A Population Pharmacokinetic Model of Oral Docetaxel Coadministered With Ritonavir to Support Early Clinical Development
Oral administration of docetaxel is an attractive alternative for conventional intravenous (IV) administration. The low bioavailability of docetaxel, however, hinders the application of oral docetaxel in the clinic. The aim of the current study was to develop a population pharmacokinetic (PK) model...
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| Veröffentlicht in: | Journal of clinical pharmacology 2020-03, Vol.60 (3), p.340-350 |
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| creator | Yu, Huixin Janssen, Julie M. Sawicki, Emilia Hasselt, J. G. Coen Weger, Vincent A. Nuijen, Bastiaan Schellens, Jan H. M. Beijnen, Jos H. Huitema, Alwin D. R. |
| description | Oral administration of docetaxel is an attractive alternative for conventional intravenous (IV) administration. The low bioavailability of docetaxel, however, hinders the application of oral docetaxel in the clinic. The aim of the current study was to develop a population pharmacokinetic (PK) model for docetaxel and ritonavir based on the phase 1 studies and to support drug development of this combination treatment. PK data were collected from 191 patients who received IV docetaxel and different oral docetaxel formulations (drinking solution, ModraDoc001 capsule, and ModraDoc006 tablet) coadministered with ritonavir. A PK model was first developed for ritonavir. Subsequently, a semiphysiological PK model was developed for docetaxel, which incorporated the inhibition of docetaxel metabolism by ritonavir. The uninhibited intrinsic clearance of docetaxel was estimated based on data on IV docetaxel as 1980 L/h (relative standard error, 11%). Ritonavir coadministration extensively inhibited the hepatic metabolism of docetaxel to 9.3%, which resulted in up to 12‐fold higher docetaxel plasma concentrations compared to oral docetaxel coadministered without ritonavir. In conclusion, a semiphysiological PK model for docetaxel and ritonavir was successfully developed. Coadministration of ritonavir resulted in increased plasma concentrations of docetaxel after administration of the oral formulations of ModraDoc. Furthermore, the oral ModraDoc formulations showed lower variability in plasma concentrations between and within patients compared to the drinking solution. Comparable exposure could be reached with the oral ModraDoc formulations compared to IV administration. |
| doi_str_mv | 10.1002/jcph.1532 |
| format | Article |
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G. Coen ; Weger, Vincent A. ; Nuijen, Bastiaan ; Schellens, Jan H. M. ; Beijnen, Jos H. ; Huitema, Alwin D. R.</creator><creatorcontrib>Yu, Huixin ; Janssen, Julie M. ; Sawicki, Emilia ; Hasselt, J. G. Coen ; Weger, Vincent A. ; Nuijen, Bastiaan ; Schellens, Jan H. M. ; Beijnen, Jos H. ; Huitema, Alwin D. R.</creatorcontrib><description>Oral administration of docetaxel is an attractive alternative for conventional intravenous (IV) administration. The low bioavailability of docetaxel, however, hinders the application of oral docetaxel in the clinic. The aim of the current study was to develop a population pharmacokinetic (PK) model for docetaxel and ritonavir based on the phase 1 studies and to support drug development of this combination treatment. PK data were collected from 191 patients who received IV docetaxel and different oral docetaxel formulations (drinking solution, ModraDoc001 capsule, and ModraDoc006 tablet) coadministered with ritonavir. A PK model was first developed for ritonavir. Subsequently, a semiphysiological PK model was developed for docetaxel, which incorporated the inhibition of docetaxel metabolism by ritonavir. The uninhibited intrinsic clearance of docetaxel was estimated based on data on IV docetaxel as 1980 L/h (relative standard error, 11%). Ritonavir coadministration extensively inhibited the hepatic metabolism of docetaxel to 9.3%, which resulted in up to 12‐fold higher docetaxel plasma concentrations compared to oral docetaxel coadministered without ritonavir. In conclusion, a semiphysiological PK model for docetaxel and ritonavir was successfully developed. Coadministration of ritonavir resulted in increased plasma concentrations of docetaxel after administration of the oral formulations of ModraDoc. Furthermore, the oral ModraDoc formulations showed lower variability in plasma concentrations between and within patients compared to the drinking solution. Comparable exposure could be reached with the oral ModraDoc formulations compared to IV administration.</description><identifier>ISSN: 0091-2700</identifier><identifier>EISSN: 1552-4604</identifier><identifier>DOI: 10.1002/jcph.1532</identifier><identifier>PMID: 31595980</identifier><language>eng</language><publisher>England: American College of Clinical Pharmacology</publisher><subject>Administration, Oral ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - blood ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - radiation effects ; Antineoplastic Combined Chemotherapy Protocols - administration & dosage ; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics ; Antiretroviral drugs ; Antiviral drugs ; Bioavailability ; Biological Availability ; Clinical Trials, Phase I as Topic ; Computer Simulation ; Cytochrome P-450 CYP3A Inhibitors - administration & dosage ; Cytochrome P-450 CYP3A Inhibitors - pharmacokinetics ; docetaxel ; Docetaxel - administration & dosage ; Docetaxel - blood ; Docetaxel - pharmacokinetics ; Dosage Forms ; Drug Administration Schedule ; Drug development ; Humans ; Infusions, Intravenous ; Intravenous administration ; Metabolism ; Models, Biological ; ModraDoc ; Neoplasms - drug therapy ; oral ; Oral administration ; Patients ; Pharmacokinetics ; population PK ; Ritonavir ; Ritonavir - administration & dosage ; Ritonavir - pharmacokinetics ; Ritonavir - poisoning ; Software</subject><ispartof>Journal of clinical pharmacology, 2020-03, Vol.60 (3), p.340-350</ispartof><rights>2019, The American College of Clinical Pharmacology</rights><rights>2020 American College of Clinical Pharmacology</rights><rights>2019 American College of Clinical Pharmacology</rights><rights>2019, The American College of Clinical Pharmacology.</rights><rights>2020, The American College of Clinical Pharmacology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4712-8c0d7c38e87575db1fd40365547160503f2d9ed0f0420463731ad50c65cd3df3</citedby><cites>FETCH-LOGICAL-c4712-8c0d7c38e87575db1fd40365547160503f2d9ed0f0420463731ad50c65cd3df3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjcph.1532$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjcph.1532$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31595980$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yu, Huixin</creatorcontrib><creatorcontrib>Janssen, Julie M.</creatorcontrib><creatorcontrib>Sawicki, Emilia</creatorcontrib><creatorcontrib>Hasselt, J. G. Coen</creatorcontrib><creatorcontrib>Weger, Vincent A.</creatorcontrib><creatorcontrib>Nuijen, Bastiaan</creatorcontrib><creatorcontrib>Schellens, Jan H. M.</creatorcontrib><creatorcontrib>Beijnen, Jos H.</creatorcontrib><creatorcontrib>Huitema, Alwin D. R.</creatorcontrib><title>A Population Pharmacokinetic Model of Oral Docetaxel Coadministered With Ritonavir to Support Early Clinical Development</title><title>Journal of clinical pharmacology</title><addtitle>J Clin Pharmacol</addtitle><description>Oral administration of docetaxel is an attractive alternative for conventional intravenous (IV) administration. The low bioavailability of docetaxel, however, hinders the application of oral docetaxel in the clinic. The aim of the current study was to develop a population pharmacokinetic (PK) model for docetaxel and ritonavir based on the phase 1 studies and to support drug development of this combination treatment. PK data were collected from 191 patients who received IV docetaxel and different oral docetaxel formulations (drinking solution, ModraDoc001 capsule, and ModraDoc006 tablet) coadministered with ritonavir. A PK model was first developed for ritonavir. Subsequently, a semiphysiological PK model was developed for docetaxel, which incorporated the inhibition of docetaxel metabolism by ritonavir. The uninhibited intrinsic clearance of docetaxel was estimated based on data on IV docetaxel as 1980 L/h (relative standard error, 11%). Ritonavir coadministration extensively inhibited the hepatic metabolism of docetaxel to 9.3%, which resulted in up to 12‐fold higher docetaxel plasma concentrations compared to oral docetaxel coadministered without ritonavir. In conclusion, a semiphysiological PK model for docetaxel and ritonavir was successfully developed. Coadministration of ritonavir resulted in increased plasma concentrations of docetaxel after administration of the oral formulations of ModraDoc. Furthermore, the oral ModraDoc formulations showed lower variability in plasma concentrations between and within patients compared to the drinking solution. Comparable exposure could be reached with the oral ModraDoc formulations compared to IV administration.</description><subject>Administration, Oral</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - blood</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - radiation effects</subject><subject>Antineoplastic Combined Chemotherapy Protocols - administration & dosage</subject><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics</subject><subject>Antiretroviral drugs</subject><subject>Antiviral drugs</subject><subject>Bioavailability</subject><subject>Biological Availability</subject><subject>Clinical Trials, Phase I as Topic</subject><subject>Computer Simulation</subject><subject>Cytochrome P-450 CYP3A Inhibitors - administration & dosage</subject><subject>Cytochrome P-450 CYP3A Inhibitors - pharmacokinetics</subject><subject>docetaxel</subject><subject>Docetaxel - administration & dosage</subject><subject>Docetaxel - blood</subject><subject>Docetaxel - pharmacokinetics</subject><subject>Dosage Forms</subject><subject>Drug Administration Schedule</subject><subject>Drug development</subject><subject>Humans</subject><subject>Infusions, Intravenous</subject><subject>Intravenous administration</subject><subject>Metabolism</subject><subject>Models, Biological</subject><subject>ModraDoc</subject><subject>Neoplasms - drug therapy</subject><subject>oral</subject><subject>Oral administration</subject><subject>Patients</subject><subject>Pharmacokinetics</subject><subject>population PK</subject><subject>Ritonavir</subject><subject>Ritonavir - administration & dosage</subject><subject>Ritonavir - pharmacokinetics</subject><subject>Ritonavir - poisoning</subject><subject>Software</subject><issn>0091-2700</issn><issn>1552-4604</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU9vFSEUxYnR2Gd14RcwJG7qYtoLDPNn2Yyt1bTpizZxOaHAZHhlhhGYtu_by_ieLoyVDeHyu4fLOQi9JXBMAOjJRk79MeGMPkMrwjnN8gLy52gFUJOMlgAH6FUIGwBS5Jy8RAeM8JrXFazQ4yleu2m2Iho34nUv_CCkuzOjjkbiK6e0xa7D115Y_NFJHcVjqjROqMGMJkTttcLfTezxVxPdKO6Nx9Hhb_M0OR_xmfB2ixubWLko6Htt3TToMb5GLzphg36z3w_RzfnZTXORXV5_-tycXmYyLwnNKgmqlKzSVclLrm5Jp3JgBefptgAOrKOq1go6yCnkBSsZEYqDLLhUTHXsEB3tZCfvfsw6xHYwQWprxajdHFrKgNFkTFkn9P1f6MbNfkzDJYpDVReE0UR92FHSuxC87trJm0H4bUugXdJolzTaJY3EvtsrzreDVn_I3_YnINsBD84mK8OdnR-0b3stbOz_KZj_h4e08pR2RiF9iaVTtpSq1HaybzNWb58euP3SrC9-PfQTqLOy9Q</recordid><startdate>202003</startdate><enddate>202003</enddate><creator>Yu, Huixin</creator><creator>Janssen, Julie M.</creator><creator>Sawicki, Emilia</creator><creator>Hasselt, J. 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G. Coen</au><au>Weger, Vincent A.</au><au>Nuijen, Bastiaan</au><au>Schellens, Jan H. M.</au><au>Beijnen, Jos H.</au><au>Huitema, Alwin D. R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Population Pharmacokinetic Model of Oral Docetaxel Coadministered With Ritonavir to Support Early Clinical Development</atitle><jtitle>Journal of clinical pharmacology</jtitle><addtitle>J Clin Pharmacol</addtitle><date>2020-03</date><risdate>2020</risdate><volume>60</volume><issue>3</issue><spage>340</spage><epage>350</epage><pages>340-350</pages><issn>0091-2700</issn><eissn>1552-4604</eissn><abstract>Oral administration of docetaxel is an attractive alternative for conventional intravenous (IV) administration. The low bioavailability of docetaxel, however, hinders the application of oral docetaxel in the clinic. 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In conclusion, a semiphysiological PK model for docetaxel and ritonavir was successfully developed. Coadministration of ritonavir resulted in increased plasma concentrations of docetaxel after administration of the oral formulations of ModraDoc. Furthermore, the oral ModraDoc formulations showed lower variability in plasma concentrations between and within patients compared to the drinking solution. Comparable exposure could be reached with the oral ModraDoc formulations compared to IV administration.</abstract><cop>England</cop><pub>American College of Clinical Pharmacology</pub><pmid>31595980</pmid><doi>10.1002/jcph.1532</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Access via Wiley Online Library |
| subjects | Administration, Oral Antineoplastic Agents - administration & dosage Antineoplastic Agents - blood Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - radiation effects Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics Antiretroviral drugs Antiviral drugs Bioavailability Biological Availability Clinical Trials, Phase I as Topic Computer Simulation Cytochrome P-450 CYP3A Inhibitors - administration & dosage Cytochrome P-450 CYP3A Inhibitors - pharmacokinetics docetaxel Docetaxel - administration & dosage Docetaxel - blood Docetaxel - pharmacokinetics Dosage Forms Drug Administration Schedule Drug development Humans Infusions, Intravenous Intravenous administration Metabolism Models, Biological ModraDoc Neoplasms - drug therapy oral Oral administration Patients Pharmacokinetics population PK Ritonavir Ritonavir - administration & dosage Ritonavir - pharmacokinetics Ritonavir - poisoning Software |
| title | A Population Pharmacokinetic Model of Oral Docetaxel Coadministered With Ritonavir to Support Early Clinical Development |
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