I-087 Alessandro Di Deo

Model-based evaluation of predictive markers of response to adalimumab in juvenile idiopathic arthritis

Alessandro Di Deo (1), Giusyda Tarantino (2), Silvia Magni Manzoni (2), Raffaele Simeoli (2), Bianca Maria Goffredo (2), Fabrizio De Benedetti (2), Oscar Della Pasqua (1)

(1) Clinical Pharmacology & Therapeutics, University College London, United Kingdom, (2) Bambino Gesù Children's Hospital IRCCS, Rome, Italy

Introduction: Juvenile Idiopathic Arthritis (JIA) is a group of heterogeneous idiopathic inflammatory arthritis characterised by childhood-onset [1]. The ability of biologic drugs to selectively inhibit specific pathways of the immune system activity has established them as the cornerstone for the treatment of rheumatic diseases [2-5]. Adalimumab (ADA) is a monoclonal TNF inhibitor that demonstrated to be efficacious for the treatment of rheumatoid arthritis as monotherapy or in combination with other disease-modifying anti-rheumatic drugs [6]. However, a significant proportion of patients (≈30%) presents refractory symptom recurrence [7-8]. Even though multiple prognostic factors influencing the efficacy of ADA have been investigated (i.e., anti-ADA antibody, C-reactive protein, pharmacokinetic variability), the relationship between exposure and treatment response remains unclear.

Objectives: this study aimed to assess the influence of clinical and demographic characteristics on the pharmacokinetics of ADA in paediatric patients with JIA and to characterise the exposure-response relationship considering the cJADAS10 as an outcome measure. This endpoint is sensitive to the varying degree of severity of disease and provides a score that takes into account of any involved joint, irrespective of its type. The final goal was to propose an optimised management algorithm considering dose and treatment selection based on individual exposure and predicted symptom trajectories, thereby reducing the proportion of patients who do not show inactive disease or are more likely to show recurrent symptoms.

Methods: this was a retrospective, single centre, observational study in 110 paediatric patients with JIA receiving either 20 mg or 40 mg once a week or every two weeks. Clinical and demographic baseline and treatment follow-up data were integrated with pharmacokinetic data from therapeutic monitoring, including both ADA and anti-ADA antibody concentrations (N=443 samples). A nonlinear mixed effects modelling approach was implemented using prior parameter distributions to describe the pharmacokinetic profile of ADA in children [9]. Subsequently, an inhibitory sigmoid Emax model was identified to explore the exposure-response relationship. Eventually, a clinical management algorithm was evaluated using simulations according to a real world setting to optimise the dose and dosing regimen of ADA, as well as alternative treatment options based on the anticipated response at 6 months. The proportion of subjects reaching a complete remission within either 3 or 6 months from the start of ADA has been used as performance metrics of the proposed algorithm.

Results: the pharmacokinetics of ADA in paediatric JIA patients could be described by a one-compartment model. Inclusion of body weight at baseline, anti-adalimumab antibody levels and C-reactive protein were found to be significant covariates on clearance, despite considerable inter-occasion and interindividual variability in drug disposition. Aligned with literature data, around 30% of the patients included in this analysis had still a mild or high disease activity at 6 months since the start of the treatment. Lower exposure to ADA in non-responders was found to partly explain the time course of clinical symptoms, as assessed by cJADAS10 in this subgroup of subjects. Predicted median Css,av (90%-CI) was 4.9 (0.93-13.29) ng/mL and 3 (0.58-11.7) ng/mL in patients achieving complete remission within 6 months and those with, respectively, high or moderate disease activity. Finally, simulation scenarios showed that the use of weight-banded doses, taking into account disease activity at baseline along with other clinical and demographic factors affecting ADA levels leads to a significant increase in the proportion of patients achieving complete remission within six months since the start of the treatment.

Conclusion: current clinical management of paediatric patients affected by JIA should be revisited. The assessment of systemic exposure to ADA at the start of the treatment, taking into account baseline disease severity allows for prompt dose adjustment, if required. Most importantly, the availability of a drug-disease model describing the cJADAS10 trajectory in individual patients offers an opportunity to predict the probability of response and time to remission. It also supports clinical decision making with regard to the need to consider an alternative treatments (e.g., infliximab, tocilizumab).

References:

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Reference: PAGE 32 (2024) Abstr 11215 [www.page-meeting.org/?abstract=11215]

Poster: Drug/Disease Modelling - Other Topics