II-091 Sebastiano Lava

Study design optimization in paediatric rare diseases: a case study on empagliflozin in paediatric heart failure

Sebastiano A.G. Lava, Alessandro Di Deo, Oscar Della Pasqua

Clinical Pharmacology & Therapeutics, University College of London, London, UK

Objectives: Paediatric heart failure is rare (1-8/100’000), but it represents a relevant health burden. Current therapy is unsatisfactory, with 5-year mortality rates of 30-50%. Trials in this population have often failed, mainly because of suboptimal dose and poor characterization of pharmacodynamics prior to establishing clinical outcomes. Recently, empagliflozin and dapagliflozin have been repurposed successfully in heart failure in adults. Here we apply a model-based approach to optimize the study protocol design and assess opportunities to increase the probability of pharmacological success in a prospective trial in children with heart failure. More specifically, we aimed to evaluate the pharmacokinetics, pharmacodynamics, safety and dose rationale for empagliflozin. Given the low prevalence and incidence of the condition, in this investigation we explore the advantages of using prior information ($PRIOR) and optimality principles ($DESIGN) to ensure an informative trial design, taking into account feasibility aspects and patient burden. From a technical perspective, we also illustrate how simulation-re-estimation procedures can be implemented in an integrated manner as a tool for the evaluation of pharmacokinetics and pharmacodynamics in rare diseases.

Methods: A nonlinear mixed effects approach was used to illustrate the principles of paediatric extrapolation, incorporating prior information from pharmacokinetics and pharmacodynamics in adult patients. Protocol elements of interest were sample size, sampling schedule, dose, number of visits and treatment duration. Metrics of performance included precision and accuracy of pharmacokinetic and pharmacodynamic parameter estimates. Simulation scenarios were developed initially in a virtual paediatric population (weight range: 10 – 80 kg) with the scope of establishing the dose rationale and pharmacokinetics in the target population for which a suitable dosage form is available (5-18 years old). Comparable PKPD relationship was assumed between adult and paediatric population, with glucosuria as endpoint describing the pharmacodynamic effect(s). The impact of incorporating priors along with optimisation procedures (e.g. number of samples per patient, number of visits) for the characterization of pharmacokinetics and anticipated pharmacodynamics was evaluated using 2 reference scenarios (unoptimized empirical sampling, rich empirical sampling) in a simulation re-estimation procedure (SSE), in which 500 trial replicates were simulated, with both informative and non-informative priors. Secondary PK parameters (AUC, Cmax, Css) and predicted mean treatment response were summarised and compared with reported data in adults.

Results: A 2-compartment PK model with sequential zero- and first-order absorption, absorption lag time, first-order elimination and a proportional error was used to describe the disposition of empagliflozin in children. Clearance and distribution parameters were assumed to vary allometrically with body weight  We identified a lowest safe weight of 13 kg as inclusion criterion for the prospective trial, achieving, with the lowest commercially available tablet of 10mg, a median AUC ratio of 1.16 (IQR 1.15-1.17) relative to adults receiving the top recommended dose of 25mg (median 7196, IQR 6196-8337 nmol*h/L). Based on the SSE step, the optimized sampling scheme with 12 patients divided into 4 different sampling groups, both with informative and non-informative priors, performed well, with a ratio of simulated to estimated CL/F of 0.99 (IQR 0.94-1.07), Vc/F 0.90 (IQR 0.89-0.92), Vp/F 0.90 (IQR 0.81-1.06), and Q/F 1.00 (IQR 0.76-1.23). The empirical unoptimized sampling scheme, the optimized 2 groups and individualized sampling schemes showed inferior performances. The anticipated treatment response in this group was similar to adults when accounting for relevant covariates.

Conclusions: Protocol design optimization based on pharmacokinetic and pharmacodynamic principles should be a mandatory step in the evaluation of rare conditions in children. As opposed to empirical bridging pharmacokinetic protocols, design optimisation procedures increase significantly the information content, taking into account relevant prior information as well as practical limitations. In addition to reducing attrition,  the use of optimisation and simulations reduce the study burden to patients and families, thereby increasing trial feasibility.

References:

  1. Das BB. Current State of Pediatric Heart Failure. Children (Basel). 2018;5(7):88
  2. Towbin JA, Lowe AM, Colan SD, Sleeper LA, Orav EJ, Clunie S, et al. Incidence, causes, and outcomes of dilated cardiomyopathy in children. JAMA. 2006;296(15):1867-1876.
  3. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020;383(15):1413-1424.
  4. Braunwald E. Gliflozins in the Management of Cardiovascular Disease. N Engl J Med. 2022;386(21):2024-2034.
  5. Lava SAG, Laurence C, Di Deo A, Sekarski N, Burch M, Della Pasqua O. Dapagliflozin and Empagliflozin in Paediatric Indications: a Systematic Review and Meta-Analysis. Pediatr Drugs. 2024 (accepted for publication)
  6. Bellanti F, Della Pasqua O. Modelling and simulation as research tools in paediatric drug development. Eur J Clin Pharmacol. 2011;67 Suppl 1(Suppl 1):75-86.
  7. Mondick J, Riggs M, Sasaki T, Sarashina A, Broedl UC, Retlich S. Mixed-effects modelling to quantify the effect of empagliflozin on renal glucose reabsorption in patients with type 2 diabetes. Diabetes Obes Metab. 2016;18(3):241-248.
  8. Laffel LMB, Tamborlane WV, Yver A, Simons G, Wu J, Nock V, Hobson D, Hughan KS, Kaspers S, Marquard J. Pharmacokinetic and pharmacodynamic profile of the sodium-glucose co-transporter-2 inhibitor empagliflozin in young people with Type 2 diabetes: a randomized trial. Diabet Med. 2018;35(8):1096-1104.

Reference: PAGE 32 (2024) Abstr 11167 [www.page-meeting.org/?abstract=11167]

Poster: Drug/Disease Modelling - Paediatrics