Anisa Khan1, Elisa Alessandrini1, Alessandro Di Deo1, Catherine Tuleu2, Oscar Della Pasqua1
1Clinical Pharmacology & Therapeutics Group, University College London, 2Pharmaceutics, School of Pharmacy, University College London
INTRODUCTION Medication adherence refers to the extent to which patients take their medicines as prescribed [1]. Variable adherence is particularly common, especially among children which leads to significant clinical concerns [2,3]. In children, patient acceptability – defined as the overall ability and willingness of the patient to use the medicine as intended – plays a crucial role in medication adherence [4]. In fact, it has been recognised that poor patient acceptability can result in suboptimal adherence and potentially negative treatment outcomes. This is particularly relevant for orally administered medications, where unpleasant taste and difficulties in swallowing are common barriers to adherence [5]. However, the effect of acceptability on adherence is hard to quantify. To date, no studies are available that define acceptance limits based on pharmacokinetic (PK) and/or pharmacodynamic (PD) criteria. Here, we use deferasirox (DFX) and amoxicillin (AMOX) as paradigms compounds to illustrate the implications of poor acceptability in children. DFX, an oral iron-chelating agent used for the treatment of haemoglobinopathies, has an unpleasant taste that affects its acceptability in young patients [6,7]. AMOX, a widely used beta-lactam antibiotic for its broad antibacterial spectrum and high oral bioavailability, has a distinct odour and bitter, metallic taste [7,8].Thus, this study aims to quantify the potential impact of poor adherence due to acceptability issues on treatment outcomes using PKPD modelling and simulation scenarios. METHODS A nonlinear mixed-effects modelling approach was used alongside extrapolation principles to predict the PK and PD of DFX and AMOX in children between 2 to 18 years old (n = 1500). Age and weight-related changes in the PK were described using allometry. For both drugs previously published models [9,10] were employed to derive relevant measures of drug exposure (i.e., area under the curve (AUC), steady-state concentration (Css) and maximum plasma concentration (Cmax)) for the following scenarios: perfect adherence (i.e., 100% of doses are taken), random missingness of 20% (SC1) and 50% (SC2) of the prescribed doses, and partial dose intake, i.e., 1/3 (SC3) or 1/2 (SC4) of the total volume in 20% of dosing events over the treatment period. The exposure-response relationships have been previously established in adults and children [9 – 11]. For DFX, the implications of poor acceptability were evaluated using a published Emax model describing the effect of chelation on serum ferritin [12]. Simulation scenarios were then implemented taking into account relevant covariates, such as baseline ferritin levels (i.e. 2000, 3500 and 5000 ng/mL). For AMOX, the probability of target attainment (PTA) was calculated for different thresholds. i.e., 40%, 50% and 90% for the time above the minimum inhibitory concentration (T>MIC), with MIC values ranging from 0.125 to 16 µg/mL. RESULTS For DFX, the median AUC0-24 (90% CI) estimates for perfect adherence was 475 (233 – 1054) mg/mL.h. When compared to perfect adherence, SC1, SC2, SC3 and SC4 showed a clear reduction in exposure (i.e., 360 (15.0 – 890), 229 (0 – 690), 430 (187 – 990) and 420 (175 – 970) mg/mL.h, respectively). When considering the treatment response, a 10% reduction in ferritin levels was predicted for the scenario with perfect adherence. SC2 proved to be the worst scenario, resulting in no ferritin reduction irrespective of the baseline ferritin levels. For AMOX, the median AUC0-24 (90% CI) for perfect adherence was 99.8 (61.4 – 182.0) µg/mL.h. When compared to perfect adherence, SC1, SC2, SC3 and SC4 showed a clear reduction in exposure (i.e., 81.5 (36.7 – 165.3), 53.6 (13.8 – 131.2), 94.0 (54.4 – 174.8) and 91.2 (50.5 – 172.9) µg/mL.h, respectively). In this case, both SC1 and SC2 proved to be the worst scenarios, as PTA estimates were close to 0 when T>MIC 90%. CONCLUSION This study represents the first attempt to explore the implications of poor acceptability on treatment adherence and response in children using an in silico simulation study. Understanding the clinical consequences of poor palatability can assist the development of better dosage and delivery forms for children. The evaluation of treatment performance using modelling and simulation also offers a unique opportunity to assess the forgiveness of different compounds, distinguishing forgiving from non-forgiving interventions.
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Reference: PAGE 33 (2025) Abstr 11501 [www.page-meeting.org/?abstract=11501]
Poster: Drug/Disease Modelling - Paediatrics