Predictive value of CYP3A and ABCB1 phenotyping probes for the pharmacokinetics of sunitinib: The ClearSun study

Jacqueline S L Kloth, Heinz Josef Klümpen, Huixin Yu, Karel Eechoute, Caroline F. Samer, Boen L R Kam, Alwin D R Huitema, Youssef Daali, Aeilko H. Zwinderman, Bavanthi Balakrishnar, Roelof J. Bennink, Mark Wong, Jan H M Schellens, Ron H J Mathijssen, Howard Gurney

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Abstract

Background and 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 (99mTc-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 99mTc-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.

LanguageEnglish
Pages261-269
Number of pages9
JournalClinical Pharmacokinetics
Volume53
Issue number3
DOIs
Publication statusPublished - Mar 2014
Externally publishedYes

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Cytochrome P-450 CYP3A
Pharmacokinetics
Midazolam
Phenotype
Nonlinear Dynamics
sunitinib
Technetium
Software
Adenosine Triphosphate
Prospective Studies
Therapeutics

Cite this

Kloth, Jacqueline S L ; Klümpen, Heinz Josef ; Yu, Huixin ; Eechoute, Karel ; Samer, Caroline F. ; Kam, Boen L R ; Huitema, Alwin D R ; Daali, Youssef ; Zwinderman, Aeilko H. ; Balakrishnar, Bavanthi ; Bennink, Roelof J. ; Wong, Mark ; Schellens, Jan H M ; Mathijssen, Ron H J ; Gurney, Howard. / Predictive value of CYP3A and ABCB1 phenotyping probes for the pharmacokinetics of sunitinib : The ClearSun study. In: Clinical Pharmacokinetics. 2014 ; Vol. 53, No. 3. pp. 261-269.
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title = "Predictive value of CYP3A and ABCB1 phenotyping probes for the pharmacokinetics of sunitinib: The ClearSun study",
abstract = "Background and 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 (99mTc-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 99mTc-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.",
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Kloth, JSL, Klümpen, HJ, Yu, H, Eechoute, K, Samer, CF, Kam, BLR, Huitema, ADR, Daali, Y, Zwinderman, AH, Balakrishnar, B, Bennink, RJ, Wong, M, Schellens, JHM, Mathijssen, RHJ & Gurney, H 2014, 'Predictive value of CYP3A and ABCB1 phenotyping probes for the pharmacokinetics of sunitinib: The ClearSun study', Clinical Pharmacokinetics, vol. 53, no. 3, pp. 261-269. https://doi.org/10.1007/s40262-013-0111-4

Predictive value of CYP3A and ABCB1 phenotyping probes for the pharmacokinetics of sunitinib : The ClearSun study. / Kloth, Jacqueline S L; Klümpen, Heinz Josef; Yu, Huixin; Eechoute, Karel; Samer, Caroline F.; Kam, Boen L R; Huitema, Alwin D R; Daali, Youssef; Zwinderman, Aeilko H.; Balakrishnar, Bavanthi; Bennink, Roelof J.; Wong, Mark; Schellens, Jan H M; Mathijssen, Ron H J; Gurney, Howard.

In: Clinical Pharmacokinetics, Vol. 53, No. 3, 03.2014, p. 261-269.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Predictive value of CYP3A and ABCB1 phenotyping probes for the pharmacokinetics of sunitinib

T2 - Clinical Pharmacokinetics

AU - Kloth, Jacqueline S L

AU - Klümpen, Heinz Josef

AU - Yu, Huixin

AU - Eechoute, Karel

AU - Samer, Caroline F.

AU - Kam, Boen L R

AU - Huitema, Alwin D R

AU - Daali, Youssef

AU - Zwinderman, Aeilko H.

AU - Balakrishnar, Bavanthi

AU - Bennink, Roelof J.

AU - Wong, Mark

AU - Schellens, Jan H M

AU - Mathijssen, Ron H J

AU - Gurney, Howard

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N2 - Background and 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 (99mTc-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 99mTc-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.

AB - Background and 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 (99mTc-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 99mTc-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.

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