Population Pharmacokinetics of Selumetinib and Its Metabolite N-desmethyl-selumetinib in Adult Patients With Advanced Solid Tumors and Children With Low-Grade Gliomas.
Selumetinib (AZD6244, ARRY-142886), a mitogen activated protein kinases (MEK1 and 2) inhibitor, has been granted orphan drug designation for differentiated thyroid cancer. The primary aim of this analysis was to characterize the population pharmacokinetics of selumetinib and its active metabolite N-desmethyl-selumetinib in patients with cancer. Concentration-time data from adult and pediatric clinical trials were pooled to develop a population pharmacokinetic model using a sequential approach where selumetinib and N-desmethyl-selumetinib data were modeled separately. A sequential zero- and first-order absorption with lag time with a two-compartment model for selumetinib and a two-compartment model for N-desmethyl-selumetinib best described the concentration-time data. Intrapatient variability in absorption was higher than interpatient variability. The apparent drug clearance (CL/F) from the central compartment was 13.5 L/hr (RSE 4.9%). Significant covariates for CL/F were age, alanine aminotransferase, and body surface area. This study confirms that flat dosing is appropriate in adults, whereas body-surface area based dosing should be used in pediatric patients.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Y T
YT
Patel
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN; currently at Gilead Sciences, San Francisco, California, USA.
V M
VM
Daryani
Manchester Pharmacy School, University of Manchester, Manchester, UK.
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P
Patel
Quantitative Clinical Pharmacology, AstraZeneca Pharmaceuticals, Waltham, Massachusetts, USA.
D
D
Zhou
Ann and Robert H. Lurie Children's Hospital of Chicago and the Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
J
J
Fangusaro
Innovative Medicine and Early Development, AstraZeneca, Da Vinci Building, Melbourn Science Park, Cambridge, UK, AstraZeneca, UK.
D J
DJ
Carlile
Quantitative Clinical Pharmacology, AstraZeneca, Cheshire, UK; currently at Sandoz, Clinical Pharmacology, Holzkirchen, Germany.
P D
PD
Martin
Manchester Pharmacy School, University of Manchester, Manchester, UK.
L
L
Aarons
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
C F
CF
Stewart
D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001562:Benzimidazoles / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D055815:Young Adult
C517975:AZD 6244; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors