Modeling and Simulation Support Eltrombopag Dosing in Pediatric Patients With Immune Thrombocytopenia

Abstract

Our objective was to support initial eltrombopag doses and dose titration based on modeling and simulation of plasma exposure and platelet count response in pediatric patients aged 1-17 years with previously treated chronic immune thrombocytopenia enrolled in two clinical studies. Data from 168 pediatric patients were used to develop a life-span population pharmacokinetic and pharmacodynamic model including three pharmacokinetic and four pharmacodynamic compartments enabling simulation of platelet counts for various starting doses and dose titration schedules. This work supported initial eltrombopag doses of 50 mg once daily (q.d.) for non-Asian patients aged ≥ 6 years and 25 mg q.d. for Asian patients, regardless of age, and for all patients aged 1-5 years, regardless of ethnic origin. Doses were escalated at 2-week intervals or reduced as needed according to each patient's platelet counts to both minimize the time to achieve target platelet counts and mitigate thrombocytosis. Clinicaltrials.gov Identifier: NCT00908037, NCT01520909.

Efficacy and safety of eltrombopag in the treatment of severe chronic immune thrombocytopenia in children of China: A single-center observational study

“…These may also contribute to a lower response rate to that observed in adults with CITP. Previous studies 10 have found a correlation between the efficacy of eltrombopag and its dosage, but this was not detected in our study. This discrepancy may be related to certain factors relevant to the children in our study, such as the underlying pathophysiology or the use of concomitant medication.…”

Spotlight on eltrombopag in pediatric ITP in China: a long-term observational study in real-world practice

“…In this study, the median starting dose was 25 mg per day for children age 5 years or younger, 37.5 mg for children age 6 to 11 years, and 50 mg for children age 12 years or older. Owning to the differences in pharmacokinetics among races, 14 the FDA recommends a reduced initial dose of eltrombopag for patients with East Asian ancestry. However, even with the limited data in PETIT2, we can see that the average daily dose for East Asian children did not seem to be lower than that for the total cohort.…”

“…5,13 However, eltrombopag exhibited different metabolic properties among patients with Asian ancestry in the pharmacokinetics/pharmacodynamics model, resulting in relatively high exposure to the drug. 14 There are insufficient efficacy and safety data in PETIT2 to draw a suitable dosing recommendation for Asian children.…”

Eltrombopag added to immunosuppression for children with treatment‐naïve severe aplastic anaemia

“…Due to high relapse rates, the protocol was amended so that responders would continue CSA at a reduced dose (2 mg/kg daily) from 6 months to 2 years; the majority of the patients in the paediatric EPAG group were enrolled after this amendment ( n = 33, 83%) to receive CSA for 2 years. EPAG was dosed at 150 mg daily for patients aged ≥12 years, 75 mg for those aged 6–11 years and 2·5 mg/kg for those aged 2–5 years, with standard dosing adjustments made for patients of East Asian and Southeast Asian ancestry based on PK data in immune thrombocytopenic purpura 11 . The duration of EPAG administration was either 3 or 6 months, depending on assigned cohorts enrolled consecutively (Figure S1).…”

“…EPAG was dosed at 150 mg daily for patients aged ≥12 years, 75 mg for those aged 6-11 years and 2Á5 mg/kg for those aged 2-5 years, with standard dosing adjustments made for patients of East Asian and Southeast Asian ancestry based on PK data in immune thrombocytopenic purpura. 11 The duration of EPAG administration was either 3 or 6 months, depending on assigned cohorts enrolled consecutively ( Figure S1). Responders who relapsed were restarted on CSA and/or EPAG with a duration based on clinical response (Fig 1).…”