3 nM [1]. In vivo, oral administration to rats produced dose-dependent increases in plasma GH levels, with an intravenous ED50 value of 0.05 mg/kg [1].

Growth Hormone and IGF-1 Axis Stimulation: Capromorelin stimulates pulsatile GH secretion, which in turn promotes hepatic production of insulin-like growth factor 1 (IGF-1) [3][5]. In healthy Beagle dogs receiving 3 mg/kg orally, serum GH concentrations increased within 1 hour and returned to baseline by 8 hours post-dose, while IGF-1 concentrations increased on Day 1 and remained elevated through Day 7 of dosing [5]. This sustained IGF-1 elevation despite transient GH peaks reflects the cumulative anabolic signaling of repeated daily GH pulses.

Appetite Stimulation: As a ghrelin mimetic, capromorelin activates GHS-R1a on hypothalamic neurons in the arcuate nucleus and other feeding-related brain regions, stimulating orexigenic neuropeptide Y (NPY) and agouti-related peptide (AgRP) neurons [7][12][23]. This reproduces the appetite-stimulating effects of endogenous ghrelin, directly generating hunger signaling and increased food-seeking behavior. This appetite-stimulating effect is the primary basis for capromorelin's veterinary approvals [4][7][18].

Complementary Mechanism with GHRH: GHS-R1a-mediated GH release operates through a signaling pathway (PLC/IP3/calcium) that is distinct from and complementary to the cAMP-dependent pathway used by GHRH [11]. This mechanistic complementarity means that ghrelin receptor agonists like capromorelin can synergize with endogenous GHRH to amplify GH secretion, and capromorelin also acts at the hypothalamic level to stimulate GHRH-releasing neurons while suppressing somatostatin tone [11].

Chemistry and Pharmacology

Molecular Structure

Capromorelin belongs to a novel class of pyrazolinone-piperidine dipeptide growth hormone secretagogues discovered through structure-activity relationship studies at Pfizer [1]. Key structural features include a pyrazolidinone ring system fused to a piperidine scaffold, bearing a benzyl substituent and an aminoindanone moiety. This non-peptide peptidomimetic architecture confers resistance to proteolytic degradation, enabling oral absorption [1][2].

The discovery of capromorelin emerged from efforts to improve upon earlier GH secretagogue scaffolds. Carpino et al. (2003) described how systematic modification of pyrazolinone-piperidine dipeptides yielded compounds with enhanced intestinal absorption and oral bioactivity, with capromorelin (CP-424,391) selected as the lead development candidate based on its balanced profile of receptor potency, oral bioavailability, and in vivo GH-releasing activity [1].

Pharmacokinetic Properties

In Dogs (Entyce):

• Absorption: Rapidly absorbed following oral administration at 3 mg/kg, with maximum plasma concentration (Tmax) reached at approximately 0.83 hours [7]
• Oral bioavailability: Approximately 44% [7]
• Terminal half-life: Approximately 1.19 hours [7]
• Plasma clearance: Mean total plasma clearance of 18.9 mL/min/kg [7]
• Volume of distribution: 2.0 L/kg [7]
• Protein binding: Not highly bound; unbound fraction of approximately 51% [7]

In Humans:

• In the Phase I study by Piccoli et al. (2015), single ascending oral doses of 20, 50, and 100 mg in healthy volunteers and spinal cord-injured patients demonstrated dose-dependent increases in Cmax and AUC, with broadly similar pharmacokinetic behavior between able-bodied and spinal cord-injured groups [8]
• Spinal cord-injured participants showed greater variance in pharmacokinetic parameters, with slightly delayed Tmax and half-life [8]

Capromorelin Analogues: Efforts to develop longer-acting derivatives were described by Carpino et al. (2002). Analogues with increased lipophilicity (tert-butyl, picolyl, and fluorinated substitutions) showed extended plasma elimination half-lives in dogs due to higher volumes of distribution, but these longer-acting compounds exhibited weaker GH secretagogue activity [2]. A recent 2025 study reported a novel derivative (compound 4b, hGHSR-1a EC50 = 0.49 nM) that stimulates GH release in rats at oral doses as low as 0.1 mg/kg, approximately 100-fold more potent than ibutamoren, and increased body weight and length in juvenile rats over 10 days of oral administration [21].

Researched Applications

Veterinary: Appetite Stimulation in Dogs (FDA-Approved)

Capromorelin (Entyce) is FDA-approved for appetite stimulation in dogs (NADA 141-457, approved May 16, 2016) [4][18]. This represents the primary therapeutic use of capromorelin and the most extensively documented application.

Inappetence in dogs is a common clinical problem arising from diverse underlying causes including acute illness, chronic disease, post-surgical recovery, medication side effects, and cancer. Loss of appetite leads to malnutrition, weight loss, delayed recovery, and reduced quality of life [7][12]. Capromorelin addresses this by pharmacologically activating the same ghrelin-mediated appetite pathways that drive normal hunger signaling.

Veterinary: Weight Loss Management in Cats with CKD (FDA-Approved)

Capromorelin (Elura) is FDA-approved for the management of weight loss in cats with chronic kidney disease (NADA 141-536, approved October 16, 2020) [19]. CKD is among the most common diseases in aging cats, and progressive weight loss driven by anorexia, nausea, and metabolic derangements is a hallmark feature. Capromorelin's dual mechanism of appetite stimulation and GH/IGF-1-mediated anabolic effects makes it particularly suited for this indication.

Human: Age-Related Frailty and Muscle Wasting (Discontinued)

Capromorelin was originally developed by Pfizer for the treatment of musculoskeletal frailty in older adults. The rationale was based on the well-documented age-related decline in GH secretion ("somatopause") that contributes to sarcopenia, reduced physical function, and increased frailty risk in elderly populations [3][16]. As an orally active ghrelin mimetic, capromorelin offered a convenient alternative to injectable recombinant GH therapy.

Investigational: Spinal Cord Injury

Piccoli et al. (2015) conducted a Phase I pharmacokinetic and safety study of capromorelin in spinal cord-injured volunteers, exploring the potential for GH/IGF-1 axis stimulation to counteract muscle wasting and metabolic derangements associated with chronic spinal cord injury [8].

Investigational: Poultry Growth Promotion

Lotfi et al. (2021) demonstrated that oral capromorelin administration to broiler chickens (6 or 12 mg/kg/day) produced dose-dependent linear increases in feed intake and average daily weight gain, suggesting potential applications in animal agriculture [14].

Clinical Evidence Summary

Carpino et al. 2003 --- Discovery of Capromorelin [1]

Design: Medicinal chemistry and preclinical pharmacology study conducted at Pfizer Global Research and Development. Novel pyrazolinone-piperidine dipeptide derivatives were synthesized, and their GHS-R1a binding affinity, pituitary cell GH-releasing activity, and in vivo oral pharmacology were characterized.

Key Results:

• Capromorelin bound human GHS-R1a with Ki = 7 nM
• Stimulated GH release from rat pituitary cell cultures with EC50 = 3 nM
• In vivo GH release in anesthetized rats with IV ED50 values of 0.05 mg/kg
• Enhanced intestinal absorption in rodent models compared to earlier scaffolds
• Selected as development candidate for treatment of musculoskeletal frailty in elderly adults

White et al. 2009 --- Phase II Human Frailty Trial [3]

Design: Randomized, double-blind, placebo-controlled, multicenter Phase II study conducted at 13 U.S. sites. 395 men and women aged 65-84 years with mild functional limitations were randomized to receive one of four doses of capromorelin or placebo orally once daily for 12 months. Primary endpoints included body composition and physical performance measures. Funded by Pfizer Global Research and Development.

Key Results:

• All four capromorelin doses increased GH production, sustained over 12 months
• Peak nocturnal GH levels increased with capromorelin treatment
• Sustained, dose-related increases in IGF-1 concentrations
• Lean body mass increased 1.4 kg with capromorelin versus 0.3 kg with placebo at 6 months
• Tandem walk (heel-to-toe balance test) improved by 0.9 seconds in pooled treatment groups versus placebo
• Stair climbing performance improved by 12 months
• Adverse events included fatigue, insomnia, and small increases in fasting glucose and HbA1c, all within normal range
• This was the first study to demonstrate improvements in physical performance among at-risk seniors taking a ghrelin receptor agonist

Piccoli et al. 2015 --- Phase I Spinal Cord Injury PK Study [8]

Design: Single-center, single ascending dose Phase I safety and pharmacokinetic study. Spinal cord-injured and able-bodied volunteers received ascending oral doses (20, 50, and 100 mg) of capromorelin at least one week apart, with blood collections over 12 hours and follow-up at 1 and 4 weeks.

Key Results:

• No serious adverse events at any dose in either group
• No abnormal blood pressure or heart rate changes
• Minor adverse events resolved quickly without treatment
• Dose-dependent increases in Cmax and AUC in both groups
• Pharmacokinetic behavior broadly similar between able-bodied and SCI groups
• SCI participants showed greater variance in PK parameters with slightly delayed Tmax

Zollers et al. 2016 --- Pivotal Veterinary Clinical Study (Dogs) [4]

Design: Prospective, randomized, masked, placebo-controlled, multi-site clinical study. 244 client-owned dogs reported by owners to be inappetent for at least 2 days were enrolled. Dogs received capromorelin oral solution at 3 mg/kg once daily (n=121) or placebo (n=56) for 4 days. 177 cases were included in the effectiveness analysis.

Key Results:

• 68.6% of capromorelin-treated dogs achieved treatment success (increased appetite) compared to 44.6% with placebo
• Mean body weight increased in capromorelin-treated dogs compared to placebo-treated dogs
• Adverse events were mild; no serious adverse events attributed to capromorelin
• High placebo response rate (44.6%) noted, consistent with natural disease resolution patterns
• Capromorelin-related adverse events were mild and some consistent with restored appetite

Zollers et al. 2017a --- Beagle Dose-Response Study [5]

Design: Randomized, placebo-controlled study in healthy adult Beagle dogs (n=6 per group). Dogs received placebo BID, capromorelin 3.0 mg/kg SID, 4.5 mg/kg SID, or 3.0 mg/kg BID for 7 days. Food consumption, body weight, and serum GH, IGF-1, and cortisol were measured.

Key Results:

• Capromorelin increased food consumption and body weight compared to placebo at all doses
• Serum GH increased following dosing and returned to baseline by 8 hours post-dose
• IGF-1 concentrations increased on Day 1 and remained elevated through Day 7
• The 3 mg/kg SID dose was selected for further development based on its balance of appetite stimulation and sustained IGF-1 elevation

Zollers et al. 2017b --- Long-Term Safety in Dogs [6]

Design: Safety evaluation of daily oral capromorelin administration in healthy dogs over 12 consecutive months at the labeled dose and multiples thereof.

Key Results:

• Adverse events limited to mild emesis and loose stools across all groups
• Excess salivation observed in some dogs receiving higher doses
• GH and IGF-1 levels mildly increased in capromorelin-treated dogs
• IGF-1 plasma concentrations approximately 2- to 3-fold greater than controls from Days 7 to 170 at 7 and 40 mg/kg doses
• Findings at higher doses included increased salivation, reddened/swollen paws, increased liver weights, and hepatocellular cytoplasmic vacuolation
• Supported safety at the labeled dose (3 mg/kg) for chronic use

Zollers et al. 2017c --- Short-Term Efficacy in Healthy Beagles (Entyce) [13]

Design: Randomized, masked, placebo-controlled study. Healthy adult Beagle dogs received capromorelin oral solution (Entyce, 3 mg/kg) or placebo once daily for 4 consecutive days.

Key Results:

• Capromorelin significantly increased food consumption compared to placebo
• Body weight increased in the capromorelin group
• Results confirmed the efficacy of the commercial Entyce formulation in a controlled setting

FDA Veterinary Approval: Elura for Cats with CKD [19]

Design: Randomized, masked, placebo-controlled, multicenter clinical field study. 176 client-owned cats with existing CKD and unintended weight loss of 5% or more were enrolled (118 Elura, 58 vehicle control) for 56 days.

Key Results:

• Mean percent change in body weight: +5.18% with capromorelin versus -1.65% with placebo
• Treatment effect from Day 0 to Day 55: +6.81% (P value 0.0001)
• Weight gain observed in more than 80% of treated cats versus approximately 40% of controls
• Most common adverse reactions: vomiting, hypersalivation, inappetence, behavior change, and lethargy
• Capromorelin deemed safe and effective for management of weight loss in cats with CKD

Dosing in Published Research

The following doses have been used in clinical research or approved for veterinary use. This information is provided for educational reference only and does not constitute medical or veterinary advice.

| Protocol | Dose | Frequency | Route | Duration | Source | |---|---|---|---|---|---| | Dogs --- appetite stimulation (FDA-approved, Entyce) | 3 mg/kg | Once daily | Oral solution | As prescribed | Entyce PI [4][18] | | Cats --- CKD weight loss (FDA-approved, Elura) | 2 mg/kg | Once daily | Oral solution | As prescribed | Elura PI [19] | | Dogs --- dose-response pharmacology | 3.0 mg/kg SID, 4.5 mg/kg SID, or 3.0 mg/kg BID | Daily for 7 days | Oral | 7 days | Zollers et al. 2017a [5] | | Dogs --- long-term safety | 3, 7, or 40 mg/kg | Once daily | Oral | 12 months | Zollers et al. 2017b [6] | | Human elderly frailty (Phase II) | Multiple dose levels | Once daily | Oral | 12 months | White et al. 2009 [3] | | Human PK/safety (Phase I, SCI) | 20, 50, or 100 mg | Single ascending dose | Oral | Single dose | Piccoli et al. 2015 [8] | | Broiler chickens --- feed intake | 6 or 12 mg/kg/day | Daily | Oral | Study period | Lotfi et al. 2021 [14] |

The FDA-approved dose for dogs (Entyce) is 3 mg/kg body weight administered orally once daily. For cats with CKD (Elura), the approved dose is 2 mg/kg body weight orally once daily. Both formulations are flavored oral solutions designed for palatability in the target species [18][19].

Safety and Side Effects

Veterinary Safety (Dogs --- Entyce)

The most commonly observed adverse reactions in canine clinical trials and post-marketing experience include [4][6][7][18]:

• Diarrhea (7.0% in pivotal trial)
• Vomiting (6.4%)
• Polydipsia (increased drinking, 4.1%)
• Hypersalivation (2.3%)

In the 12-month safety study, adverse events at the labeled dose (3 mg/kg) were limited to mild emesis, loose stools, and occasional hypersalivation [6]. At supratherapeutic doses (7 and 40 mg/kg), additional findings included reddened and swollen paws, increased liver weights, and hepatocellular vacuolation [6]. Entyce should be used with caution in dogs with hepatic dysfunction or renal insufficiency, and its safety has not been evaluated in breeding, pregnant, or lactating dogs [18].

Veterinary Safety (Cats --- Elura)

The most common adverse reactions in the feline CKD study included vomiting, hypersalivation (observed only in the capromorelin group), inappetence, behavior change, and lethargy [19]. Elura is contraindicated in cats with hypersomatotropism (acromegaly) due to the risk of exacerbating GH excess [19].

Human Safety (Phase II)

In the White et al. (2009) Phase II trial in elderly adults, capromorelin was generally well tolerated. Adverse events included [3]:

• Fatigue
• Insomnia
• Small increases in fasting glucose and HbA1c, all within normal range

These metabolic effects are consistent with the known diabetogenic properties of GH excess and have been observed across the class of GHS-R1a agonists [3][16][17]. No serious adverse events were specifically attributed to capromorelin in the human Phase I or Phase II studies [3][8].

GH/IGF-1 Axis Effects

Chronic capromorelin administration produces sustained elevations in IGF-1, with 2- to 3-fold increases observed in dogs at higher doses over 170 days [6]. While this elevation supports the anabolic therapeutic rationale, sustained IGF-1 elevation raises theoretical concerns regarding neoplastic cell growth, insulin resistance, and other consequences of chronic GH axis stimulation [6][12]. These concerns are shared across all GHS-R1a agonists and are a key consideration for long-term use.

Anti-Doping Considerations

Capromorelin is prohibited by the World Anti-Doping Agency (WADA) under category S2 (Peptide Hormones, Growth Factors, Related Substances, and Mimetics) at all times [22]. A 2023 study by Sobolevsky et al. demonstrated that even incidental exposure to capromorelin --- such as ingestion of as little as 1 microliter of Entyce (30 micrograms of capromorelin) or dermal contact during pet administration --- can result in detectable urinary concentrations for up to 48 hours, with maximum concentrations of 7 ng/mL (oral) and 0.7 ng/mL (dermal) [15]. This finding is relevant for athletes who may handle Entyce or Elura when administering it to their pets.

Development History and Regulatory Status

Human Development (Pfizer)

Capromorelin was discovered at Pfizer Global Research and Development, Groton Laboratories, as part of a medicinal chemistry program targeting orally active growth hormone secretagogues for the treatment of musculoskeletal frailty in elderly adults [1][2]. The compound advanced through Phase I and Phase II human clinical trials, with the landmark White et al. (2009) study providing proof-of-concept evidence for improved lean body mass and physical function in older adults [3]. However, human clinical development was subsequently discontinued, with no advancement to Phase III trials. The precise reasons for discontinuation have not been publicly disclosed, but likely involve the modest magnitude of functional improvements relative to the complexity and cost of large-scale elderly frailty trials, combined with the metabolic safety concerns (glucose homeostasis) inherent to all GHS-R1a agonists [3][16].

Veterinary Development (Aratana / Elanco)

Following discontinuation of human development, the veterinary rights to capromorelin were acquired by Aratana Therapeutics, which developed the compound under the code AT-002 for veterinary indications [4][7]. Aratana advanced Entyce through the FDA approval process, obtaining New Animal Drug Application (NADA) 141-457 approval on May 16, 2016, for appetite stimulation in dogs [18]. The company subsequently developed a feline-specific formulation (Elura, AT-002-Cat) for management of weight loss in cats with CKD.

In April 2019, Elanco Animal Health acquired Aratana Therapeutics for approximately $245 million in a stock-for-stock transaction, incorporating both Entyce and the Elura pipeline into Elanco's specialty veterinary portfolio [12]. Elura received FDA approval (NADA 141-536) on October 16, 2020, becoming the first drug approved specifically for management of weight loss in cats with CKD [19].

Ongoing Research

A 2025 publication in the Journal of Medicinal Chemistry described a new generation of capromorelin-derived compounds designed for human GH deficiency treatment. Starting from capromorelin's pyrazolinone-piperidine scaffold, researchers synthesized a derivative (compound 4b) with an hGHSR-1a EC50 of 0.49 nM that stimulated endogenous GH release in rats at oral doses as low as 0.1 mg/kg --- approximately 100-fold more potent than ibutamoren --- and increased body weight and length in juvenile rats over 10 days [21]. This suggests that the capromorelin scaffold remains a productive starting point for next-generation oral GH secretagogue development.

Comparison with Other GHS-R1a Agonists

Capromorelin belongs to the broader class of ghrelin receptor agonists that have been developed for various clinical applications. Key comparisons include:

MK-677 (Ibutamoren): Another non-peptide oral GHS-R1a agonist, developed by Merck. MK-677 has a much longer half-life (~24 hours) compared to capromorelin (~1.2 hours in dogs), enabling once-daily dosing with sustained GH elevation [11][17]. MK-677 has been more extensively studied in humans (multiple Phase II trials in elderly, obese, GH-deficient, and hip fracture populations) but was never approved for any indication. Unlike capromorelin, MK-677 has not been developed for veterinary use. Safety concerns with MK-677 include congestive heart failure risk in elderly patients [17].

Anamorelin: A non-peptide oral GHS-R1a agonist developed specifically for cancer cachexia. Anamorelin has an intermediate half-life (~7 hours) and was approved in Japan in 2021 (Adlumiz) for cancer cachexia in NSCLC, gastric, pancreatic, and colorectal cancers [16]. Unlike capromorelin, anamorelin's clinical development focused exclusively on oncology. The EMA and FDA have not approved anamorelin.

Macimorelin: An oral GHS-R1a agonist approved by the FDA in 2017 solely as a diagnostic agent (Macrilen) for adult growth hormone deficiency [20]. Unlike capromorelin, macimorelin is used as a single-dose GH stimulation test rather than a therapeutic agent. It has no veterinary applications.

Peptide GH Secretagogues (GHRP-6, GHRP-2, Hexarelin, Ipamorelin): These injectable peptide GHS-R1a agonists require subcutaneous or intravenous administration and have short half-lives (minutes to hours) [11]. None have received regulatory approval for any therapeutic indication. Capromorelin's oral bioavailability represents a significant practical advantage over these peptide-based compounds for chronic administration.

Key Differentiating Features of Capromorelin:

• Only GHS-R1a agonist with FDA-approved therapeutic veterinary indications (dogs and cats)
• Relatively short half-life (~1.2 hours in dogs) compared to MK-677 (~24 hours) and anamorelin (~7 hours), resulting in transient GH elevation with sustained IGF-1 effects
• Oral bioavailability (~44% in dogs) suitable for once-daily dosing in liquid formulation
• Both appetite stimulation and GH/IGF-1 elevation contribute to therapeutic effects in veterinary applications
• Human development discontinued, unlike anamorelin (approved in Japan) and macimorelin (approved for diagnosis)

Pharmacokinetics: Detailed Cross-Species Profile

Capromorelin pharmacokinetics have been characterized across multiple species with formal studies in dogs, humans, and preclinical models [1][2][7][8].

Dogs (approved species). Following oral administration of 3 mg/kg (the FDA-approved Entyce dose), capromorelin is rapidly absorbed with a Tmax of approximately 0.83 hours [7]. Oral bioavailability is approximately 44%, representing good absorption for an oral peptidomimetic [7]. The terminal half-life is short at approximately 1.19 hours, leading to GH peaks within 1 hour that return to baseline by 8 hours post-dose [5][7]. Plasma clearance is 18.9 mL/min/kg, volume of distribution is 2.0 L/kg, and protein binding is moderate with an unbound fraction of approximately 51% [7]. The short half-life means that daily dosing produces transient GH pulses rather than sustained GH elevation, while the downstream IGF-1 response accumulates and remains elevated throughout the dosing period -- IGF-1 increased on Day 1 and remained elevated through Day 7 in the Zollers et al. (2017) study [5].

Cats (approved species). The FDA-approved Elura dose is 2 mg/kg once daily, reflecting species-specific dose optimization for the feline CKD population [19]. Formal feline pharmacokinetic parameters have not been published in the peer-reviewed literature, but the clinical field study demonstrated effective appetite stimulation and weight gain at this dose, confirming adequate systemic exposure [19].

Humans. In the Phase I study by Piccoli et al. (2015), single ascending oral doses (20, 50, 100 mg) in healthy volunteers and spinal cord-injured patients showed dose-proportional increases in Cmax and AUC [8]. The plasma half-life in humans is short (not precisely published but consistent with the rapid absorption and clearance observed in dogs). Spinal cord-injured participants showed greater pharmacokinetic variability with slightly delayed Tmax, possibly reflecting altered gastrointestinal motility [8]. In the Phase II elderly frailty trial, daily oral dosing for 12 months produced sustained GH and IGF-1 elevation without evidence of tachyphylaxis, confirming that the receptor does not desensitize with chronic daily exposure [3].

Metabolism. Capromorelin is a non-peptide peptidomimetic with a pyrazolinone-piperidine scaffold resistant to peptidase degradation [1]. The primary routes of clearance are hepatic metabolism and renal elimination. The compound is not a significant CYP450 substrate based on its chemical structure, though formal drug interaction studies have not been published. The low protein binding (approximately 49% bound) means that drug-drug interactions through protein displacement are unlikely.

Effect of food. The Entyce prescribing information does not require fasting, and capromorelin oral solution is designed for palatability in dogs. In veterinary practice, administration with or without food is acceptable [18]. In humans, the effect of food on capromorelin bioavailability has not been formally reported.

Dose-Response Relationships

Capromorelin demonstrates clear dose-response relationships across GH release, IGF-1 elevation, appetite stimulation, and body composition endpoints [1][3][5][6].

GH release in dogs. In the Zollers et al. (2017a) Beagle dose-response study, three dose regimens were compared: 3.0 mg/kg once daily (SID), 4.5 mg/kg SID, and 3.0 mg/kg twice daily (BID) [5]. All active dose groups showed increased serum GH following dosing, with GH returning to baseline by 8 hours post-dose. Food consumption and body weight increases were observed across all dose groups compared to placebo, with the 3.0 mg/kg SID dose selected for further development based on its balance of efficacy and tolerability [5].

IGF-1 elevation in dogs. IGF-1 responses were sustained across the dosing period, with concentrations increasing from Day 1 and remaining elevated through Day 7 at all doses [5]. In the 12-month safety study, IGF-1 plasma concentrations at the 7 and 40 mg/kg doses were approximately 2- to 3-fold greater than controls from Days 7 to 170 [6]. The 3 mg/kg dose produced more modest but clinically meaningful IGF-1 elevation.

GH dose-response in humans. In the Phase II elderly frailty trial, four dose levels of capromorelin were tested daily for 12 months [3]. All four doses increased GH production, with peak nocturnal GH levels elevated versus placebo. Sustained, dose-related increases in IGF-1 concentrations were observed. Lean body mass increased by 1.4 kg with capromorelin versus 0.3 kg with placebo at 6 months, with the difference being clinically meaningful though modest [3].

Appetite stimulation dose-response. The appetite-stimulating effect appears to be engaged at the lowest effective GHS-R1a-activating dose and does not require dose escalation. In the pivotal canine clinical trial, 3 mg/kg SID was sufficient to achieve the primary endpoint of increased appetite in 68.6% of treated dogs versus 44.6% placebo [4].

Long-term safety dose-response. The 12-month canine safety study compared 3, 7, and 40 mg/kg daily [6]. Adverse findings were dose-dependent: at the labeled dose (3 mg/kg), only mild emesis and loose stools were observed. At 7 and 40 mg/kg, additional findings included increased salivation, reddened/swollen paws, increased liver weights, and hepatocellular cytoplasmic vacuolation [6]. This dose-dependent toxicity profile validates the selection of 3 mg/kg as the therapeutic dose.

Comparative Effectiveness: Capromorelin vs. MK-677 and Anamorelin

Capromorelin vs. MK-677 (Ibutamoren)

MK-677 is the most widely recognized non-peptide oral GHS-R1a agonist in both the scientific and lay communities [11][17]. Key comparative differences:

• Half-life: MK-677 has a much longer half-life of approximately 24 hours versus approximately 1.2 hours for capromorelin in dogs [7][17]. This results in continuous, 24-hour GH axis stimulation with MK-677 versus transient, pulsatile GH peaks with capromorelin.
• IGF-1 elevation: Both produce sustained IGF-1 elevation. MK-677 achieves 40-60% IGF-1 increases maintained over months of daily dosing in human studies [17]. Capromorelin produces 2-3 fold IGF-1 increases in dogs at higher doses [6].
• Safety signals: In the elderly population, MK-677 was associated with congestive heart failure risk (Nass et al. 2008), likely related to fluid retention from sustained GH/IGF-1 elevation [17]. Capromorelin's shorter half-life and transient GH peaks may produce less sustained fluid retention, though direct comparison has not been performed.
• Regulatory status: Capromorelin is FDA-approved for veterinary use in dogs and cats [18][19]. MK-677 has never been approved for any indication in any species.
• Human development: Both were discontinued for human therapeutic indications. MK-677 was studied more extensively in humans (multiple Phase II trials) but concerns about metabolic effects and the CHF signal halted development [17]. Capromorelin reached Phase II with promising body composition results before discontinuation [3].

Capromorelin vs. Anamorelin

Anamorelin is the only non-peptide oral GHS-R1a agonist approved for human therapeutic use, having received approval in Japan in 2021 for cancer cachexia (Adlumiz) [16]. Key comparisons:

• Half-life: Anamorelin has an intermediate half-life of approximately 7 hours, between capromorelin (approximately 1.2 hours) and MK-677 (approximately 24 hours).
• Clinical development path: Anamorelin was developed exclusively for oncology (cancer cachexia-anorexia syndrome), while capromorelin was developed for geriatric frailty (humans) and veterinary appetite stimulation. This difference in target population affects the risk-benefit calculus.
• Approval status: Anamorelin is approved only in Japan and was not approved by the FDA or EMA despite multiple Phase III trials. Capromorelin is FDA-approved but only for veterinary indications.
• Evidence quality: Anamorelin has the largest human clinical trial database among oral GHS-R1a agonists (ROMANA-1 and ROMANA-2 Phase III trials totaling over 800 patients). Capromorelin's human database is limited to the Phase I and Phase II studies (approximately 500 total participants).

| Feature | Capromorelin | MK-677 | Anamorelin | |---|---|---|---| | Half-life | ~1.2 h (dogs) | ~24 h | ~7 h | | Oral bioavailability | ~44% (dogs) | High | High | | Human approval | No | No | Japan only (cachexia) | | Veterinary approval | FDA (dogs, cats) | No | No | | Human Phase II data | Yes (frailty) | Yes (multiple) | Yes (cachexia) | | Key safety signal | Hepatocellular effects at high doses | CHF risk (elderly) | Hyperglycemia | | WADA prohibited | Yes | Yes | Yes |

Enhanced Safety Profile

Capromorelin's safety profile is the most comprehensively characterized among oral GHS-R1a agonists due to the extensive veterinary approval datasets and human Phase I/II data [3][4][6][7][8][18][19].

Long-term veterinary safety (strongest dataset). The 12-month canine safety study provides the most detailed long-term safety data for any GHS-R1a agonist [6]. At the approved dose (3 mg/kg), adverse events were limited to mild emesis and loose stools, with no clinically significant laboratory, organ weight, or histopathological findings. This supports chronic daily use at the labeled dose. At supratherapeutic doses (7x and 13x the labeled dose), findings included hepatocellular vacuolation, increased salivation, and paw swelling, providing a clear dose-dependent safety margin [6].

Metabolic safety in humans. In the Phase II elderly frailty trial, capromorelin produced small increases in fasting glucose and HbA1c, all within normal range [3]. This is consistent with the expected diabetogenic effects of GH elevation and has been observed across the GHS-R1a agonist class. No patients developed overt diabetes. The transient GH peak (due to capromorelin's short half-life) may produce less sustained metabolic disruption than longer-acting agents like MK-677.

Cardiovascular safety. No heart-rate-related adverse events, blood pressure abnormalities, or cardiac adverse events were reported in either human or veterinary studies [3][8]. This contrasts with MK-677, where congestive heart failure risk was identified in elderly patients [17]. The shorter duration of GH elevation with capromorelin may reduce the fluid retention that underlies the GH-related cardiac risk.

Hepatic safety. At the approved dose, no liver enzyme elevations or hepatic findings were observed in the 12-month canine study [6]. Hepatocellular cytoplasmic vacuolation at the 40 mg/kg dose (13x labeled dose) represents an expected finding of excessive GH/IGF-1 stimulation at supratherapeutic levels rather than direct hepatotoxicity.

Feline-specific safety. Elura is contraindicated in cats with hypersomatotropism (acromegaly) due to the risk of exacerbating GH excess [19]. The most common adverse reactions in cats with CKD were vomiting, hypersalivation, inappetence, behavior change, and lethargy. CKD cats represent a medically complex population, and the safety profile must be interpreted in this context.

Anti-doping exposure risk. The Sobolevsky et al. (2023) finding that incidental exposure to as little as 1 microliter of Entyce can produce detectable urinary capromorelin for up to 48 hours is a unique safety/regulatory concern for athletes who administer the product to their pets [15]. Maximum urinary concentrations of 7 ng/mL (oral exposure) and 0.7 ng/mL (dermal contact) were measured, both above WADA detection thresholds.

Related Peptides

See also: MK-677 (Ibutamoren), Anamorelin, Ipamorelin, GHRP-6

• MK-677 (Ibutamoren) --- Another non-peptide oral GHS-R1a agonist with a much longer half-life (~24 hours). Extensively studied in human Phase II trials for aging, obesity, and bone metabolism, but never approved for any indication. Not developed for veterinary use.

• Anamorelin --- A non-peptide oral GHS-R1a agonist approved in Japan for cancer cachexia (Adlumiz). Intermediate half-life (~7 hours). Development focused exclusively on oncology indications.

• Ipamorelin --- A highly selective injectable peptide GHS-R1a agonist with minimal effects on cortisol and prolactin. Requires subcutaneous injection and has a short half-life (~2 hours). Investigated in Phase II for postoperative ileus.

• GHRP-6 --- A synthetic hexapeptide GH secretagogue acting on GHS-R1a. Requires injection, stimulates appetite, GH, cortisol, and prolactin. No regulatory approvals.

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