Sorafenib Hepatobiliary Disposition: Mechanisms of Hepatic Uptake and Disposition of Generated Metabolites

Swift, Brandon; Nebot, Noelia; Lee, Jin Kyung; Han, Tianxiang Kevin; Proctor, William R.; Thakker, Dhiren R.; Lang, Dieter; Radtke, Martin; Gnoth, Mark Jean; Brouwer, Kim L. R.

doi:10.1124/dmd.112.048181

Cited by 53 publications

(53 citation statements)

References 46 publications

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“…The first order conditional estimation method with interaction (FOCE‐I) was utilized in the population PK modeling process. The PK model of sorafenib and its N‐oxide metabolite was linked to a PD model of FLT3 and ERK following a sequential PK/PD modeling approach 28, 29…”

Section: Exposure‐response Modelmentioning

confidence: 99%

“…Sorafenib N‐oxide has been noted to be 14.59‐fold more potent than the parent drug when assessing FLT3‐ITD potency 9. Sorafenib undergoes enterohepatic recirculation as an important disposition pathway with sorafenib hepatocellular uptake facilitated by organic anion‐transporting polypeptide (OATP) transporters and efflux to bile facilitated by ABC transporters after being metabolized to its glucuronide metabolite 26, 27, 28. The pharmacokinetics (PK) with enterohepatic recirculation have been quantified in humans using population PK21 and in mice using physiologically based PK modeling 29…”

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confidence: 99%

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Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

Liu

Ivaturi

Sabato

et al. 2018

Clinical Translational Sci

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Sorafenib administered at the approved dose continuously is not tolerated long‐term in patients with acute myeloid leukemia (AML). The purpose of this study was to optimize the dosing regimen by characterizing the sorafenib exposure‐response relationship in patients with AML. A one‐compartment model with a transit absorption compartment and enterohepatic recirculation described the exposure. The relationship between sorafenib exposure and target modulation of kinase targets (FMS‐like tyrosine kinase 3 (FLT3)‐ITD and extracellular signal‐regulated kinase (ERK)) were described by an inhibitory maximum effect (Emax) model. Sorafenib could inhibit FLT3‐ITD activity by 100% with an IC50 of 69.3 ng/mL and ERK activity by 84% with an IC50 of 85.7 ng/mL (both adjusted for metabolite potency). Different dosing regimens utilizing 200 or 400 mg at varying frequencies were simulated based on the exposure‐response relationship. Simulations demonstrate that a 200 mg twice daily (b.i.d.) dosing regimen showed similar FLT3‐ITD and ERK inhibitory activity compared with 400 mg b.i.d. and is recommended in further clinical trials in patients with AML.

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Section: Exposure‐response Modelmentioning

confidence: 99%

mentioning

confidence: 99%

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

Liu

Ivaturi

Sabato

et al. 2018

Clinical Translational Sci

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“…Because the organic cation uptake transporters OCT1 and OCT3 (Yonezawa et al, 2006;Herraez et al, 2013;Swift et al, 2013) and the ABC efflux transporters Fig. 4.…”

Section: Discussionmentioning

confidence: 99%

“…In the context of HCC therapy, the uptake transporters organic cation transporter (OCT) 1 (encoded by the SLC22A1 gene) and OCT3 (SLC22A3) as well as the ATP-binding cassette (ABC) efflux transporters MDR1/P-glycoprotein (ABCB1), multidrug resistance protein (MRP) 2 (ABCC2), and breast cancer resistance protein (BCRP; ABCG2) are of particular interest. They transport and confer resistance to anthracyclines, platinum drugs, and sorafenib (Cui et al, 1999;Burger et al, 2004;Yonezawa et al, 2006;Gillet and Gottesman, 2010;Herraez et al, 2013;Swift et al, 2013), which are commonly used in the treatment of HCC (El-Serag et al, 2008;Llovet et al, 2012). An increased expression of uptake transporters and a decreased expression of efflux transporters would favor the accumulation of cytostatic drugs within the tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Differential Expression of Drug Uptake and Efflux Transporters in Japanese Patients with Hepatocellular Carcinoma

et al. 2014

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Targeted chemotherapy for hepatocellular carcinoma (HCC) is impaired by intrinsic and/or acquired drug resistance. Because drugs used in HCC therapy (e.g., anthracyclines or the tyrosine kinase inhibitor sorafenib) are substrates of uptake and/or efflux transporters, variable expression of these transporters at the plasma membrane of tumor cells may contribute to drug resistance and subsequent clinical response. In this study, the variability of expression of uptake transporters [organic cation transporter (OCT) 1 and OCT3] and efflux transporters [multidrug resistance 1 (MDR1)/P-glycoprotein, multidrug resistance protein (MRP) 1, MRP2, and breast cancer resistance protein (BCRP)], selected for their implication in transporting drugs used in HCC therapy, was investigated. HCC and corresponding nontumor tissue samples were collected from 24 Japanese patients at the time of surgery.Protein expression was determined by immunohistochemistry. Expression data were correlated with clinicopathological characteristics and patients' outcome (median follow-up, 53 months). Generally, expression was highly variable among individual tumor samples. Yet median expression of OCT1, OCT3, and MDR1 in HCC was significantly lower (1.4-, 2.7-, and 2-fold, respectively) than in nontumor tissue, while expression of MRP2 persisted and BCRP showed a trend of increased levels in HCC. Patients with low BCRP expression had significantly shorter overall and recurrence-free survival times. Results suggest different expression patterns of drug transporters in HCC, which are associated only in part with clinicopathological characteristics. Detailed information on expression of drug transporters in HCC may be promising for individualization and optimization of drug therapy for liver cancer.

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“…Sorafenib is transported into hepatocytes by organic cation transporter-1 and -3 and organic anion transporting polypeptides. 54,55 These transporters are also expressed in CRPC tumors and cell lines including PC3 and LNCaP cells. [56][57][58][59] However, no transporter has been identified for nilotinib, suggesting a passive transport across the cell membrane.…”

mentioning

confidence: 99%

A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer

Archibald

Pritchard

Nehoff

et al. 2016

IJN

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Castrate-resistant prostate cancer (CRPC) remains incurable due to the lack of effective therapies. Several tyrosine kinases have been implicated in the development and growth of CRPC, as such targeting these kinases may offer an alternative therapeutic strategy. We established the combination of two tyrosine kinase inhibitors (TKIs), sorafenib and nilotinib, as the most cytotoxic. In addtion, to improve their bioavailability and reduce their metabolism, we encapsulated sorafenib and nilotinib into styrene- co -maleic acid micelles. The micelles’ charge, size, and release rate were characterized. We assessed the effect of the combination on the cytotoxicity, cell cycle, apoptosis, protein expression, tumor spheroid integrity, migration, and invasion. The micelles exhibited a mean diameter of 100 nm, a neutral charge, and appeared highly stable. The micellar TKIs promoted greater cytotoxicity, decreased cell proliferation, and increased apoptosis relative to the free TKIs. In addition, the combination reduced the expression and activity of several tyrosine kinases and reduced tumor spheroid integrity and metastatic potential of CRPC cell lines more efficiently than the single treatments. The combination increased the therapeutic potential and demonstrated the relevance of a targeted combination therapy for the treatment of CRPC. In addition, the efficacy of the encapsulated drugs provides the basis for an in vivo preclinical testing.

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Sorafenib Hepatobiliary Disposition: Mechanisms of Hepatic Uptake and Disposition of Generated Metabolites

Cited by 53 publications

References 46 publications

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

Differential Expression of Drug Uptake and Efflux Transporters in Japanese Patients with Hepatocellular Carcinoma

A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer

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