Effect of ABCG2 genotype on the oral vioavailability of topotecan

Sparreboom, Alex; Loos, Walter J.; Burger, Herman; Sissung, Tristan M.; Verweij, Jaap; Figg, William D.; Nooter, Kees; Gelderblom, Hans

doi:10.4161/cbt.4.6.1731

Cited by 151 publications

(102 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Overall, the previously published and the present pharmacogenetic results are consistent; the common genetic variants only have a limited effect on imatinib pharmacokinetics. The ABCG2 c.421C>A genotype seems to be more relevant than the others as it has been shown for topoisomerase I inhibitors (23,24). This clinical result is in accordance with cellular studies showing that imatinib has a high-affinity interaction with ABCG2 on primitive hematopoietic stem cells (25).…”

Section: Discussionsupporting

confidence: 79%

Population Pharmacokinetics and Pharmacogenetics of Imatinib in Children and Adults

Pétain

Kattygnarath²,

Azard³

et al. 2008

Clinical Cancer Research

129

View full text Add to dashboard Cite

and On behalf of the InnovativeTherapies with Children with Cancer European consortium Abstract Purpose: The aim of this study was to explore the effect of several demographic, biological, and pharmacogenetic covariates on the disposition of imatinib and its main metabolite (CGP74588) in both adults and children. Experimental Design: Thirty-three children with solid malignancies included in a phase II exploratory study and 34 adults with gastrointestinal stromal tumors received 340 mg/m 2 and 400 mg imatinib, respectively. Plasma imatinib and CGP74588 concentrations observed on day 1 and at steady-state were analyzed by a population pharmacokinetic method (NONMEM) to evaluate the effect of age, body weight, age, sex, albuminemia, plasma a1-acid glycoprotein (AGP), and eight polymorphisms corresponding to ABCB1, ABCG2, CYP3A4, CYP3A5, and AGP (pharmacogenetic data available for 46 of 67 patients).Results: Analysis of the whole data set in 67 patients showed that apparent clearance (CL/F) of imatinib was positively correlated with body weight and albuminemia and negatively with AGP. By considering these three covariates, the interindividual variability on CL/F decreased from 47% to 19%. The apparent clearance of CGP74588 was similarly dependent on both body weight and AGP and significantly lower (30% reduction) at steady-state. By adding genotype status to the final covariate imatinib model, a 22% reduction in CL/F was observed in heterozygous compared with wild-type patients corresponding to ABCG2 c.421C>A (P < 0.05).Conclusions: By considering morphologic and biological covariates, a unique covariate model could be used to accurately describe imatinib pharmacokinetics in patients ages 2 to 84 years. Morphologic and biological characteristics have a stronger influence than pharmacogenetics on imatinib pharmacokinetics.

show abstract

Section: Discussionsupporting

confidence: 79%

Population Pharmacokinetics and Pharmacogenetics of Imatinib in Children and Adults

Pétain

Kattygnarath²,

Azard³

et al. 2008

Clinical Cancer Research

129

View full text Add to dashboard Cite

show abstract

“…Specifically, the ABC transporters BCRP and MDR1 have been implicated in specifically expelling chemotherapeutic agents from cells and thus may mediate chemoresistance when expressed by CSCs. MDR1 has been shown to remove vinblastine 50 and paclitaxel 51 , while BCRP prevents accumulation of imatinib mesylate 52 , topotecan 53 and methotrexate 54 .…”

Section: Cscs and Chemotherapy Resistancementioning

confidence: 99%

Survival of the Fittest: Cancer Stem Cells in Therapeutic Resistance and Angiogenesis

Eyler

Rich

2008

JCO

652

481

View full text Add to dashboard Cite

In an increasing number of cancers, tumor populations called cancer stem cells (CSCs) or tumor initiating cells have been defined in functional assays of self-renewal and tumor initiation. Moreover, recent work in several different cancers has suggested the CSC population as a source of chemo-and radiation-therapy resistance within tumors. Work in glioblastoma and breast cancers supports the idea that CSCs may possess innate resistance mechanisms against radiation-and chemotherapyinduced cancer cell death, allowing them to survive and initiate tumor recurrence. Several resistance mechanisms have been proposed, including amplified checkpoint activation and DNA damage repair as well as increased Wnt/β-Catenin and Notch signalling. Novel targeted therapies against the DNA damage checkpoint or stem cell maintenance pathways may sensitize CSCs to radiation or other therapies. Another important category of cancer therapies are anti-angiogenic and vascular targeting agents which are also becoming integrated in the treatment paradigm of an increasing number of cancers. Recent results from our laboratory and others support a role for CSCs in the angiogenic drive as well as the mechanism of anti-angiogenic agents. Identifying and targeting the molecular mechanisms responsible for CSC therapeutic resistance may improve the efficacy of current cancer therapies.

show abstract

“…ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/ (Zaher et al, 2006) c.34GG and c.421AA/CC/CA: ,2-to 4-fold AUC increases; inconsistent findings between studies (Adkison et al, 2010;Schnepf and Zolk, 2013) No significant association with PK (+dual MDR1/ BCRP inhibitor: pantoprazole) (Adkison et al, 2010); 3.2 max fold AUC increase (+BCRP and enzymes inhibitor: curcumin) (Kusuhara et al, 2012) OATP2B1 substrate (Kusuhara et al, 2012 (Kitamura et al, 2008) c.421CA/AA: 2-to 2.4-fold AUC increases (Zhang et al,. 2006 ;Ieiri et al, 2009;Keskitalo et al, 2009b) 1.6 max fold AUC increase (+ dual OATP/BCRP inhibitors: eltrombopag, ritonavir) (Allred et al, 2011); 7-fold increase (+multiple transporters and enzymes inhibitor: CsA) (Schnepf and Zolk, 2013) (Mizuno et al, 2012); no impact on plasma exposure but on brain distribution (Tang et al, 2012;Schnepf and Zolk, 2013) c.421CA/AA 1.7-to 3-fold AUC increase (Mizuno et al, 2012) (Yamagata et al, 2007) c.421CA: increase in F from ;30% to ;40%, no significant change in AUC, very small sample size (Sparreboom et al, 2005) Increase in F from ;40% to ;100% (+dual MDR1 / BCRP inhibitor: elacridar) (Schnepf a...…”

Section: Introductionmentioning

confidence: 99%

The Need for Human Breast Cancer Resistance Protein Substrate and Inhibition Evaluation in Drug Discovery and Development: Why, When, and How?

et al. 2014

View full text Add to dashboard Cite

Although the multiplicity in transport proteins assessed during drug development is continuously increasing, the clinical relevance of the breast cancer resistance protein (BCRP) is still under debate. Here, our aim is to rationalize the need to consider BCRP substrate and inhibitor interactions and to define optimum selection and acceptance criteria between cell-based and vesicle-based assays in vitro. Information on the preclinical and clinical pharmacokinetics (PK), drug-drug interactions, and pharmacogenomics data was collated for 13 marketed drugs whose PK is reportedly associated with BCRP interaction. Clinical examples where BCRP impacts drug PK and efficacy appear to be rare and confounded by interactions with other transporters. Thirty-seven compounds were selected to be tested as BCRP substrates in a cell-based assay using MDCKII cells (Madin-Darby canine kidney cells) and 18 in membrane vesicles. Depending on the physicochemical compound properties, we observed both in vitro systems to give false-negative readouts. In addition, the inhibition potential of 19 compounds against BCRP was assessed in vesicles and in MDCKII cells, where we observed significant system and substrate-dependent IC 50 values. Therefore, neither of the two test systems is superior to the other. Instead, one system may offer advantages under certain situations (e.g., low permeability) and thus should be selected based on the physicochemical compound properties. Finally, given the clinical relevance of BCRP, we propose that its evaluation should remain issue-driven: for low permeable, low bioavailable drugs, in particular when other more common processes do not allow a mechanistic understanding of any unexpected absorption or brain disposition, and for drugs with a low therapeutic window.

show abstract

Effect of ABCG2 genotype on the oral vioavailability of topotecan

Cited by 151 publications

References 17 publications

Population Pharmacokinetics and Pharmacogenetics of Imatinib in Children and Adults

Population Pharmacokinetics and Pharmacogenetics of Imatinib in Children and Adults

Survival of the Fittest: Cancer Stem Cells in Therapeutic Resistance and Angiogenesis

The Need for Human Breast Cancer Resistance Protein Substrate and Inhibition Evaluation in Drug Discovery and Development: Why, When, and How?

Contact Info

Product

Resources

About