Pharmaceutical Technology - March 2021

Pharmaceutical Technology - Regulatory Sourcebook - March 2021

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Pharmaceutical Technology REGULATORY SOURCEBOOK MARCH 2021 45 Dasatinib is a small molecule, BCR-ABL tyrosine ki- nase inhibitor (TKI) approved in adults and pediatrics for treating Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) and Ph+ acute lymphoblastic leukemia (ALL). Dasatinib daily oral doses in adults are 100 mg for CML-CP and 140 mg for advanced phases CML and ALL. Dosing for children (1 year of age and older) and adolescents is based on body- weight tier. Dasatinib is administered orally once daily as either film-coated tablets or powder for oral suspension in pediatrics subjects. The dasatinib pediatric development progra m was based on extrapolation principles of disease similarity and response to treatment in Philadelphia chromosome positive (Ph+) CML-CP and ALL between adult and pedi- atric patients of all age groups. It supports extrapolation of adult efficacy data in the proposed indication by not requiring a fully powered confirmatory Phase III trial in pediatrics. In the Phase I study, no maximum-tolerated dose (MTD) was identified with body surface area-based dosing at 60, 80, 100, and 120 mg/m 2 once daily. Dasatinib exposure from 60 mg/m 2 in pediatric subjects was compa- rable to 100 mg in adults and served as the target exposure for weight-tier dose recommendations and development of an age-appropriate formulation for pediatric patients (12, 13). The integrated PB/PK model was developed to elucidate the absorption mechanism and role of various factors such as physicochemical properties, absorption characteristics, and inherent differences in dosage form transit behavior related to dasatinib bioequivalence. In the absence of the observed PK data in ALL pediatric patients, simulations based on the PB/PK model were used to ex- trapolate PK from monotherapy in CML patients to the dasatinib-chemo combination in ALL patients and further justify body weight-based dosing recommendations for the new formulation (14). In summary, extrapolation supported the successful ap- proval of a pediatric indication for dasatinib and informed dosing and posology. Impact of data extrapolation While pediatric legislation in the United States and Europe has led to accelerated growth in the number of medicines approved for use in children, a lengthy delay between ini- Figure 2. Shift from a pediatric development program employing multiple pharmacokinetic (PK)/pharmacodynamics (PD) trials followed by full placebo-controlled Phase III (top box) to a single small PK/PD study followed by a smaller Phase III with virtual placebo (bottom box) by means of extrapolation. Age groups: 4 to <12 years, 12 to < 18 years. IND is Induction, MNT is maintenance, LD is low dose, HD is high dose, OLE is open label extension.

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