A Phase I Study to Evaluate the Pharmacokinetics and Safety of Lorlatinib in Adults with Mild, Moderate, and Severe Renal Impairment
Background and Objectives Lorlatinib is approved (100 mg once daily [QD]) for the treatment of patients with anaplastic lymphoma kinase - (ALK) positive metastatic non-small cell lung cancer. This study evaluated the impact of varying degrees of renal impairment on the safety and pharmacokinetics of...
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| Veröffentlicht in: | European journal of drug metabolism and pharmacokinetics 2022-03, Vol.47 (2), p.235-245 |
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| creator | Lin, Swan Gong, Jason Canas, George C. Winkle, Peter Pelletier, Kathleen LaBadie, Robert R. Ginman, Katherine Pithavala, Yazdi K. |
| description | Background and Objectives
Lorlatinib is approved (100 mg once daily [QD]) for the treatment of patients with
anaplastic lymphoma kinase
- (ALK) positive metastatic non-small cell lung cancer. This study evaluated the impact of varying degrees of renal impairment on the safety and pharmacokinetics of lorlatinib.
Methods
Participants were assigned to mild, moderate, and severe renal impairment groups and to a matching normal renal function group based on absolute estimated glomerular filtration rate (eGFR, based on the Modification of Diet in Renal Disease equation and adjusted for body surface area [BSA]) and were evaluated for pharmacokinetics and safety.
Results
A total of 29 participants (5 with severe renal impairment; 8 each with moderate and mild impairment and normal renal function) were enrolled and received a single dose of lorlatinib 100 mg. One of the participants with severe renal impairment had end-stage renal disease with a baseline absolute eGFR of 10.3 mL/min. No serious adverse events (AEs) were reported. Eighteen AEs, all mild or moderate in severity, were reported by 12 participants (5, 2, 4, and 1 in the normal, mild, moderate, and severe groups, respectively). Area under the plasma concentration–time profile from time zero extrapolated to infinity (AUC
inf
) for lorlatinib was increased by 4%, 19%, and 41% in the mild, moderate, and severe renal impairment groups, respectively, compared with the normal renal function cohort.
Conclusion
Lorlatinib 100 mg was well tolerated. As participants with mild and moderate renal impairment did not experience clinically meaningful increases in lorlatinib exposure, no lorlatinib dose adjustment is recommended in these populations. Patients with severe renal impairment are recommended to reduce the starting dose of lorlatinib from 100 mg QD to 75 mg QD.
Clinicaltrials.gov identifier
NCT03542305 (available May 31, 2018 on clinicaltrials.gov) |
| doi_str_mv | 10.1007/s13318-021-00747-4 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8917008</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2619212089</sourcerecordid><originalsourceid>FETCH-LOGICAL-c446t-3e435e451b346d9eeb7f2516758c9ad2c84d5dad92e432ca7db8a9bcdcf0e6c83</originalsourceid><addsrcrecordid>eNp9kc1u1DAUhS0EoqO2L8ACecmiof6JE2eDNKpaGGmqIgpry7FvOi5JPNjOoNn3wetpSgUbvLGs851zr3wQekfJR0pIfR4p51QWhNEiP8u6KF-hBaOkLgiV5DVaEF7Lom6q6gidxnhP8uGyEaJ6i464yJAQfIEelvjrRkfAK3ybJrvHyePLne4nnQCnDRzUMGjjf7oRkjMR69HiW91B2mPf4bUPvU5udC12I17aqU8R_3Zpg69db8_wtbcQctbZ7IMdBMDfYNQ9Xg1b7cIAYzpBbzrdRzh9vo_Rj6vL7xdfivXN59XFcl2YsqxSwaHkAkpBW15WtgFo644JWtVCmkZbZmRphdW2YRlkRte2lbppjTUdgcpIfow-zbnbqR3Amjw66F5tgxt02CuvnfpXGd1G3fmdkg2tCTkEfHgOCP7XBDGpwUUDfa9H8FNUrKINo4zIJqNsRk3wMQboXsZQog4NqrlBlRtUTw2qMpve_73gi-VPXxngMxCzNN5BUPd-Cvk34_9iHwF1Tai_</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2619212089</pqid></control><display><type>article</type><title>A Phase I Study to Evaluate the Pharmacokinetics and Safety of Lorlatinib in Adults with Mild, Moderate, and Severe Renal Impairment</title><source>MEDLINE</source><source>SpringerLink Journals - AutoHoldings</source><creator>Lin, Swan ; Gong, Jason ; Canas, George C. ; Winkle, Peter ; Pelletier, Kathleen ; LaBadie, Robert R. ; Ginman, Katherine ; Pithavala, Yazdi K.</creator><creatorcontrib>Lin, Swan ; Gong, Jason ; Canas, George C. ; Winkle, Peter ; Pelletier, Kathleen ; LaBadie, Robert R. ; Ginman, Katherine ; Pithavala, Yazdi K.</creatorcontrib><description>Background and Objectives
Lorlatinib is approved (100 mg once daily [QD]) for the treatment of patients with
anaplastic lymphoma kinase
- (ALK) positive metastatic non-small cell lung cancer. This study evaluated the impact of varying degrees of renal impairment on the safety and pharmacokinetics of lorlatinib.
Methods
Participants were assigned to mild, moderate, and severe renal impairment groups and to a matching normal renal function group based on absolute estimated glomerular filtration rate (eGFR, based on the Modification of Diet in Renal Disease equation and adjusted for body surface area [BSA]) and were evaluated for pharmacokinetics and safety.
Results
A total of 29 participants (5 with severe renal impairment; 8 each with moderate and mild impairment and normal renal function) were enrolled and received a single dose of lorlatinib 100 mg. One of the participants with severe renal impairment had end-stage renal disease with a baseline absolute eGFR of 10.3 mL/min. No serious adverse events (AEs) were reported. Eighteen AEs, all mild or moderate in severity, were reported by 12 participants (5, 2, 4, and 1 in the normal, mild, moderate, and severe groups, respectively). Area under the plasma concentration–time profile from time zero extrapolated to infinity (AUC
inf
) for lorlatinib was increased by 4%, 19%, and 41% in the mild, moderate, and severe renal impairment groups, respectively, compared with the normal renal function cohort.
Conclusion
Lorlatinib 100 mg was well tolerated. As participants with mild and moderate renal impairment did not experience clinically meaningful increases in lorlatinib exposure, no lorlatinib dose adjustment is recommended in these populations. Patients with severe renal impairment are recommended to reduce the starting dose of lorlatinib from 100 mg QD to 75 mg QD.
Clinicaltrials.gov identifier
NCT03542305 (available May 31, 2018 on clinicaltrials.gov)</description><identifier>ISSN: 0378-7966</identifier><identifier>ISSN: 2107-0180</identifier><identifier>EISSN: 2107-0180</identifier><identifier>DOI: 10.1007/s13318-021-00747-4</identifier><identifier>PMID: 35018553</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Adult ; Aminopyridines - adverse effects ; Aminopyridines - pharmacokinetics ; Area Under Curve ; Biomedical and Life Sciences ; Biomedicine ; Carcinoma, Non-Small-Cell Lung - drug therapy ; Human Physiology ; Humans ; Lactams - adverse effects ; Lactams - pharmacokinetics ; Lung Neoplasms - drug therapy ; Medical Biochemistry ; NCT ; NCT03542305 ; Original ; Original Research Article ; Pharmaceutical Sciences/Technology ; Pharmacology/Toxicology ; Pharmacy ; Pyrazoles - adverse effects ; Pyrazoles - pharmacokinetics ; Renal Insufficiency - drug therapy</subject><ispartof>European journal of drug metabolism and pharmacokinetics, 2022-03, Vol.47 (2), p.235-245</ispartof><rights>The Author(s) 2022. corrected publication 2022</rights><rights>2022. The Author(s).</rights><rights>The Author(s) 2022, corrected publication 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c446t-3e435e451b346d9eeb7f2516758c9ad2c84d5dad92e432ca7db8a9bcdcf0e6c83</citedby><cites>FETCH-LOGICAL-c446t-3e435e451b346d9eeb7f2516758c9ad2c84d5dad92e432ca7db8a9bcdcf0e6c83</cites><orcidid>0000-0002-7705-9401</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s13318-021-00747-4$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s13318-021-00747-4$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,27923,27924,41487,42556,51318</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35018553$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lin, Swan</creatorcontrib><creatorcontrib>Gong, Jason</creatorcontrib><creatorcontrib>Canas, George C.</creatorcontrib><creatorcontrib>Winkle, Peter</creatorcontrib><creatorcontrib>Pelletier, Kathleen</creatorcontrib><creatorcontrib>LaBadie, Robert R.</creatorcontrib><creatorcontrib>Ginman, Katherine</creatorcontrib><creatorcontrib>Pithavala, Yazdi K.</creatorcontrib><title>A Phase I Study to Evaluate the Pharmacokinetics and Safety of Lorlatinib in Adults with Mild, Moderate, and Severe Renal Impairment</title><title>European journal of drug metabolism and pharmacokinetics</title><addtitle>Eur J Drug Metab Pharmacokinet</addtitle><addtitle>Eur J Drug Metab Pharmacokinet</addtitle><description>Background and Objectives
Lorlatinib is approved (100 mg once daily [QD]) for the treatment of patients with
anaplastic lymphoma kinase
- (ALK) positive metastatic non-small cell lung cancer. This study evaluated the impact of varying degrees of renal impairment on the safety and pharmacokinetics of lorlatinib.
Methods
Participants were assigned to mild, moderate, and severe renal impairment groups and to a matching normal renal function group based on absolute estimated glomerular filtration rate (eGFR, based on the Modification of Diet in Renal Disease equation and adjusted for body surface area [BSA]) and were evaluated for pharmacokinetics and safety.
Results
A total of 29 participants (5 with severe renal impairment; 8 each with moderate and mild impairment and normal renal function) were enrolled and received a single dose of lorlatinib 100 mg. One of the participants with severe renal impairment had end-stage renal disease with a baseline absolute eGFR of 10.3 mL/min. No serious adverse events (AEs) were reported. Eighteen AEs, all mild or moderate in severity, were reported by 12 participants (5, 2, 4, and 1 in the normal, mild, moderate, and severe groups, respectively). Area under the plasma concentration–time profile from time zero extrapolated to infinity (AUC
inf
) for lorlatinib was increased by 4%, 19%, and 41% in the mild, moderate, and severe renal impairment groups, respectively, compared with the normal renal function cohort.
Conclusion
Lorlatinib 100 mg was well tolerated. As participants with mild and moderate renal impairment did not experience clinically meaningful increases in lorlatinib exposure, no lorlatinib dose adjustment is recommended in these populations. Patients with severe renal impairment are recommended to reduce the starting dose of lorlatinib from 100 mg QD to 75 mg QD.
Clinicaltrials.gov identifier
NCT03542305 (available May 31, 2018 on clinicaltrials.gov)</description><subject>Adult</subject><subject>Aminopyridines - adverse effects</subject><subject>Aminopyridines - pharmacokinetics</subject><subject>Area Under Curve</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Carcinoma, Non-Small-Cell Lung - drug therapy</subject><subject>Human Physiology</subject><subject>Humans</subject><subject>Lactams - adverse effects</subject><subject>Lactams - pharmacokinetics</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Medical Biochemistry</subject><subject>NCT</subject><subject>NCT03542305</subject><subject>Original</subject><subject>Original Research Article</subject><subject>Pharmaceutical Sciences/Technology</subject><subject>Pharmacology/Toxicology</subject><subject>Pharmacy</subject><subject>Pyrazoles - adverse effects</subject><subject>Pyrazoles - pharmacokinetics</subject><subject>Renal Insufficiency - drug therapy</subject><issn>0378-7966</issn><issn>2107-0180</issn><issn>2107-0180</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><recordid>eNp9kc1u1DAUhS0EoqO2L8ACecmiof6JE2eDNKpaGGmqIgpry7FvOi5JPNjOoNn3wetpSgUbvLGs851zr3wQekfJR0pIfR4p51QWhNEiP8u6KF-hBaOkLgiV5DVaEF7Lom6q6gidxnhP8uGyEaJ6i464yJAQfIEelvjrRkfAK3ybJrvHyePLne4nnQCnDRzUMGjjf7oRkjMR69HiW91B2mPf4bUPvU5udC12I17aqU8R_3Zpg69db8_wtbcQctbZ7IMdBMDfYNQ9Xg1b7cIAYzpBbzrdRzh9vo_Rj6vL7xdfivXN59XFcl2YsqxSwaHkAkpBW15WtgFo644JWtVCmkZbZmRphdW2YRlkRte2lbppjTUdgcpIfow-zbnbqR3Amjw66F5tgxt02CuvnfpXGd1G3fmdkg2tCTkEfHgOCP7XBDGpwUUDfa9H8FNUrKINo4zIJqNsRk3wMQboXsZQog4NqrlBlRtUTw2qMpve_73gi-VPXxngMxCzNN5BUPd-Cvk34_9iHwF1Tai_</recordid><startdate>20220301</startdate><enddate>20220301</enddate><creator>Lin, Swan</creator><creator>Gong, Jason</creator><creator>Canas, George C.</creator><creator>Winkle, Peter</creator><creator>Pelletier, Kathleen</creator><creator>LaBadie, Robert R.</creator><creator>Ginman, Katherine</creator><creator>Pithavala, Yazdi K.</creator><general>Springer International Publishing</general><scope>C6C</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><orcidid>https://orcid.org/0000-0002-7705-9401</orcidid></search><sort><creationdate>20220301</creationdate><title>A Phase I Study to Evaluate the Pharmacokinetics and Safety of Lorlatinib in Adults with Mild, Moderate, and Severe Renal Impairment</title><author>Lin, Swan ; Gong, Jason ; Canas, George C. ; Winkle, Peter ; Pelletier, Kathleen ; LaBadie, Robert R. ; Ginman, Katherine ; Pithavala, Yazdi K.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c446t-3e435e451b346d9eeb7f2516758c9ad2c84d5dad92e432ca7db8a9bcdcf0e6c83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Adult</topic><topic>Aminopyridines - adverse effects</topic><topic>Aminopyridines - pharmacokinetics</topic><topic>Area Under Curve</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Carcinoma, Non-Small-Cell Lung - drug therapy</topic><topic>Human Physiology</topic><topic>Humans</topic><topic>Lactams - adverse effects</topic><topic>Lactams - pharmacokinetics</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Medical Biochemistry</topic><topic>NCT</topic><topic>NCT03542305</topic><topic>Original</topic><topic>Original Research Article</topic><topic>Pharmaceutical Sciences/Technology</topic><topic>Pharmacology/Toxicology</topic><topic>Pharmacy</topic><topic>Pyrazoles - adverse effects</topic><topic>Pyrazoles - pharmacokinetics</topic><topic>Renal Insufficiency - drug therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lin, Swan</creatorcontrib><creatorcontrib>Gong, Jason</creatorcontrib><creatorcontrib>Canas, George C.</creatorcontrib><creatorcontrib>Winkle, Peter</creatorcontrib><creatorcontrib>Pelletier, Kathleen</creatorcontrib><creatorcontrib>LaBadie, Robert R.</creatorcontrib><creatorcontrib>Ginman, Katherine</creatorcontrib><creatorcontrib>Pithavala, Yazdi K.</creatorcontrib><collection>SpringerOpen</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>European journal of drug metabolism and pharmacokinetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lin, Swan</au><au>Gong, Jason</au><au>Canas, George C.</au><au>Winkle, Peter</au><au>Pelletier, Kathleen</au><au>LaBadie, Robert R.</au><au>Ginman, Katherine</au><au>Pithavala, Yazdi K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Phase I Study to Evaluate the Pharmacokinetics and Safety of Lorlatinib in Adults with Mild, Moderate, and Severe Renal Impairment</atitle><jtitle>European journal of drug metabolism and pharmacokinetics</jtitle><stitle>Eur J Drug Metab Pharmacokinet</stitle><addtitle>Eur J Drug Metab Pharmacokinet</addtitle><date>2022-03-01</date><risdate>2022</risdate><volume>47</volume><issue>2</issue><spage>235</spage><epage>245</epage><pages>235-245</pages><issn>0378-7966</issn><issn>2107-0180</issn><eissn>2107-0180</eissn><abstract>Background and Objectives
Lorlatinib is approved (100 mg once daily [QD]) for the treatment of patients with
anaplastic lymphoma kinase
- (ALK) positive metastatic non-small cell lung cancer. This study evaluated the impact of varying degrees of renal impairment on the safety and pharmacokinetics of lorlatinib.
Methods
Participants were assigned to mild, moderate, and severe renal impairment groups and to a matching normal renal function group based on absolute estimated glomerular filtration rate (eGFR, based on the Modification of Diet in Renal Disease equation and adjusted for body surface area [BSA]) and were evaluated for pharmacokinetics and safety.
Results
A total of 29 participants (5 with severe renal impairment; 8 each with moderate and mild impairment and normal renal function) were enrolled and received a single dose of lorlatinib 100 mg. One of the participants with severe renal impairment had end-stage renal disease with a baseline absolute eGFR of 10.3 mL/min. No serious adverse events (AEs) were reported. Eighteen AEs, all mild or moderate in severity, were reported by 12 participants (5, 2, 4, and 1 in the normal, mild, moderate, and severe groups, respectively). Area under the plasma concentration–time profile from time zero extrapolated to infinity (AUC
inf
) for lorlatinib was increased by 4%, 19%, and 41% in the mild, moderate, and severe renal impairment groups, respectively, compared with the normal renal function cohort.
Conclusion
Lorlatinib 100 mg was well tolerated. As participants with mild and moderate renal impairment did not experience clinically meaningful increases in lorlatinib exposure, no lorlatinib dose adjustment is recommended in these populations. Patients with severe renal impairment are recommended to reduce the starting dose of lorlatinib from 100 mg QD to 75 mg QD.
Clinicaltrials.gov identifier
NCT03542305 (available May 31, 2018 on clinicaltrials.gov)</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>35018553</pmid><doi>10.1007/s13318-021-00747-4</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-7705-9401</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0378-7966 |
| ispartof | European journal of drug metabolism and pharmacokinetics, 2022-03, Vol.47 (2), p.235-245 |
| issn | 0378-7966 2107-0180 2107-0180 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8917008 |
| source | MEDLINE; SpringerLink Journals - AutoHoldings |
| subjects | Adult Aminopyridines - adverse effects Aminopyridines - pharmacokinetics Area Under Curve Biomedical and Life Sciences Biomedicine Carcinoma, Non-Small-Cell Lung - drug therapy Human Physiology Humans Lactams - adverse effects Lactams - pharmacokinetics Lung Neoplasms - drug therapy Medical Biochemistry NCT NCT03542305 Original Original Research Article Pharmaceutical Sciences/Technology Pharmacology/Toxicology Pharmacy Pyrazoles - adverse effects Pyrazoles - pharmacokinetics Renal Insufficiency - drug therapy |
| title | A Phase I Study to Evaluate the Pharmacokinetics and Safety of Lorlatinib in Adults with Mild, Moderate, and Severe Renal Impairment |
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