Pharmacokinetics, pharmacodynamics and toxicities of methotrexate in healthy and collagen‐induced arthritic rats

Abstract

Methotrexate (MTX) is an anchor drug used to treat rheumatoid arthritis (RA), but responsiveness is variable in effectiveness and toxicity. Methotrexate and its polyglutamate conjugates (MTXPGn) in red blood cells (RBC) have been associated with patient response. In the current study, 13 collagen-induced arthritic (CIA) rats and 12 healthy rats were given subcutaneous doses of either saline or 0.3 or 1.5 mg/kg per 2 days of MTX from day 21 to 43 post-induction. Blood samples were obtained at various times to measure MTX in plasma, and MTX and MTXPGn in RBC. Effects on disease progression were indicated by body weight and paw size. After multiple-doses, RBC MTX reached steady-state (82.4 nM) within 4 days. The MTXPG2 and MTXPG3 in RBC kept increasing until the end of the study attaining 12.5 and 17.7 nM. Significant weight loss was observed after dosing of 1.5 mg/kg/2 days, whereas moderate effectiveness was observed after dosing of 0.3 mg/kg/2 days. A pharmacokinetic/ pharmacodynamic/disease (PK/PD/DIS) model with indirect mechanisms and transduction components incorporating plasma MTX, RBC MTX, and RBC MTXPGn concentrations, and paw size was developed using naïve data pooling and ADAPT 5. The PK/PD in CIA rats dosed at 0.3 mg/kg/2 days were captured well by our proposed model. MTX showed modest (Imaxd = 0.16) but sensitive (IC50d = 0.712 nM) effectiveness on paw edema. The higher dose produced toxicity. The proposed model offers improved understanding of MTX effects on rheumatoid arthritis.

Modeling pharmacokinetics/pharmacodynamics of abatacept and disease progression in collagen-induced arthritic rats: a population approach

“…DEX inhibits gene expression of TNF-α, IL-1β, and IL-6, and thus is more effective than the biologics which block only one of these cytokines. Our study results with etanercept, anakinra, and abatacept also agreed with the previous DEX study that TNF-α inhibitors are the most effective protein therapeutic for suppressing paw swelling in this animal model [12], and this is indicated by the greater inhibitory effect of etanercept ( I max = 0.289) [13] compared with that of anakinra ( I max = 0.279) [14], MTX ( I max = 0.160) [41], and abatacept ( I max = 0.161).…”

“…Therefore, such dosing groups were added to our subsequent studies with anakinra [14], methotrexate (MTX) [41], and abatacept. The doses selected in our studies were based on previous findings that showed successful use of the drug in similar animal models [39,42,43].…”

“…The other evidence supporting this hypothesis came from our study with MTX, which is considered the “gold standard” drug for RA. MTX presumably causes apoptosis of activated lymphocytes and adenosine [46] and requires further metabolism within the red blood cells for exerting its effects [47,41]. It only partly inhibits production of some cytokines (mainly TNF-α) and is not effective on others [48], which is likely the reason why it showed only modest effects on paw edema in CIA rats [41].…”

A validated LC‐MS/MS assay for simultaneous quantification of methotrexate and tofacitinib in rat plasma: application to a pharmacokinetic study

“…A literature survey revealed that there have been a few LC‐MS/MS methods reported for quantification of MTX alone (Turci et al ., ; Liu et al ., ) or with other drugs (Thappali et al ., ). The method described by Turci et al .…”

Quantitative Predictive Modelling Approaches to Understanding Rheumatoid Arthritis: A Brief Review

“…While the ODE models discussed above focused on the immunological mechanisms behind RA development and treatment, there is also a large class of ODE models that focus exclusively on the pharmacokinetics and pharmacodynamics of various drugs used to treat RA; see, for example, [75,80,48,49,113,60,58,77] and references therein. For example, [113] used a two-compartment pharmacokinetic ODE model to study the kinetics of the drug infliximab in RA patients, and how the kinetics are affected by inflammatory activity and methotrexate co-treatment.…”