Reported hepatotoxicity and hepatotoxicity guidance in the product information of protein kinase inhibitors in oncology registered at the European Medicines Agency
Abstract Protein kinase inhibitors (PKIs) used in oncology can induce severe and even fatal hepatotoxicity. Several PKIs are registered within a certain class to target a specific kinase. No systematic comparison of the reported hepatotoxicity and clinical guidance for monitoring and management of h...
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| Format: | Article |
| Language: | English |
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Wiley
2023-04-01
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| Series: | Pharmacology Research & Perspectives |
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| Online Access: | https://doi.org/10.1002/prp2.1067 |
| _version_ | 1797849175408246784 |
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| author | Marc Maliepaard Yoran S. Faber Mark T. J. vanBussel |
| author_facet | Marc Maliepaard Yoran S. Faber Mark T. J. vanBussel |
| author_sort | Marc Maliepaard |
| collection | DOAJ |
| description | Abstract Protein kinase inhibitors (PKIs) used in oncology can induce severe and even fatal hepatotoxicity. Several PKIs are registered within a certain class to target a specific kinase. No systematic comparison of the reported hepatotoxicity and clinical guidance for monitoring and management of hepatotoxic events between the various PKI summaries of product characteristics (SmPC) is yet available. A systematic analysis of data on 21 hepatotoxicity parameters obtained from the SmPCs and European public assessment reports (EPARs) of European Medicines Agency‐approved antineoplastic PKIs (n = 55) has been conducted. The median reported incidence (range) of all grades of aspartate aminotransferase (AST) elevations was 16.9% (2.0%–86.4%) for PKI monotherapy, with 2.1% (0.0%–10.3%) being grade 3/4 and for all grades alanine aminotransferase (ALT) elevations 17.6% (2.0%–85.5%), with 3.0% (0.0%–25.0%) being grade 3/4. Fatalities due to hepatotoxicity were reported for 22 out of 47 PKIs (monotherapy) and for 5 out of 8 PKIs (combination therapy). A maximum grade of grade 4 and grade 3 hepatotoxicity was reported for 45% (n = 25) and 6% (n = 3), respectively. Liver parameter monitoring recommendations were present in 47 of the 55 SmPCs. Dose reductions were recommended for 18 PKIs. Discontinuation was recommended for patients meeting Hy's law criteria (16 out of 55 SmPCs). Severe hepatotoxic events are reported in approximately 50% of the analyzed SmPCs and EPARs. Differences in the degree of hepatotoxicity are apparent. Although liver parameter monitoring recommendations are present in the vast majority of the analyzed PKI SmPCs, the clinical guidance for hepatotoxicity was not standardized. |
| first_indexed | 2024-04-09T18:39:39Z |
| format | Article |
| id | doaj.art-60060a6d23e54144baa3ee63f5e9e2e3 |
| institution | Directory Open Access Journal |
| issn | 2052-1707 |
| language | English |
| last_indexed | 2024-04-09T18:39:39Z |
| publishDate | 2023-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Pharmacology Research & Perspectives |
| spelling | doaj.art-60060a6d23e54144baa3ee63f5e9e2e32023-04-11T06:38:37ZengWileyPharmacology Research & Perspectives2052-17072023-04-01112n/an/a10.1002/prp2.1067Reported hepatotoxicity and hepatotoxicity guidance in the product information of protein kinase inhibitors in oncology registered at the European Medicines AgencyMarc Maliepaard0Yoran S. Faber1Mark T. J. vanBussel2Dutch Medicines Evaluation Board (CBG‐MEB) College ter Beoordeling van Geneesmiddelen Utrecht The NetherlandsDutch Medicines Evaluation Board (CBG‐MEB) College ter Beoordeling van Geneesmiddelen Utrecht The NetherlandsDutch Medicines Evaluation Board (CBG‐MEB) College ter Beoordeling van Geneesmiddelen Utrecht The NetherlandsAbstract Protein kinase inhibitors (PKIs) used in oncology can induce severe and even fatal hepatotoxicity. Several PKIs are registered within a certain class to target a specific kinase. No systematic comparison of the reported hepatotoxicity and clinical guidance for monitoring and management of hepatotoxic events between the various PKI summaries of product characteristics (SmPC) is yet available. A systematic analysis of data on 21 hepatotoxicity parameters obtained from the SmPCs and European public assessment reports (EPARs) of European Medicines Agency‐approved antineoplastic PKIs (n = 55) has been conducted. The median reported incidence (range) of all grades of aspartate aminotransferase (AST) elevations was 16.9% (2.0%–86.4%) for PKI monotherapy, with 2.1% (0.0%–10.3%) being grade 3/4 and for all grades alanine aminotransferase (ALT) elevations 17.6% (2.0%–85.5%), with 3.0% (0.0%–25.0%) being grade 3/4. Fatalities due to hepatotoxicity were reported for 22 out of 47 PKIs (monotherapy) and for 5 out of 8 PKIs (combination therapy). A maximum grade of grade 4 and grade 3 hepatotoxicity was reported for 45% (n = 25) and 6% (n = 3), respectively. Liver parameter monitoring recommendations were present in 47 of the 55 SmPCs. Dose reductions were recommended for 18 PKIs. Discontinuation was recommended for patients meeting Hy's law criteria (16 out of 55 SmPCs). Severe hepatotoxic events are reported in approximately 50% of the analyzed SmPCs and EPARs. Differences in the degree of hepatotoxicity are apparent. Although liver parameter monitoring recommendations are present in the vast majority of the analyzed PKI SmPCs, the clinical guidance for hepatotoxicity was not standardized.https://doi.org/10.1002/prp2.1067European public assessment reporthepatotoxicityoncologyprotein kinase inhibitorssummary of product characteristics |
| spellingShingle | Marc Maliepaard Yoran S. Faber Mark T. J. vanBussel Reported hepatotoxicity and hepatotoxicity guidance in the product information of protein kinase inhibitors in oncology registered at the European Medicines Agency Pharmacology Research & Perspectives European public assessment report hepatotoxicity oncology protein kinase inhibitors summary of product characteristics |
| title | Reported hepatotoxicity and hepatotoxicity guidance in the product information of protein kinase inhibitors in oncology registered at the European Medicines Agency |
| title_full | Reported hepatotoxicity and hepatotoxicity guidance in the product information of protein kinase inhibitors in oncology registered at the European Medicines Agency |
| title_fullStr | Reported hepatotoxicity and hepatotoxicity guidance in the product information of protein kinase inhibitors in oncology registered at the European Medicines Agency |
| title_full_unstemmed | Reported hepatotoxicity and hepatotoxicity guidance in the product information of protein kinase inhibitors in oncology registered at the European Medicines Agency |
| title_short | Reported hepatotoxicity and hepatotoxicity guidance in the product information of protein kinase inhibitors in oncology registered at the European Medicines Agency |
| title_sort | reported hepatotoxicity and hepatotoxicity guidance in the product information of protein kinase inhibitors in oncology registered at the european medicines agency |
| topic | European public assessment report hepatotoxicity oncology protein kinase inhibitors summary of product characteristics |
| url | https://doi.org/10.1002/prp2.1067 |
| work_keys_str_mv | AT marcmaliepaard reportedhepatotoxicityandhepatotoxicityguidanceintheproductinformationofproteinkinaseinhibitorsinoncologyregisteredattheeuropeanmedicinesagency AT yoransfaber reportedhepatotoxicityandhepatotoxicityguidanceintheproductinformationofproteinkinaseinhibitorsinoncologyregisteredattheeuropeanmedicinesagency AT marktjvanbussel reportedhepatotoxicityandhepatotoxicityguidanceintheproductinformationofproteinkinaseinhibitorsinoncologyregisteredattheeuropeanmedicinesagency |