Population Pharmacokinetics of Glasdegib in Patients With Advanced Hematologic Malignancies and Solid Tumors

Glasdegib is an inhibitor of the Hedgehog pathway recently approved in the United States for the treatment of acute myeloid leukemia. A population pharmacokinetic analysis was conducted to characterize the kinetic behavior of glasdegib and its sources of variability (covariates) by utilizing data fr...

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Bibliographic Details
Published in:Journal of clinical pharmacology 2020-05, Vol.60 (5), p.605-616
Main Authors: Lin, Swan, Shaik, Naveed, Martinelli, Giovanni, Wagner, Andrew J., Cortes, Jorge, Ruiz‐Garcia, Ana
Format: Article
Language:English
Subjects:
Acute myeloid leukemia
Blood cancer
Body weight
Bone marrow
Creatinine
Cytochrome P450
Hedgehog
myelodysplastic syndrome
Myelodysplastic syndromes
Patients
Pharmacokinetics
Pharmacometrics
population pharmacokinetics
Smoothened inhibitor
Solid tumors
Statistical analysis
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Summary:Glasdegib is an inhibitor of the Hedgehog pathway recently approved in the United States for the treatment of acute myeloid leukemia. A population pharmacokinetic analysis was conducted to characterize the kinetic behavior of glasdegib and its sources of variability (covariates) by utilizing data from 269 patients with cancer treated with oral glasdegib doses ranging from 5 to 640 mg/d. Nonlinear mixed‐effects modeling was conducted using NONMEM (v.7.3) and Perl‐speaks NONMEM (v.4.2.0). The estimated apparent total clearance, apparent central volume of distribution, and apparent peripheral volume of distribution were 6.27 L/h, 3.32 L, and 279.2 L, respectively. Age, sex, race, and hepatic function were not significant covariates on glasdegib pharmacokinetic parameters. Baseline body weight, percentage bone marrow blasts, creatinine clearance, and use of moderate or strong cytochrome P450 3A inhibitors were statistically significant covariates on apparent total clearance; however, the magnitude of the effects was not considered clinically meaningful.
ISSN:0091-2700
1552-4604
DOI:10.1002/jcph.1556