(W-137) Immune thrombocytopenia purpura (ITP) indication extension allowing for administration of Eltrombopag in adult patients who are refractory to 1L-treatment irrespective of time since diagnosis
Deok Yong Yoon, PharmD, PhD: No relevant disclosure to display
Objectives: At the time of initial approval, eltrombopag was indicated for the treatment of chronic ITP, defined as ITP lasting up to 6 months or longer from diagnosis for patients who are refractory to 1L-treatments (e.g., corticosteroids, immunoglobulins). The key objective of this work was to leverage model-informed drug development (MIDD) to explore an earlier start of eltrombopag. A previously developed popPK-platelet model was enriched with the new clinical data and the effect of time-since-diagnosis was added on key PD parameters. The updated model was then used to confirm similar efficacy (percentage of patients reaching the threshold for platelet count of 50 G/L) at early administration of eltrombopag compared to start of eltrombopag 6 months or later after the diagnosis.
Methods: Data from 5 clinical studies (2 ITP registration studies and 3 additional ITP studies) were used for popPK-platelet modeling. The established population PK model in ITP indication was retained and used to simulate PK parameters in the 3 new studies. Platelet model, which consisted of 1 precursor compartment, two maturation compartments and one platelet compartment, was updated based on the pooled data, and time since diagnosis was tested as a covariate on PD parameters. Covariates previously incorporated in the model were retested. Platelet count profiles were simulated from the updated model for all patients with the available time since diagnosis, and proportion of patients who reached the platelet threshold of 50 G/L at Weeks 2, 3, and 4 were compared for patients who started eltrombopag 6 months or more from diagnosis and those who started earlier.
Results: Platelet count data from 283 eltrombopag treated patients with available “time from diagnosis” were used in the model development. The final platelet model incorporated the effect of time since eltrombopag administration relative to time since diagnosis as a categorical covariate ( < 6 months vs ≥6 months since diagnosis) on first-order maturation of platelet precursors (KOUT), and the effect of gender on platelet production rate. The estimated effect of “time since diagnosis” on KOUT was estimated as 1.12 (close to 1), indicating that platelet dynamics is expected to be similar regardless of the time since ITP diagnosis. Simulations from the popPK-platelet model also indicate that the mean percentage of patients who achieved a platelet count of at least 50 G/L is similar irrespective of the time since ITP diagnosis.
Conclusions: MIDD approach allowed eltrombopag ITP label extensions allowing adult ITP patients who are refractory to other 1L-treatments to be treated with eltrombopag after first line irrespective of time from initial diagnosis were approved in several countries around the world.
Citations: [1] Gibiansky, E. et. al. Population pharmacokinetics of eltrombopag in healthy subjects and patients with chronic idiopathic thrombocytopenic purpura. J. Clin. Pharmacol. 51 (2011).
