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Aims: To develop a non‐linear mixed‐effects population pharmacokinetic and pharmacodynamic (PK‐PD) model describing the change in the concentration of methotrexate polyglutamates in erythrocytes (ery‐MTX‐PGn with "n" number of glutamate, representing PK component) and how this relates to modified 28‐joint Disease Activity Score incorporating erythrocyte sedimentation rate (DAS‐28‐3) for rheumatoid arthritis (RA), representing PD component. Methods: An existing PK model was fitted to data from a study consisting of 117 RA patients. The estimation of population PK‐PD parameters was performed using stochastic approximation expectation maximisation algorithm in Monolix 2021R2. The model was used to perform Monte Carlo simulations of a loading dose regimen (50mg subcutaneous methotrexate as loading doses, then 20mg weekly oral methotrexate) compared to a standard dosing regimen (10mg weekly oral methotrexate for 2 weeks, then 20mg weekly oral methotrexate). Results: Every 40 nmol/L increase in ery‐MTX‐PG3‐5 total concentration correlated with 1‐unit reduction in DAS‐28‐3. Significant covariate effects on the therapeutic response of methotrexate included the use of prednisolone in the first 4 weeks (positive use correlated with 25% reduction in DAS‐28‐3 when other variables were constant) and patient age (every 10‐year increase in age correlated with 3.4% increase in DAS‐28‐3 when other variables were constant). 4 methotrexate loading doses led to a higher percentage of patients achieving a good/moderate response compared to the standard regimen (Week 4: 87.6% vs. 39.8%; Week 10: 64.7% vs. 57.0%). Conclusions: A loading dose regimen was more likely to achieve higher ery‐MTX‐PG concentration and better therapeutic response after 4 weeks of methotrexate treatment. [ABSTRACT FROM AUTHOR]

Nearly two decades after the Peck and Cross article '"Getting the dose right: facts, a blueprint, and encouragements" was published, a review of dose recommendations for biologics shows that the success in getting the dose right appears to have improved given the relatively low incidence of drug withdrawals and dosing/label changes. However, the clinical experience with monoclonal antibodies (MAbs) following approval has been less than perfect. In inflammatory diseases, the disease burden changes with time and high treatment failure rates have been reported. In addition, the use of concomitant steroids and immunosuppressant drugs with MAbs is common. These concomitant agents have their own safety issues and many immunosuppressant agents are not well‐tolerated although they have been shown to reduce the incidence of anti‐drug antibodies (ADA). This same complexity is seen in MAbs used in oncology as well, although with these agents the doses appear to be higher than needed, which results in high treatment costs and incidence of adverse events. Given the complexity of MAb pharmacokinetics, which makes providing a detailed description of dose options difficult, product labeling should include the options for alternative dose strategies and potentially include the use of therapeutic drug monitoring with dose individualization which have been shown to improve clinical response and reduce the incidence of ADA. So, while the recommended dosing for biologics seems improved over the issues noted 17 years ago, we still have some work to do. [ABSTRACT FROM AUTHOR]

Precision‐dosing models forecast infliximab doses to achieve targeted trough concentrations in patients with inflammatory bowel disease (IBD). These models have shown to reduce nonresponse and improve patient outcomes. We compared infliximab doses determined by iDOSE precision dosing with standard dosing, and the associated drug costs, in patients with IBD. In this retrospective study, patients with IBD treated with infliximab every 8 weeks at 5 mg/kg were included. An infliximab dose was named dose X if 3 previous infliximab doses, laboratory values including trough infliximab concentrations, and the patient's weight were recorded. The actual dose X was compared to an iDOSE‐predicted dose X. Net drug use and costs were evaluated. A total of 174 patients—56% men; median age, 36 (interquartile range, 29‐47) years; 135 with Crohn disease; and 31 with ulcerative colitis—were included, with 417 dose X recordings. Median prior infliximab therapy was 2 (0‐4) years. Comparing actual dose X with predicted dose X, 52% and 32% of doses were subtherapeutic when aiming for trough concentrations of 5‐10 and 3‐7 μg/mL, respectively. Treatment costs increased by 102% and 29% for the 2 trough ranges, respectively. On multivariate regression analysis, subtherapeutic infliximab concentrations were associated with ulcerative colitis compared with Crohn disease (odds ratio, 9.81; 95% confidence interval, 1.28‐75.40; P =.028) and predose X infliximab trough concentration [odds ratio, 0.07; 95% confidence interval, 0.03‐0.15; P <.001]. Over half of maintenance infliximab drug doses were too low to achieve infliximab blood concentrations of 5 μg/mL or greater. While applying precision dosing may improve patient outcomes, drug costs could be considerably greater. [ABSTRACT FROM AUTHOR]