Population pharmacokinetic analysis of sorafenib in patients with solid tumours
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Sorafenib is a multikinase inhibitor with activity against B‐raf, C‐raf, VEGFR2, PDGFRβ and FGFR1. • Sorafenib is clinically approved for the treatment of renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). • The pharmacokinetics (PK) of sorafeni...
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| Veröffentlicht in: | British journal of clinical pharmacology 2011-08, Vol.72 (2), p.294-305 |
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| creator | Jain, Lokesh Woo, Sukyung Gardner, Erin R. Dahut, William L. Kohn, Elise C. Kummar, Shivaani Mould, Diane R. Giaccone, Giuseppe Yarchoan, Robert Venitz, Jürgen Figg, William D. |
| description | WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Sorafenib is a multikinase inhibitor with activity against B‐raf, C‐raf, VEGFR2, PDGFRβ and FGFR1.
• Sorafenib is clinically approved for the treatment of renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC).
• The pharmacokinetics (PK) of sorafenib are highly variable between subjects.
• Sorafenib exposure increases less than dose proportionally (likely due to limited solubility).
• Sorafenib undergoes enterohepatic recycling (EHC).
WHAT THIS STUDY ADDS
• This is the first study to characterize the PK of sorafenib using a model based on sorafenib's known disposition characteristics such as delayed/solubility‐limited GI absorption and EHC. The parameterization of the EHC model used a square wave function to describe the gall bladder emptying.
• This study evaluated the effect of baseline bodyweight, BSA, age, gender, liver function parameters, kidney function parameters and genotype with respect to CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5 on sorafenib PK. No clinically important covariates were identified.
• This model can be used to simulate and explore alternative dosing regimens and to develop exposure–response relationships for sorafenib.
AIMS To characterize the pharmacokinetics (PK) of sorafenib in patients with solid tumours and to evaluate the possible effects of demographic, clinical and pharmacogenetic (CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5) covariates on the disposition of sorafenib.
METHODS PK were assessed in 111 patients enrolled in five phase I and II clinical trials, where sorafenib 200 or 400 mg was administered twice daily as a single agent or in combination therapy. All patients were genotyped for polymorphisms in metabolic enzymes for sorafenib. Population PK analysis was performed by using nonlinear mixed effects modelling (NONMEM). The final model was validated using visual predictive checks and nonparametric bootstrap analysis.
RESULTS A one compartment model with four transit absorption compartments and enterohepatic circulation (EHC) adequately described sorafenib disposition. Baseline bodyweight was a statistically significant covariate for distributional volume, accounting for 4% of inter‐individual variability (IIV). PK model parameter estimates (range) for an 80 kg patient were clearance 8.13 l h−1 (3.6–22.3 l h−1), volume 213 l (50–1000 l), mean absorption transit time 1.98 h (0.5–13 h), fraction undergoing EHC 50% and average time to gall bladder emptying 6.13 h.
CO |
| doi_str_mv | 10.1111/j.1365-2125.2011.03963.x |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3162659</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>876239857</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5033-e38382ac06d938e3d26763b26d6c0a3140ed1ad4fffc4bcab1826c3b41915b253</originalsourceid><addsrcrecordid>eNqNkUFv1DAQhS1ERZfCX0C5IE4Jtid2kgNIdEUBqVJ7gLM1cRzWixMvdkK7_74Ouyzlhi-2NN-8Gb9HSMZowdJ5uy0YSJFzxkXBKWMFhUZCcf-ErE6Fp2RFgcpccMHOyfMYt5QyYFI8I-ecQcNpVa7Iza3fzQ4n68dst8EwoPY_7GgmqzMc0e2jjZnvs-gD9ma0bWYTmHgzTjG7s9MmlZztsmke_BziC3LWo4vm5fG-IN-uPn5df86vbz59WX-4zrWgALmBGmqOmsqugdpAx2UloeWyk5oisJKajmFX9n2vy1Zjy2ouNbQla5houYAL8v6gu5vbwXQ6rRPQqV2wA4a98mjVv5XRbtR3_0slB7gUTRJ4cxQI_uds4qQGG7VxDkfj56jqSnJoalElsj6QOvgYg-lPUxhVSxxqqxbX1eK6WuJQv-NQ96n11eMtT41__E_A6yOAUaPrA47axr9cCQC8Wr777sDdWWf2_72AulzfLi94AM0kqAQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>876239857</pqid></control><display><type>article</type><title>Population pharmacokinetic analysis of sorafenib in patients with solid tumours</title><source>Wiley Free Content</source><source>MEDLINE</source><source>Wiley Online Library Journals Frontfile Complete</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><creator>Jain, Lokesh ; Woo, Sukyung ; Gardner, Erin R. ; Dahut, William L. ; Kohn, Elise C. ; Kummar, Shivaani ; Mould, Diane R. ; Giaccone, Giuseppe ; Yarchoan, Robert ; Venitz, Jürgen ; Figg, William D.</creator><creatorcontrib>Jain, Lokesh ; Woo, Sukyung ; Gardner, Erin R. ; Dahut, William L. ; Kohn, Elise C. ; Kummar, Shivaani ; Mould, Diane R. ; Giaccone, Giuseppe ; Yarchoan, Robert ; Venitz, Jürgen ; Figg, William D.</creatorcontrib><description>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Sorafenib is a multikinase inhibitor with activity against B‐raf, C‐raf, VEGFR2, PDGFRβ and FGFR1.
• Sorafenib is clinically approved for the treatment of renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC).
• The pharmacokinetics (PK) of sorafenib are highly variable between subjects.
• Sorafenib exposure increases less than dose proportionally (likely due to limited solubility).
• Sorafenib undergoes enterohepatic recycling (EHC).
WHAT THIS STUDY ADDS
• This is the first study to characterize the PK of sorafenib using a model based on sorafenib's known disposition characteristics such as delayed/solubility‐limited GI absorption and EHC. The parameterization of the EHC model used a square wave function to describe the gall bladder emptying.
• This study evaluated the effect of baseline bodyweight, BSA, age, gender, liver function parameters, kidney function parameters and genotype with respect to CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5 on sorafenib PK. No clinically important covariates were identified.
• This model can be used to simulate and explore alternative dosing regimens and to develop exposure–response relationships for sorafenib.
AIMS To characterize the pharmacokinetics (PK) of sorafenib in patients with solid tumours and to evaluate the possible effects of demographic, clinical and pharmacogenetic (CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5) covariates on the disposition of sorafenib.
METHODS PK were assessed in 111 patients enrolled in five phase I and II clinical trials, where sorafenib 200 or 400 mg was administered twice daily as a single agent or in combination therapy. All patients were genotyped for polymorphisms in metabolic enzymes for sorafenib. Population PK analysis was performed by using nonlinear mixed effects modelling (NONMEM). The final model was validated using visual predictive checks and nonparametric bootstrap analysis.
RESULTS A one compartment model with four transit absorption compartments and enterohepatic circulation (EHC) adequately described sorafenib disposition. Baseline bodyweight was a statistically significant covariate for distributional volume, accounting for 4% of inter‐individual variability (IIV). PK model parameter estimates (range) for an 80 kg patient were clearance 8.13 l h−1 (3.6–22.3 l h−1), volume 213 l (50–1000 l), mean absorption transit time 1.98 h (0.5–13 h), fraction undergoing EHC 50% and average time to gall bladder emptying 6.13 h.
CONCLUSIONS Overall, population PK analysis was consistent with known biopharmaceutical/PK characteristics of oral sorafenib. No clinically important PK covariates were identified.</description><identifier>ISSN: 0306-5251</identifier><identifier>ISSN: 1365-2125</identifier><identifier>EISSN: 1365-2125</identifier><identifier>DOI: 10.1111/j.1365-2125.2011.03963.x</identifier><identifier>PMID: 21392074</identifier><identifier>CODEN: BCPHBM</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Aged ; Aged, 80 and over ; Antineoplastic Agents - pharmacokinetics ; Benzenesulfonates - pharmacokinetics ; Biological and medical sciences ; Carcinoma, Hepatocellular - metabolism ; Carcinoma, Renal Cell - metabolism ; CYP3A4 ; Cytochrome P-450 CYP3A - metabolism ; Female ; Glucuronosyltransferase - metabolism ; Humans ; Liver Neoplasms - metabolism ; Male ; Medical sciences ; Middle Aged ; Models, Theoretical ; Multiple tumors. Solid tumors. Tumors in childhood (general aspects) ; Niacinamide - analogs & derivatives ; Pharmacology. Drug treatments ; Phenylurea Compounds ; population pharmacokinetics ; Protein-Tyrosine Kinases - antagonists & inhibitors ; Protein-Tyrosine Kinases - metabolism ; Pyridines - pharmacokinetics ; Sorafenib ; Statistics as Topic ; Tumors ; tyrosine kinase inhibitor ; UDP-Glucuronosyltransferase 1A9 ; UGT1A9 ; Uropharmacology Themed Section</subject><ispartof>British journal of clinical pharmacology, 2011-08, Vol.72 (2), p.294-305</ispartof><rights>British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society. No claims to original US government works</rights><rights>2015 INIST-CNRS</rights><rights>British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society. No claims to original US government works.</rights><rights>Copyright © 2011 The British Pharmacological Society 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5033-e38382ac06d938e3d26763b26d6c0a3140ed1ad4fffc4bcab1826c3b41915b253</citedby><cites>FETCH-LOGICAL-c5033-e38382ac06d938e3d26763b26d6c0a3140ed1ad4fffc4bcab1826c3b41915b253</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fj.1365-2125.2011.03963.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1365-2125.2011.03963.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,776,780,881,1411,1427,27903,27904,45553,45554,46387,46811</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24333275$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21392074$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jain, Lokesh</creatorcontrib><creatorcontrib>Woo, Sukyung</creatorcontrib><creatorcontrib>Gardner, Erin R.</creatorcontrib><creatorcontrib>Dahut, William L.</creatorcontrib><creatorcontrib>Kohn, Elise C.</creatorcontrib><creatorcontrib>Kummar, Shivaani</creatorcontrib><creatorcontrib>Mould, Diane R.</creatorcontrib><creatorcontrib>Giaccone, Giuseppe</creatorcontrib><creatorcontrib>Yarchoan, Robert</creatorcontrib><creatorcontrib>Venitz, Jürgen</creatorcontrib><creatorcontrib>Figg, William D.</creatorcontrib><title>Population pharmacokinetic analysis of sorafenib in patients with solid tumours</title><title>British journal of clinical pharmacology</title><addtitle>Br J Clin Pharmacol</addtitle><description>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Sorafenib is a multikinase inhibitor with activity against B‐raf, C‐raf, VEGFR2, PDGFRβ and FGFR1.
• Sorafenib is clinically approved for the treatment of renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC).
• The pharmacokinetics (PK) of sorafenib are highly variable between subjects.
• Sorafenib exposure increases less than dose proportionally (likely due to limited solubility).
• Sorafenib undergoes enterohepatic recycling (EHC).
WHAT THIS STUDY ADDS
• This is the first study to characterize the PK of sorafenib using a model based on sorafenib's known disposition characteristics such as delayed/solubility‐limited GI absorption and EHC. The parameterization of the EHC model used a square wave function to describe the gall bladder emptying.
• This study evaluated the effect of baseline bodyweight, BSA, age, gender, liver function parameters, kidney function parameters and genotype with respect to CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5 on sorafenib PK. No clinically important covariates were identified.
• This model can be used to simulate and explore alternative dosing regimens and to develop exposure–response relationships for sorafenib.
AIMS To characterize the pharmacokinetics (PK) of sorafenib in patients with solid tumours and to evaluate the possible effects of demographic, clinical and pharmacogenetic (CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5) covariates on the disposition of sorafenib.
METHODS PK were assessed in 111 patients enrolled in five phase I and II clinical trials, where sorafenib 200 or 400 mg was administered twice daily as a single agent or in combination therapy. All patients were genotyped for polymorphisms in metabolic enzymes for sorafenib. Population PK analysis was performed by using nonlinear mixed effects modelling (NONMEM). The final model was validated using visual predictive checks and nonparametric bootstrap analysis.
RESULTS A one compartment model with four transit absorption compartments and enterohepatic circulation (EHC) adequately described sorafenib disposition. Baseline bodyweight was a statistically significant covariate for distributional volume, accounting for 4% of inter‐individual variability (IIV). PK model parameter estimates (range) for an 80 kg patient were clearance 8.13 l h−1 (3.6–22.3 l h−1), volume 213 l (50–1000 l), mean absorption transit time 1.98 h (0.5–13 h), fraction undergoing EHC 50% and average time to gall bladder emptying 6.13 h.
CONCLUSIONS Overall, population PK analysis was consistent with known biopharmaceutical/PK characteristics of oral sorafenib. No clinically important PK covariates were identified.</description><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Benzenesulfonates - pharmacokinetics</subject><subject>Biological and medical sciences</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>Carcinoma, Renal Cell - metabolism</subject><subject>CYP3A4</subject><subject>Cytochrome P-450 CYP3A - metabolism</subject><subject>Female</subject><subject>Glucuronosyltransferase - metabolism</subject><subject>Humans</subject><subject>Liver Neoplasms - metabolism</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Models, Theoretical</subject><subject>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</subject><subject>Niacinamide - analogs & derivatives</subject><subject>Pharmacology. Drug treatments</subject><subject>Phenylurea Compounds</subject><subject>population pharmacokinetics</subject><subject>Protein-Tyrosine Kinases - antagonists & inhibitors</subject><subject>Protein-Tyrosine Kinases - metabolism</subject><subject>Pyridines - pharmacokinetics</subject><subject>Sorafenib</subject><subject>Statistics as Topic</subject><subject>Tumors</subject><subject>tyrosine kinase inhibitor</subject><subject>UDP-Glucuronosyltransferase 1A9</subject><subject>UGT1A9</subject><subject>Uropharmacology Themed Section</subject><issn>0306-5251</issn><issn>1365-2125</issn><issn>1365-2125</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkUFv1DAQhS1ERZfCX0C5IE4Jtid2kgNIdEUBqVJ7gLM1cRzWixMvdkK7_74Ouyzlhi-2NN-8Gb9HSMZowdJ5uy0YSJFzxkXBKWMFhUZCcf-ErE6Fp2RFgcpccMHOyfMYt5QyYFI8I-ecQcNpVa7Iza3fzQ4n68dst8EwoPY_7GgmqzMc0e2jjZnvs-gD9ma0bWYTmHgzTjG7s9MmlZztsmke_BziC3LWo4vm5fG-IN-uPn5df86vbz59WX-4zrWgALmBGmqOmsqugdpAx2UloeWyk5oisJKajmFX9n2vy1Zjy2ouNbQla5houYAL8v6gu5vbwXQ6rRPQqV2wA4a98mjVv5XRbtR3_0slB7gUTRJ4cxQI_uds4qQGG7VxDkfj56jqSnJoalElsj6QOvgYg-lPUxhVSxxqqxbX1eK6WuJQv-NQ96n11eMtT41__E_A6yOAUaPrA47axr9cCQC8Wr777sDdWWf2_72AulzfLi94AM0kqAQ</recordid><startdate>201108</startdate><enddate>201108</enddate><creator>Jain, Lokesh</creator><creator>Woo, Sukyung</creator><creator>Gardner, Erin R.</creator><creator>Dahut, William L.</creator><creator>Kohn, Elise C.</creator><creator>Kummar, Shivaani</creator><creator>Mould, Diane R.</creator><creator>Giaccone, Giuseppe</creator><creator>Yarchoan, Robert</creator><creator>Venitz, Jürgen</creator><creator>Figg, William D.</creator><general>Blackwell Publishing Ltd</general><general>Blackwell</general><general>Blackwell Science Inc</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201108</creationdate><title>Population pharmacokinetic analysis of sorafenib in patients with solid tumours</title><author>Jain, Lokesh ; Woo, Sukyung ; Gardner, Erin R. ; Dahut, William L. ; Kohn, Elise C. ; Kummar, Shivaani ; Mould, Diane R. ; Giaccone, Giuseppe ; Yarchoan, Robert ; Venitz, Jürgen ; Figg, William D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5033-e38382ac06d938e3d26763b26d6c0a3140ed1ad4fffc4bcab1826c3b41915b253</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Benzenesulfonates - pharmacokinetics</topic><topic>Biological and medical sciences</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>Carcinoma, Renal Cell - metabolism</topic><topic>CYP3A4</topic><topic>Cytochrome P-450 CYP3A - metabolism</topic><topic>Female</topic><topic>Glucuronosyltransferase - metabolism</topic><topic>Humans</topic><topic>Liver Neoplasms - metabolism</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Models, Theoretical</topic><topic>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</topic><topic>Niacinamide - analogs & derivatives</topic><topic>Pharmacology. Drug treatments</topic><topic>Phenylurea Compounds</topic><topic>population pharmacokinetics</topic><topic>Protein-Tyrosine Kinases - antagonists & inhibitors</topic><topic>Protein-Tyrosine Kinases - metabolism</topic><topic>Pyridines - pharmacokinetics</topic><topic>Sorafenib</topic><topic>Statistics as Topic</topic><topic>Tumors</topic><topic>tyrosine kinase inhibitor</topic><topic>UDP-Glucuronosyltransferase 1A9</topic><topic>UGT1A9</topic><topic>Uropharmacology Themed Section</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jain, Lokesh</creatorcontrib><creatorcontrib>Woo, Sukyung</creatorcontrib><creatorcontrib>Gardner, Erin R.</creatorcontrib><creatorcontrib>Dahut, William L.</creatorcontrib><creatorcontrib>Kohn, Elise C.</creatorcontrib><creatorcontrib>Kummar, Shivaani</creatorcontrib><creatorcontrib>Mould, Diane R.</creatorcontrib><creatorcontrib>Giaccone, Giuseppe</creatorcontrib><creatorcontrib>Yarchoan, Robert</creatorcontrib><creatorcontrib>Venitz, Jürgen</creatorcontrib><creatorcontrib>Figg, William D.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of clinical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jain, Lokesh</au><au>Woo, Sukyung</au><au>Gardner, Erin R.</au><au>Dahut, William L.</au><au>Kohn, Elise C.</au><au>Kummar, Shivaani</au><au>Mould, Diane R.</au><au>Giaccone, Giuseppe</au><au>Yarchoan, Robert</au><au>Venitz, Jürgen</au><au>Figg, William D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Population pharmacokinetic analysis of sorafenib in patients with solid tumours</atitle><jtitle>British journal of clinical pharmacology</jtitle><addtitle>Br J Clin Pharmacol</addtitle><date>2011-08</date><risdate>2011</risdate><volume>72</volume><issue>2</issue><spage>294</spage><epage>305</epage><pages>294-305</pages><issn>0306-5251</issn><issn>1365-2125</issn><eissn>1365-2125</eissn><coden>BCPHBM</coden><abstract>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Sorafenib is a multikinase inhibitor with activity against B‐raf, C‐raf, VEGFR2, PDGFRβ and FGFR1.
• Sorafenib is clinically approved for the treatment of renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC).
• The pharmacokinetics (PK) of sorafenib are highly variable between subjects.
• Sorafenib exposure increases less than dose proportionally (likely due to limited solubility).
• Sorafenib undergoes enterohepatic recycling (EHC).
WHAT THIS STUDY ADDS
• This is the first study to characterize the PK of sorafenib using a model based on sorafenib's known disposition characteristics such as delayed/solubility‐limited GI absorption and EHC. The parameterization of the EHC model used a square wave function to describe the gall bladder emptying.
• This study evaluated the effect of baseline bodyweight, BSA, age, gender, liver function parameters, kidney function parameters and genotype with respect to CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5 on sorafenib PK. No clinically important covariates were identified.
• This model can be used to simulate and explore alternative dosing regimens and to develop exposure–response relationships for sorafenib.
AIMS To characterize the pharmacokinetics (PK) of sorafenib in patients with solid tumours and to evaluate the possible effects of demographic, clinical and pharmacogenetic (CYP3A4*1B, CYP3A5*3C, UGT1A9*3 and UGT1A9*5) covariates on the disposition of sorafenib.
METHODS PK were assessed in 111 patients enrolled in five phase I and II clinical trials, where sorafenib 200 or 400 mg was administered twice daily as a single agent or in combination therapy. All patients were genotyped for polymorphisms in metabolic enzymes for sorafenib. Population PK analysis was performed by using nonlinear mixed effects modelling (NONMEM). The final model was validated using visual predictive checks and nonparametric bootstrap analysis.
RESULTS A one compartment model with four transit absorption compartments and enterohepatic circulation (EHC) adequately described sorafenib disposition. Baseline bodyweight was a statistically significant covariate for distributional volume, accounting for 4% of inter‐individual variability (IIV). PK model parameter estimates (range) for an 80 kg patient were clearance 8.13 l h−1 (3.6–22.3 l h−1), volume 213 l (50–1000 l), mean absorption transit time 1.98 h (0.5–13 h), fraction undergoing EHC 50% and average time to gall bladder emptying 6.13 h.
CONCLUSIONS Overall, population PK analysis was consistent with known biopharmaceutical/PK characteristics of oral sorafenib. No clinically important PK covariates were identified.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>21392074</pmid><doi>10.1111/j.1365-2125.2011.03963.x</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | British journal of clinical pharmacology, 2011-08, Vol.72 (2), p.294-305 |
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| source | Wiley Free Content; MEDLINE; Wiley Online Library Journals Frontfile Complete; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Aged Aged, 80 and over Antineoplastic Agents - pharmacokinetics Benzenesulfonates - pharmacokinetics Biological and medical sciences Carcinoma, Hepatocellular - metabolism Carcinoma, Renal Cell - metabolism CYP3A4 Cytochrome P-450 CYP3A - metabolism Female Glucuronosyltransferase - metabolism Humans Liver Neoplasms - metabolism Male Medical sciences Middle Aged Models, Theoretical Multiple tumors. Solid tumors. Tumors in childhood (general aspects) Niacinamide - analogs & derivatives Pharmacology. Drug treatments Phenylurea Compounds population pharmacokinetics Protein-Tyrosine Kinases - antagonists & inhibitors Protein-Tyrosine Kinases - metabolism Pyridines - pharmacokinetics Sorafenib Statistics as Topic Tumors tyrosine kinase inhibitor UDP-Glucuronosyltransferase 1A9 UGT1A9 Uropharmacology Themed Section |
| title | Population pharmacokinetic analysis of sorafenib in patients with solid tumours |
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