Pharmacokinetics of low‐dose methotrexate in healthy beagle dogs

Abstract

Methotrexate may be an alternative to ciclosporin in the treatment of canine atopic dermatitis (cAD) as suggested by recent data. The aim of the study was to investigate both the tolerance and the pharmacokinetic behavior of methotrexate (MTX) in plasma, following intravenous (i.v.), subcutaneous (s.c.) or oral (OR) administration over several weeks. Six healthy dogs were given oral MTX once a week, respectively, per dog at 2.5 mg/1 week, 5 mg/4 weeks, 7.5 mg/3 weeks, 10 mg/6 weeks and 12.5 mg/5 weeks. No clinically relevant abnormalities of laboratory parameters were noticed. A high inter-individual variation of MTX plasma concentration was observed with a suspicion of saturation phenomenon in absorption. To compare with other routes of administration, six healthy beagle dogs followed a crossover design study at 7.5 mg per dog MTX. The absolute bioavailability was 93% for SC injection and 30% for the oral route. The inter-individual variability was quite low following SC administration compared to oral route. Just as in human, given the substantial variability of oral absorption, clinicians cannot assume consistent oral bioavailability of MTX. Therefore, they may consider switching dogs to the SC route in case of absence of clinical response with a weekly oral dose.

Granulomatous mural folliculitis in a dog treated with ciclosporin and methotrexate

“…7,8 MTX seems to be well-tolerated in dogs, although mild gastrointestinal signs can be observed 24-48 h after administration. 5,6 A minor decrease in leukocytes was described, still within the reference range, transient elevations in liver enzymes, especially alanine aminotransferase, c-glutamyl transferase and bilirubin, were observed. 5 The bioavailability appears to be higher following subcutaneous administration compared to the oral route 5 and, in the present authors' clinical experience, subcutaneous administration also helped in decreasing gastrointestinal adverse effects.…”

“…It appears to be safe and has been used in canine atopic dermatitis. 5,6 Its reasonable cost could make it an option for owners who cannot afford ciclosporin (Cs). A case is reported herein of granulomatous mural folliculitis managed long-term with Cs and then with weekly subcutaneous MTX.…”

Pharmacokinetics of low‐dose methotrexate in horses

“…One of our objectives was to evaluate the routes of administration. The influence of food intake on bioavailability is already controversial in humans (Godfrey, Sweeney, Miller, Hamilton, & Kremer, 1998;Hamilton & Kremer, 1995;Oguey, Kölliker, Gerber, & Reichen, 1992 (Rostang et al, 2018) or in humans (Tian & Cronstein, 2007). Differences may be related to the interspecies diversity of gastrointestinal anatomy and physiology.…”

“…Thus, extrapolation of PK results between different species must be conducted (Toutain, Ferran, & Bousquet-Mélou, 2010). Despite a non-total absolute subcutaneous bioavailability in horses, unlike the results observed in humans (Edelman, Biggs, Jamali, & Russell, 1984;Jundt, Browne, Fiocco, Steele, & Mock, 1993) or in dogs (Rostang et al, 2018), we decided to conduct our LT-Study using the SC administration of MTX, which is the most relevant and practical route used by owners and veterinary practitioners.…”

“…Similarly, minor hematological effects (mild to moderate leukopenia, or even thrombocytopenia) are commonly observed in humans or dogs receiving low-dose MTX, occurring in up to 24% of patients followed for long periods (Mathers & Russell, 1993;Rostang et al, 2018). However, no changes in the hematological profile have yet been observed in horses administered low doses.…”