Advancements in Pet Drugs and Pharmacokinetic Insights from FDA-Approved Products

As the number of pet-owning families continues to rise, pet drugs have gained significant attention in drug research and development. As common companions in daily life, the health and well-being of dogs and cats are major concerns for pet owners, covering areas like regular deworming, pain management after neutering, and reducing stress during transport. Along with the trend of pet aging, there is an explosive growth in demand for treating chronic diseases and geriatric diseases in pets. This article summarizes the pharmacokinetic characteristics of traditional pet medications, focusing on the current state of drug development for dogs and cats, regulatory requirements, and case studies in pharmacokinetics.

Current status of pet drug development

Statistics indicate that the therapeutic areas for pet medications are more focused compared to those for humans. Table 1 summarizes the global distribution of therapeutic areas for the top 30 products in human and pet drugs. Human medications span 16 therapeutic areas, with cancer being the most prominent. In contrast, the top 30 pet drugs cover 9 therapeutic areas, with deworming as the leading focus. Currently, there are no shared ingredients between pet drugs and human drugs, which also indicates that the drug needs of humans and pets differ, as do their in vivo targeting properties^[1].

Table 1. Distribution of therapeutic areas for the top 30 human and pet drugs globally ^[1]

As pets are experiencing an aging trend, the development of innovative pet drugs is likely to rise, similar to human drugs' indications in various therapeutic areas. Data shows that in 2023, there are 13.09 million pets in China entering middle and old age (Figure 1)^[2]. The ongoing trend of aging pets will inevitably increase medical demand and further stimulate growth in the pet healthcare market.

Figure 1. The number of pet dogs and cats in China by age group in 2023^[2].

Regulatory guidance for pet drug development

According to the Federal Food, Drug, and Cosmetic Act (the "Act"), an "animal drug" is defined as any drug intended for animals, other than humans, whose composition is not generally recognized by qualified experts as safe and effective for its labeled use. Generally, a new animal drug can be legally introduced into interstate commerce through an approved new animal drug application (NADA) or abbreviated new animal drug application (ANADA) under section 512 of the Act, and approved by the FDA's Center for Veterinary Medicine (CVM)^[3].

The pharmacokinetic research challenges faced in the product development of animal drugs are similar to those of human drugs. However, the species differences, metabolism, and biological variations of target animals are more complex, and the differences in pharmacokinetics and pharmacodynamics play a crucial role in such research activities^[4]. Therefore, the results of pharmacokinetic and pharmacodynamic studies lay a critical foundation for the early stages of veterinary drug development.

Case study: pharmacokinetic research of pet drugs

Oclacitinib maleate

Oclacitinib maleate is the main ingredient of the world's first targeted antipruritic drug for dogs, "Apoquel", used to control pruritus caused by allergic dermatitis and atopic dermatitis in dogs over 12 months of age. The drug was approved in the United States in 2013. Itching and inflammation of the skin in dogs are mainly caused by cytokines such as IL-31, IL-2, and IL-6. These cytokines, when bound to receptors, activate intracellular JAK pathways to produce bioactive substances that trigger itching and inflammation. Oclacitinib can inhibit cytokines that depend on JAK1 and JAK3 enzyme activity, targeting and blocking the transmission of itch signals to the central nervous system. It does not affect hematopoietic cytokines (which depend on JAK2), making it superior to traditional glucocorticoid therapy^[5,6].

Oclacitinib is rapidly absorbed orally and is not affected by the dog's feeding status or breed. After oral administration of 0.4~0.6mg/kg of oclacitinib in dogs, the peak plasma concentration of 324 ng/mL was reached within one hour. The absolute bioavailability was 89%, and the plasma elimination half-life was approximately 3.5 hours. The plasma protein binding rate was relatively low, ranging from 66.3% to 69.7%. Oclacitinib is primarily eliminated in dogs through metabolism, with a small amount excreted via the kidneys. Oclacitinib has a minimal inhibitory effect on canine cytochrome P450 enzyme, with its inhibitor concentration exceeding 50 times the therapeutic peak concentration^[6]. Due to its rapid action and relatively short elimination half-life, oclacitinib has been clinically approved for administration twice daily for up to 14 consecutive days.

Pregabalin

Pregabalin, the main ingredient of "Bonqat^@", is the first antistress drug for cats approved by the United States Food and Drug Administration (FDA). It is used to alleviate acute anxiety and fear in cats associated with transportation and veterinary visits and was approved in the United States in November 2023. Pregabalin is a ligand for the voltage-gated calcium channel α₂δ subunit. By reducing the presynaptic influx of calcium ions in neurons, it decreases the release of various neurotransmitters (such as glutamate, norepinephrine, serotonin, dopamine, substance P, and calcitonin gene-related peptide) in the central nervous system, thereby exerting its anxiolytic effect^[7].

In a pharmacokinetic study by Terttu Lamminen et al., healthy shorthair cats (3 neutered males and 3 females; aged 1 to 4.5 years; weighing 4.4 kg to 5.4 kg) were used. After fasting, they have administrated a single dose of 2.5, 5, and 7.5 mg/kg of pregabalin, or 5 mg/kg of pregabalin orally for two consecutive days. The concentration of pregabalin in plasma samples was measured using liquid chromatography-tandem mass spectrometry. The results showed that the mean maximum plasma concentration of 10.1 μg/mL was reached between 0.5 h and 1 h after oral administration of the clinical dose of 5 mg/kg. The mean half-life after oral administration of dose 5 mg/kg was 14.7 h and the mean systemic bioavailability was 94%. The pharmacokinetic parameters of Pregabalin showed linear changes in the range of 2.5~7.5 mg/kg, and the pharmacokinetic data of 5 mg/kg of Pregabalin orally for two consecutive days had good reproducibility with single oral administration, indicating that it was metabolically stable in vivo and suitable for transient use. The specific pharmacokinetic parameters are summarized in Table 2 and Figure 2. During the test, pregabalin showed good sedation, and at a dose of 7.5 mg/kg, a small number of cats were observed to have mild ataxia. The above results indicate that pregabalin has fast oral absorption, high bioavailability, stable metabolism, moderate sedative effect, and minimized safety issues, and can be used for sedation and anxiolytic in clinical pets and laboratory animals^[8].

Table 2. Pharmacokinetic parameters of pregabalin after single doses of 2.5, 5, 7.5 mg/kg, and 5 mg/kg on two consecutive days of pregabalin 50mg/kg oral solution formulation in fasted cats^[8].

Abbreviations: (1) AUC_0-24h, the area under the plasma concentration-time curve within 24h after dosing; (2) C_max, peak plasma concentration; (3) F, oral bioavailability; (4) NA, not available; (5) SD, standard deviation; (6) T_1/2, elimination half-life; (7) T_max, time to maximum concentration.

a. Mean± SD values, except range for T_max and mean(range) for F.

b. Animals with incomplete dosing, due to spillage or salivation after dosing, are excluded.

Figure 2. Pregabalin mean (± standard deviation) concentration achieved in plasma after an accurate single dose of 2.5(N=6), 5(N=4), and 7.5(N=5) mg/kg of pregabalin 50mg/kg oral solution formulation in fasted cats^[8]

From these two clinical research cases, it can be seen that the focus of pharmacokinetic research on animal drugs is very similar to that of human drugs. The pharmacokinetic properties can help clinicians and researchers better understand the effects and potential side effects of the drug, thereby helping to determine the appropriate dosage and duration of administration.

Conclusions

Whether it is an innovative drug or a generic drug, the development content and standards of pet drugs are similar to those for human drugs. The development of human drugs has laid the foundation for innovation in pet drugs in terms of talent, technology, and experimental conditions, making innovation in pet drugs possible. WuXi AppTec DMPK has many years of experience in preclinical animal pharmacokinetic studies, which can help accelerate the research and development of pet drugs.

WuXi AppTec DMPK possesses comprehensive in vivo pharmacokinetic experimental research capabilities. Leveraging the company platform, cross-team collaboration can be achieved, providing customers with integrated drug development services. The animal facilities of the DMPK department are located in Shanghai, Nanjing, Suzhou, and Nantong. All animal facilities are accredited by the Association for the Assessment and Accreditation of Laboratory Animals Care International (AAALAC International). The types of animals include rats, mice, guinea pigs, hamsters, dogs, monkeys, rabbits, pigs, and cats. The team formulates pharmacokinetic screening strategies based on the characteristics of different studies, including the selection of drug formulations, dose setting, administration routes, determination of sampling time points, and selection of sample matrices. We are committed to meeting our customers' experimental requirements for in vivo pharmacokinetic drug evaluation, thereby facilitating the rapid advancement of new drug development.

Authors: Chao Xu, Wenjun Zhu, Lingling Zhang

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