Vemurafenib (Zelboraf) is an orally available BRAFV600E inhibitor approved for the treatment of unresectable or metastatic BRAFV600E -mutant melanoma. The primary objective of this work was to characterize the pharmacokinetics (PK) of vemurafenib in pediatric patients with recurrent/refractory astrocytomas harboring the BRAFV600E mutation. The study was also designed to evaluate the feasibility of replacing whole vemurafenib tablets with crushed tablets in young children unable to swallow tablets. Twenty-five pediatric patients (median age, 8.8 years; range, 3.3-19.2) with recurrent/refractory BRAFV600E -mutant astrocytomas received whole (n = 19) or crushed (n = 6) vemurafenib tablets twice daily. Plasma samples were collected on days 1, 15, and 22 in cycle 1 of vemurafenib treatment. Descriptive PK analyses demonstrated significant variability (approximately 6-fold) in drug exposure. A 1-compartment model with first-order absorption and elimination was developed by adjusting the vemurafenib PK model previously validated in adults with mutant BRAFV600E melanoma. After inclusion of allometric scaling on total body weight, the model adequately described the PK of vemurafenib in children between a wide age range of 3 to 19 years old. In the crushed-tablet cohort, relative bioavailability was approximately 96% (95% confidence interval, 49%-142%) compared to that seen in pediatric patients receiving whole tablets based on the preliminary comparison analysis results. Moderate intrapatient variability (48%) of vemurafenib clearance was observed. There was significant correlation (R2 = 0.83) between area under the plasma concentration-time curve and trough concentration at steady state. These results will help increase the number of pediatric patients for whom vemurafenib is accessible and facilitate improved dosing in pediatric patients with recurrent/refractory BRAFV600E astrocytomas.
Keywords: astrocytomas; crushed tablets; pediatrics; pharmacokinetics; vemurafenib.
© 2020, The American College of Clinical Pharmacology.