Population exposure-efficacy and exposure-safety analyses for rucaparib in patients with recurrent ovarian carcinoma from Study 10 and ARIEL2
To evaluate correlations between rucaparib exposure and selected efficacy and safety endpoints in patients with recurrent ovarian carcinoma using pooled data from Study 10 and ARIEL2. Efficacy analyses were limited to patients with carcinomas harboring a deleterious BRCA1 or BRCA2 mutation who had r...
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| Veröffentlicht in: | Gynecologic oncology 2021-06, Vol.161 (3), p.668-675 |
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| creator | Konecny, Gottfried E. Oza, Amit M. Tinker, Anna V. Oaknin, Ana Shapira-Frommer, Ronnie Ray-Coquard, Isabelle Aghajanian, Carol Coleman, Robert L. O'Malley, David M. Leary, Alexandra Chen, Lee-may Provencher, Diane Ma, Ling Brenton, James D. Castro, Cesar Green, Michelle Simmons, Andrew D. Beltman, Jeri Harding, Thomas Lin, Kevin K. Goble, Sandra Maloney, Lara Kristeleit, Rebecca S. McNeish, Iain A. Swisher, Elizabeth M. Xiao, Jim J. |
| description | To evaluate correlations between rucaparib exposure and selected efficacy and safety endpoints in patients with recurrent ovarian carcinoma using pooled data from Study 10 and ARIEL2.
Efficacy analyses were limited to patients with carcinomas harboring a deleterious BRCA1 or BRCA2 mutation who had received ≥2 prior lines of chemotherapy. Safety was evaluated in all patients who received ≥1 rucaparib dose. Steady-state daily area under the concentration-time curve (AUCss) and maximum concentration (Cmax,ss) for rucaparib were calculated for each patient and averaged by actual dose received over time (AUCavg,ss and Cmax,avg,ss) using a previously developed population pharmacokinetic model.
Rucaparib exposure was dose-proportional and not associated with baseline patient weight. In the exposure-efficacy analyses (n = 121), AUCavg,ss was positively associated with independent radiology review-assessed RECIST response in the subgroup of patients with platinum-sensitive recurrent disease (n = 75, p = 0.017). In the exposure-safety analyses (n = 393, 40 mg once daily to 840 mg twice daily [BID] starting doses), most patients received a 600 mg BID rucaparib starting dose, with 27% and 21% receiving 1 or ≥2 dose reductions, respectively. Cmax,ss was significantly correlated with grade ≥2 serum creatinine increase, grade ≥3 alanine transaminase/aspartate transaminase increase, platelet decrease, fatigue/asthenia, and maximal hemoglobin decrease (p |
| doi_str_mv | 10.1016/j.ygyno.2021.03.015 |
| format | Article |
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Efficacy analyses were limited to patients with carcinomas harboring a deleterious BRCA1 or BRCA2 mutation who had received ≥2 prior lines of chemotherapy. Safety was evaluated in all patients who received ≥1 rucaparib dose. Steady-state daily area under the concentration-time curve (AUCss) and maximum concentration (Cmax,ss) for rucaparib were calculated for each patient and averaged by actual dose received over time (AUCavg,ss and Cmax,avg,ss) using a previously developed population pharmacokinetic model.
Rucaparib exposure was dose-proportional and not associated with baseline patient weight. In the exposure-efficacy analyses (n = 121), AUCavg,ss was positively associated with independent radiology review-assessed RECIST response in the subgroup of patients with platinum-sensitive recurrent disease (n = 75, p = 0.017). In the exposure-safety analyses (n = 393, 40 mg once daily to 840 mg twice daily [BID] starting doses), most patients received a 600 mg BID rucaparib starting dose, with 27% and 21% receiving 1 or ≥2 dose reductions, respectively. Cmax,ss was significantly correlated with grade ≥2 serum creatinine increase, grade ≥3 alanine transaminase/aspartate transaminase increase, platelet decrease, fatigue/asthenia, and maximal hemoglobin decrease (p < 0.05).
The exposure-response analyses provide support for the approved starting dose of rucaparib 600 mg BID for maximum clinical benefit with subsequent dose modification only following the occurrence of a treatment-emergent adverse event in patients with BRCA-mutated recurrent ovarian carcinoma.
•Rucaparib exposure and efficacy/safety relationship were studied using pooled Study 10 and ARIEL2 data.•Rucaparib exposure and response were positively correlated in patients with platinum-sensitive recurrent ovarian carcinoma.•We found no significant association between the model-predicted rucaparib exposure and baseline body weight.•Our analyses support starting rucaparib 600 mg twice daily with subsequent dose modification based on adverse events.</description><identifier>ISSN: 0090-8258</identifier><identifier>EISSN: 1095-6859</identifier><identifier>DOI: 10.1016/j.ygyno.2021.03.015</identifier><identifier>PMID: 33752918</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Administration, Oral ; Aged ; Area Under Curve ; BRCA1 Protein ; Carcinoma, Ovarian Epithelial - drug therapy ; Dose-Response Relationship, Drug ; Efficacy ; Exposure ; Female ; Humans ; Indoles - administration & dosage ; Indoles - pharmacokinetics ; Middle Aged ; Neoplasm Recurrence, Local - drug therapy ; Ovarian carcinoma ; Ovarian Neoplasms - drug therapy ; Pharmacokinetics ; Platinum ; Rucaparib ; Safety</subject><ispartof>Gynecologic oncology, 2021-06, Vol.161 (3), p.668-675</ispartof><rights>2021</rights><rights>Copyright © 2021. Published by Elsevier Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c459t-d3eb6c1041b16fef55849b527a3b28db4e984d9bb592334646e6c8e29249bb133</citedby><cites>FETCH-LOGICAL-c459t-d3eb6c1041b16fef55849b527a3b28db4e984d9bb592334646e6c8e29249bb133</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0090825821002353$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33752918$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Konecny, Gottfried E.</creatorcontrib><creatorcontrib>Oza, Amit M.</creatorcontrib><creatorcontrib>Tinker, Anna V.</creatorcontrib><creatorcontrib>Oaknin, Ana</creatorcontrib><creatorcontrib>Shapira-Frommer, Ronnie</creatorcontrib><creatorcontrib>Ray-Coquard, Isabelle</creatorcontrib><creatorcontrib>Aghajanian, Carol</creatorcontrib><creatorcontrib>Coleman, Robert L.</creatorcontrib><creatorcontrib>O'Malley, David M.</creatorcontrib><creatorcontrib>Leary, Alexandra</creatorcontrib><creatorcontrib>Chen, Lee-may</creatorcontrib><creatorcontrib>Provencher, Diane</creatorcontrib><creatorcontrib>Ma, Ling</creatorcontrib><creatorcontrib>Brenton, James D.</creatorcontrib><creatorcontrib>Castro, Cesar</creatorcontrib><creatorcontrib>Green, Michelle</creatorcontrib><creatorcontrib>Simmons, Andrew D.</creatorcontrib><creatorcontrib>Beltman, Jeri</creatorcontrib><creatorcontrib>Harding, Thomas</creatorcontrib><creatorcontrib>Lin, Kevin K.</creatorcontrib><creatorcontrib>Goble, Sandra</creatorcontrib><creatorcontrib>Maloney, Lara</creatorcontrib><creatorcontrib>Kristeleit, Rebecca S.</creatorcontrib><creatorcontrib>McNeish, Iain A.</creatorcontrib><creatorcontrib>Swisher, Elizabeth M.</creatorcontrib><creatorcontrib>Xiao, Jim J.</creatorcontrib><title>Population exposure-efficacy and exposure-safety analyses for rucaparib in patients with recurrent ovarian carcinoma from Study 10 and ARIEL2</title><title>Gynecologic oncology</title><addtitle>Gynecol Oncol</addtitle><description>To evaluate correlations between rucaparib exposure and selected efficacy and safety endpoints in patients with recurrent ovarian carcinoma using pooled data from Study 10 and ARIEL2.
Efficacy analyses were limited to patients with carcinomas harboring a deleterious BRCA1 or BRCA2 mutation who had received ≥2 prior lines of chemotherapy. Safety was evaluated in all patients who received ≥1 rucaparib dose. Steady-state daily area under the concentration-time curve (AUCss) and maximum concentration (Cmax,ss) for rucaparib were calculated for each patient and averaged by actual dose received over time (AUCavg,ss and Cmax,avg,ss) using a previously developed population pharmacokinetic model.
Rucaparib exposure was dose-proportional and not associated with baseline patient weight. In the exposure-efficacy analyses (n = 121), AUCavg,ss was positively associated with independent radiology review-assessed RECIST response in the subgroup of patients with platinum-sensitive recurrent disease (n = 75, p = 0.017). In the exposure-safety analyses (n = 393, 40 mg once daily to 840 mg twice daily [BID] starting doses), most patients received a 600 mg BID rucaparib starting dose, with 27% and 21% receiving 1 or ≥2 dose reductions, respectively. Cmax,ss was significantly correlated with grade ≥2 serum creatinine increase, grade ≥3 alanine transaminase/aspartate transaminase increase, platelet decrease, fatigue/asthenia, and maximal hemoglobin decrease (p < 0.05).
The exposure-response analyses provide support for the approved starting dose of rucaparib 600 mg BID for maximum clinical benefit with subsequent dose modification only following the occurrence of a treatment-emergent adverse event in patients with BRCA-mutated recurrent ovarian carcinoma.
•Rucaparib exposure and efficacy/safety relationship were studied using pooled Study 10 and ARIEL2 data.•Rucaparib exposure and response were positively correlated in patients with platinum-sensitive recurrent ovarian carcinoma.•We found no significant association between the model-predicted rucaparib exposure and baseline body weight.•Our analyses support starting rucaparib 600 mg twice daily with subsequent dose modification based on adverse events.</description><subject>Administration, Oral</subject><subject>Aged</subject><subject>Area Under Curve</subject><subject>BRCA1 Protein</subject><subject>Carcinoma, Ovarian Epithelial - drug therapy</subject><subject>Dose-Response Relationship, Drug</subject><subject>Efficacy</subject><subject>Exposure</subject><subject>Female</subject><subject>Humans</subject><subject>Indoles - administration & dosage</subject><subject>Indoles - pharmacokinetics</subject><subject>Middle Aged</subject><subject>Neoplasm Recurrence, Local - drug therapy</subject><subject>Ovarian carcinoma</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Pharmacokinetics</subject><subject>Platinum</subject><subject>Rucaparib</subject><subject>Safety</subject><issn>0090-8258</issn><issn>1095-6859</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9Udtu1DAQtRCILoUvQEL-gYSxHWfjB5CqqkCllUBcni3bGbde7caRnWzJR_DPeLtQ4IWn0YzPZTyHkJcMagasfb2tl5tliDUHzmoQNTD5iKwYKFm1nVSPyQpAQdVx2Z2RZzlvAUAA40_JmRBryRXrVuTHpzjOOzOFOFD8PsY8J6zQ--CMW6gZ-j_TbDxOx5nZLRkz9THRNDszmhQsDQMdiwwOU6Z3YbqlCd2cUulpPBSEGagzyYUh7g31Ke7pl2nuF8rg3uXi8_XVhj8nT7zZZXzxq56Tb--uvl5-qDYf319fXmwq10g1Vb1A2zoGDbOs9eil7BplJV8bYXnX2wZV1_TKWqm4EE3btNi6DrniBWaZEOfk7Ul3nO0ee1e2TGanxxT2Ji06mqD_fRnCrb6JB62kkK1YFwFxEnAp5pzQP3AZ6GM6eqvv09HHdDQIXdIprFd_2z5wfsdRAG9OACyfPwRMOrtyUod9KOecdB_Dfw1-AoZ4pkI</recordid><startdate>20210601</startdate><enddate>20210601</enddate><creator>Konecny, Gottfried E.</creator><creator>Oza, Amit M.</creator><creator>Tinker, Anna V.</creator><creator>Oaknin, Ana</creator><creator>Shapira-Frommer, Ronnie</creator><creator>Ray-Coquard, Isabelle</creator><creator>Aghajanian, Carol</creator><creator>Coleman, Robert L.</creator><creator>O'Malley, David M.</creator><creator>Leary, Alexandra</creator><creator>Chen, Lee-may</creator><creator>Provencher, Diane</creator><creator>Ma, Ling</creator><creator>Brenton, James D.</creator><creator>Castro, Cesar</creator><creator>Green, Michelle</creator><creator>Simmons, Andrew D.</creator><creator>Beltman, Jeri</creator><creator>Harding, Thomas</creator><creator>Lin, Kevin K.</creator><creator>Goble, Sandra</creator><creator>Maloney, Lara</creator><creator>Kristeleit, Rebecca S.</creator><creator>McNeish, Iain A.</creator><creator>Swisher, Elizabeth M.</creator><creator>Xiao, Jim J.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</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>5PM</scope></search><sort><creationdate>20210601</creationdate><title>Population exposure-efficacy and exposure-safety analyses for rucaparib in patients with recurrent ovarian carcinoma from Study 10 and ARIEL2</title><author>Konecny, Gottfried E. ; Oza, Amit M. ; Tinker, Anna V. ; Oaknin, Ana ; Shapira-Frommer, Ronnie ; Ray-Coquard, Isabelle ; Aghajanian, Carol ; Coleman, Robert L. ; O'Malley, David M. ; Leary, Alexandra ; Chen, Lee-may ; Provencher, Diane ; Ma, Ling ; Brenton, James D. ; Castro, Cesar ; Green, Michelle ; Simmons, Andrew D. ; Beltman, Jeri ; Harding, Thomas ; Lin, Kevin K. ; Goble, Sandra ; Maloney, Lara ; Kristeleit, Rebecca S. ; McNeish, Iain A. ; Swisher, Elizabeth M. ; Xiao, Jim J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c459t-d3eb6c1041b16fef55849b527a3b28db4e984d9bb592334646e6c8e29249bb133</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Administration, Oral</topic><topic>Aged</topic><topic>Area Under Curve</topic><topic>BRCA1 Protein</topic><topic>Carcinoma, Ovarian Epithelial - drug therapy</topic><topic>Dose-Response Relationship, Drug</topic><topic>Efficacy</topic><topic>Exposure</topic><topic>Female</topic><topic>Humans</topic><topic>Indoles - administration & dosage</topic><topic>Indoles - pharmacokinetics</topic><topic>Middle Aged</topic><topic>Neoplasm Recurrence, Local - drug therapy</topic><topic>Ovarian carcinoma</topic><topic>Ovarian Neoplasms - drug therapy</topic><topic>Pharmacokinetics</topic><topic>Platinum</topic><topic>Rucaparib</topic><topic>Safety</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Konecny, Gottfried E.</creatorcontrib><creatorcontrib>Oza, Amit M.</creatorcontrib><creatorcontrib>Tinker, Anna V.</creatorcontrib><creatorcontrib>Oaknin, Ana</creatorcontrib><creatorcontrib>Shapira-Frommer, Ronnie</creatorcontrib><creatorcontrib>Ray-Coquard, Isabelle</creatorcontrib><creatorcontrib>Aghajanian, Carol</creatorcontrib><creatorcontrib>Coleman, Robert L.</creatorcontrib><creatorcontrib>O'Malley, David M.</creatorcontrib><creatorcontrib>Leary, Alexandra</creatorcontrib><creatorcontrib>Chen, Lee-may</creatorcontrib><creatorcontrib>Provencher, Diane</creatorcontrib><creatorcontrib>Ma, Ling</creatorcontrib><creatorcontrib>Brenton, James D.</creatorcontrib><creatorcontrib>Castro, Cesar</creatorcontrib><creatorcontrib>Green, Michelle</creatorcontrib><creatorcontrib>Simmons, Andrew D.</creatorcontrib><creatorcontrib>Beltman, Jeri</creatorcontrib><creatorcontrib>Harding, Thomas</creatorcontrib><creatorcontrib>Lin, Kevin K.</creatorcontrib><creatorcontrib>Goble, Sandra</creatorcontrib><creatorcontrib>Maloney, Lara</creatorcontrib><creatorcontrib>Kristeleit, Rebecca S.</creatorcontrib><creatorcontrib>McNeish, Iain A.</creatorcontrib><creatorcontrib>Swisher, Elizabeth M.</creatorcontrib><creatorcontrib>Xiao, Jim J.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Gynecologic oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Konecny, Gottfried E.</au><au>Oza, Amit M.</au><au>Tinker, Anna V.</au><au>Oaknin, Ana</au><au>Shapira-Frommer, Ronnie</au><au>Ray-Coquard, Isabelle</au><au>Aghajanian, Carol</au><au>Coleman, Robert L.</au><au>O'Malley, David M.</au><au>Leary, Alexandra</au><au>Chen, Lee-may</au><au>Provencher, Diane</au><au>Ma, Ling</au><au>Brenton, James D.</au><au>Castro, Cesar</au><au>Green, Michelle</au><au>Simmons, Andrew D.</au><au>Beltman, Jeri</au><au>Harding, Thomas</au><au>Lin, Kevin K.</au><au>Goble, Sandra</au><au>Maloney, Lara</au><au>Kristeleit, Rebecca S.</au><au>McNeish, Iain A.</au><au>Swisher, Elizabeth M.</au><au>Xiao, Jim J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Population exposure-efficacy and exposure-safety analyses for rucaparib in patients with recurrent ovarian carcinoma from Study 10 and ARIEL2</atitle><jtitle>Gynecologic oncology</jtitle><addtitle>Gynecol Oncol</addtitle><date>2021-06-01</date><risdate>2021</risdate><volume>161</volume><issue>3</issue><spage>668</spage><epage>675</epage><pages>668-675</pages><issn>0090-8258</issn><eissn>1095-6859</eissn><abstract>To evaluate correlations between rucaparib exposure and selected efficacy and safety endpoints in patients with recurrent ovarian carcinoma using pooled data from Study 10 and ARIEL2.
Efficacy analyses were limited to patients with carcinomas harboring a deleterious BRCA1 or BRCA2 mutation who had received ≥2 prior lines of chemotherapy. Safety was evaluated in all patients who received ≥1 rucaparib dose. Steady-state daily area under the concentration-time curve (AUCss) and maximum concentration (Cmax,ss) for rucaparib were calculated for each patient and averaged by actual dose received over time (AUCavg,ss and Cmax,avg,ss) using a previously developed population pharmacokinetic model.
Rucaparib exposure was dose-proportional and not associated with baseline patient weight. In the exposure-efficacy analyses (n = 121), AUCavg,ss was positively associated with independent radiology review-assessed RECIST response in the subgroup of patients with platinum-sensitive recurrent disease (n = 75, p = 0.017). In the exposure-safety analyses (n = 393, 40 mg once daily to 840 mg twice daily [BID] starting doses), most patients received a 600 mg BID rucaparib starting dose, with 27% and 21% receiving 1 or ≥2 dose reductions, respectively. Cmax,ss was significantly correlated with grade ≥2 serum creatinine increase, grade ≥3 alanine transaminase/aspartate transaminase increase, platelet decrease, fatigue/asthenia, and maximal hemoglobin decrease (p < 0.05).
The exposure-response analyses provide support for the approved starting dose of rucaparib 600 mg BID for maximum clinical benefit with subsequent dose modification only following the occurrence of a treatment-emergent adverse event in patients with BRCA-mutated recurrent ovarian carcinoma.
•Rucaparib exposure and efficacy/safety relationship were studied using pooled Study 10 and ARIEL2 data.•Rucaparib exposure and response were positively correlated in patients with platinum-sensitive recurrent ovarian carcinoma.•We found no significant association between the model-predicted rucaparib exposure and baseline body weight.•Our analyses support starting rucaparib 600 mg twice daily with subsequent dose modification based on adverse events.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>33752918</pmid><doi>10.1016/j.ygyno.2021.03.015</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0090-8258 |
| ispartof | Gynecologic oncology, 2021-06, Vol.161 (3), p.668-675 |
| issn | 0090-8258 1095-6859 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9535637 |
| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | Administration, Oral Aged Area Under Curve BRCA1 Protein Carcinoma, Ovarian Epithelial - drug therapy Dose-Response Relationship, Drug Efficacy Exposure Female Humans Indoles - administration & dosage Indoles - pharmacokinetics Middle Aged Neoplasm Recurrence, Local - drug therapy Ovarian carcinoma Ovarian Neoplasms - drug therapy Pharmacokinetics Platinum Rucaparib Safety |
| title | Population exposure-efficacy and exposure-safety analyses for rucaparib in patients with recurrent ovarian carcinoma from Study 10 and ARIEL2 |
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