Impact of CYP3A4*22 on Pazopanib Pharmacokinetics in Cancer Patients

Bins, Sander; Huitema, Alwin D. R.; Laven, P; Bouazzaoui, Samira El; Yu, Huixin; Erp, Nielka van; Herpen, Carla van; Hamberg, Paul; Gelderblom, Hans; Steeghs, Neeltje; Sleijfer, Stefan; Schaik, Ron H.N. van; Mathijssen, Ron H.J.; Koolen, Stijn L.W.

doi:10.1007/s40262-018-0719-5

Cited by 23 publications

(20 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Bins et al reported that the SNP in CYP3A4 which was also related to sunitinib clearance, namely CYP3A4*22 , resulted in a decreased clearance of pazopanib of 35% …”

Section: Methodsmentioning

confidence: 99%

“…In order to be able to understand the PK characteristics of pazopanib and to investigate the influence of different factors (covariates), population PK models for pazopanib have been developed . Some covariates were identified that explain part of the interpatient variability observed.…”

Section: Methodsmentioning

confidence: 99%

“…45 Bins et al reported that the SNP in CYP3A4 which was also related to sunitinib clearance, namely CYP3A4*22, resulted in a decreased clearance of pazopanib of 35%. 130 Finally, two PK models described saturated absorption of pazopanib and a 40-59% higher relative bioavailability for a dose of 400 mg compared to 800 mg. 8,129 Furthermore, these models observed that the exposure of pazopanib decreases in the first 4 weeks after start of treatment with~25%. 8,129 This observation is in line with findings in an earlier study.…”

Section: Pazopanibmentioning

confidence: 99%

See 2 more Smart Citations

Imatinib, sunitinib and pazopanib: From flat‐fixed dosing towards a pharmacokinetically guided personalized dose

Westerdijk¹,

Desar²,

Steeghs

et al. 2020

Brit J Clinical Pharma

Self Cite

View full text Add to dashboard Cite

Tyrosine kinase inhibitors (TKIs) are anti‐cancer drugs that target tyrosine kinases, enzymes that are involved in multiple cellular processes. Currently, multiple oral TKIs have been introduced in the treatment of solid tumours, all administered in a fixed dose, although large interpatient pharmacokinetic (PK) variability is described. For imatinib, sunitinib and pazopanib exposure‐treatment outcome (efficacy and toxicity) relationships have been established and therapeutic windows have been defined, therefore dose optimization based on the measured blood concentration, called therapeutic drug monitoring (TDM), can be valuable in increasing efficacy and reducing the toxicity of these drugs. In this review, an overview of the current knowledge on TDM guided individualized dosing of imatinib, sunitinib and pazopanib for the treatment of solid tumours is presented. We summarize preclinical and clinical data that have defined thresholds for efficacy and toxicity. Furthermore, PK models and factors that influence the PK of these drugs which partly explain the interpatient PK variability are summarized. Finally, pharmacological interventions that have been performed to optimize plasma concentrations are described. Based on current literature, we advise which methods should be used to optimize exposure to imatinib, sunitinib and pazopanib.

show abstract

“…Bins et al reported that the SNP in CYP3A4 which was also related to sunitinib clearance, namely CYP3A4*22 , resulted in a decreased clearance of pazopanib of 35% …”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Pazopanibmentioning

confidence: 99%

See 1 more Smart Citation

Imatinib, sunitinib and pazopanib: From flat‐fixed dosing towards a pharmacokinetically guided personalized dose

Westerdijk¹,

Desar²,

Steeghs

et al. 2020

Brit J Clinical Pharma

Self Cite

View full text Add to dashboard Cite

show abstract

“…Using midazolam as a CYP3A phenotyping probe in cancer patients, Barr et al (2014) and de Wit et al (2014) demonstrated that sunitinib exposure significantly correlated with midazolam exposure; intestinal and hepatic CYP3A activity was proposed to explain approximately 40%-50% of the interpatient viability in sunitinib exposure. Presence of the CYP3A4 reducedfunction allele *22 reduced pazopanib clearance in simulated cancer patients compared with patients with wildtype CYP3A4 (Bins et al, 2019). Moreover, using a physiologically based pharmacokinetic model, Sorich et al (2019) reported that CYP3A abundance was the dominant factor affecting variability in exposure to axitinib.…”

Section: Downloaded Frommentioning

confidence: 99%

Interindividual Variation in CYP3A Activity Influences Lapatinib Bioactivation

et al. 2019

View full text Add to dashboard Cite

Lapatinib is a dual tyrosine kinase inhibitor associated with rare but potentially severe idiosyncratic hepatotoxicity. We have previously shown that cytochromes P450 CYP3A4 and CYP3A5 quantitatively contribute to lapatinib bioactivation, leading to formation of a reactive, potentially toxic quinone imine. CYP3A5 is highly polymorphic; however, the impact of CYP3A5 polymorphism on lapatinib metabolism has not been fully established. The goal of this study was to determine the effect of CYP3A5 genotype and individual variation in CYP3A activity on the metabolic activation of lapatinib using human-relevant in vitro systems. Lapatinib metabolism was examined using CYP3A5-genotyped human liver microsomes and cryopreserved human hepatocytes. CYP3A and CYP3A5-selective activities were measured in liver tissues using probe substrates midazolam and T-5 (T-1032), respectively, to evaluate the correlation between enzymatic activity and lapatinib metabolite formation. Drug metabolites were measured by high-performance liquid chromatographytandem mass spectrometry. Further, the relative contributions of CYP3A4 and CYP3A5 to lapatinib O-debenzylation were estimated using selective chemical inhibitors of CYP3A. The results from this study demonstrated that lapatinib O-debenzylation and quinone imine-GSH conjugate formation were highly correlated with hepatic CYP3A activity, as measured by midazolam 19-hydroxylation. CYP3A4 played a dominant role in lapatinib bioactivation in all liver tissues evaluated. The CYP3A5 contribution to lapatinib bioactivation varied by individual donor and was dependent on CYP3A5 genotype and activity. CYP3A5 contributed approximately 20%-42% to lapatinib O-debenzylation in livers from CYP3A5 expressers. These findings indicate that individual CYP3A activity, not CYP3A5 genotype alone, is a key determinant of lapatinib bioactivation and likely influences exposure to reactive metabolites. SIGNIFICANCE STATEMENT This study is the first to examine the effect of CYP3A5 genotype, total CYP3A activity, and CYP3A5-selective activity on lapatinib bioactivation in individual human liver tissues. The results of this investigation indicate that lapatinib bioactivation via oxidative O-debenzylation is highly correlated with total hepatic CYP3A activity, and not CYP3A5 genotype alone. These findings provide insight into the individual factors, namely, CYP3A activity, that may affect individual exposure to reactive, potentially toxic metabolites of lapatinib.

show abstract

“…4 polymorphisms. 11,12 Genotyping was performed using TaqMan SNP genotyping assays (Thermo Fisher Scientific, Tokyo, Japan).…”

Section: What This Study Addsmentioning

confidence: 99%

Pharmacokinetically guided dosing has the potential to improve real‐world outcomes of pazopanib

Fukudo

Tamaki

Azumi

et al. 2020

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

Impact of CYP3A4*22 on Pazopanib Pharmacokinetics in Cancer Patients

Cited by 23 publications

References 32 publications

Imatinib, sunitinib and pazopanib: From flat‐fixed dosing towards a pharmacokinetically guided personalized dose

Imatinib, sunitinib and pazopanib: From flat‐fixed dosing towards a pharmacokinetically guided personalized dose

Interindividual Variation in CYP3A Activity Influences Lapatinib Bioactivation

Pharmacokinetically guided dosing has the potential to improve real‐world outcomes of pazopanib

Contact Info

Product

Resources

About