Predictive value of CYP3A and ABCB1 phenotyping probes for the pharmacokinetics of sunitinib: the ClearSun study.
OBJECTIVE
The wide inter-patient variability in drug exposure partly explains the toxicity and efficacy profile of sunitinib treatment. In this prospective study cytochrome P450 (CYP) 3A and adenosine triphosphate binding cassette (ABC) B1 phenotypes were correlated to the pharmacokinetics of sunitinib and its active metabolite N-desethylsunitinib.


METHODS
A correlation analysis was performed between sunitinib pharmacokinetics and 1'OH-midazolam/midazolam ratio and parameters derived from technetium-99m-2-methoxy isobutyl isonitrile ((99m)Tc-MIBI) scans, respectively. A population pharmacokinetic model using non-linear mixed-effects modeling software NONMEM was built, which included the phenotype tests as covariate.


RESULTS
In 52 patients, the mean trough concentration of sunitinib plus metabolite increased from 21.4 ng/mL at day 1 of a cycle to 88.1 ng/mL in the fourth week of treatment. A trend for a correlation was observed between (99m)Tc-MIBI elimination constant and trough concentrations of N-desethylsunitinib; however, this was not significant. Correlations were found between 1'OH-midazolam/midazolam ratio and sunitinib clearance (P = 0.008) and day 1 N-desethylsunitinib trough concentrations (P = 0.005), respectively. Moreover, patients suffering from grade 3 toxicities had significant lower clearance of sunitinib than patients without grade 3 toxicities (34.4 vs. 41.4 L/h; P = 0.025).


CONCLUSIONS
Phenotype tests for ABCB1 and CYP3A4 did not explain inter-individual variability of sunitinib exposure sufficiently. However, the correlation between sunitinib clearance and the occurrence of severe toxicity suggests a direct exposure-toxicity relationship.
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Jacqueline S L
JS
Kloth
Department of Medical Oncology, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.
Heinz-Josef
HJ
Klümpen
Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands.
Huixin
H
Yu
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Karel
K
Eechoute
Department of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.|Swiss Center of Applied Human Toxicology, Basel, Switzerland.
Caroline F
CF
Samer
Department of Nuclear Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
Boen L R
BL
Kam
Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands.
Alwin D R
AD
Huitema
Department of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.
Youssef
Y
Daali
Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.
Aeilko H
AH
Zwinderman
Department of Medical Oncology, University of Sydney, Westmead Hospital, Westmead, NSW, Australia.
Bavanthi
B
Balakrishnar
Department of Nuclear Medicine, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.
Roelof J
RJ
Bennink
Department of Medical Oncology, University of Sydney, Westmead Hospital, Westmead, NSW, Australia.
Mark
M
Wong
Department of Clinical Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands.|Division of Drug Toxicology, Department of Pharmaceutical Sciences, Science Faculty, Utrecht University, Utrecht, The Netherlands.
Jan H M
JH
Schellens
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Ron H J
RH
Mathijssen
Department of Medical Oncology, University of Sydney, Westmead Hospital, Westmead, NSW, Australia. howard.gurney@sydney.edu.au.
Howard
H
Gurney
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000737:chemistry / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D001711:Biotransformation; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry* / Q000235:genetics; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics; D008875:Middle Aged; D010641:Phenotype; D011446:Prospective Studies; D011758:Pyrroles / Q000009:adverse effects / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D000077210:Sunitinib; D017256:Technetium Tc 99m Sestamibi / Q000493:pharmacokinetics
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D006993:Hypnotics and Sedatives; D007211:Indoles; D011758:Pyrroles; D019275:Radiopharmaceuticals; D017256:Technetium Tc 99m Sestamibi; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam; D000077210:Sunitinib