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Vincristine is a cytotoxic chemotherapeutic agent used as first‐line therapy for pediatric acute lymphocytic leukemia. It is cleared by hepatic oxidative metabolism by  CYP 3A4 and  CYP 3A5 and via hepatic (biliary) efflux mediated by P‐glycoprotein (P‐gp) transporter. Bottom‐up physiologically based pharmacokinetic ( PBPK ) models were developed to predict vincristine disposition in pediatric and adult populations. The models incorporated physicochemical properties, metabolism by  CYP 3A4/5, efflux by P‐gp, and intracellular binding to β‐tubulin. The adult and pediatric  PBPK  models predicted pharmacokinetics ( PK ) within twofold of the observed  PK  parameters (area under the curve, terminal half‐life, volume of distribution, and clearance). Simulating a higher hypothetical (4.9‐fold) pediatric expression of β‐tubulin relative to adult improved predictions of vincristine  PKs . To our knowledge, this is the first time that intracellular binding has been incorporated into a pediatric  PBPK  model. Utilizing this  PBPK  modeling approach, safe and effective doses of vincristine could be predicted.

Physiologically Based Pharmacokinetic Models for Adults and Children Reveal a Role of Intracellular Tubulin Binding in Vincristine Disposition