Christian Rolfo1, Nicolas Isambert2, Antoine Italiano3, L Rhoda Molife4, Jan H M Schellens5,6, Jean-Yves Blay7, Thomas Decaens8, Rebecca Kristeleit9, Olivier Rosmorduc10, Regina Demlova11, Myung-Ah Lee12, Alain Ravaud13, Katerina Kopeckova14, Maria Learoyd15, Wendy Bannister16, Gershon Locker17, Judith de Vos-Geelen18. 1. Marlene and Stewart Greenebaum Comprehensive Cancer Center, Experimental Therapeutics Program, University of Maryland School of Medicine, Baltimore, Maryland, USA. 2. Centre Georges François Leclerc, Dijon, France. 3. Institut Bergonié, Gironde, France. 4. *Royal Marsden Hospital, London, UK. 5. The Netherlands Cancer Institute, Amsterdam, The Netherlands. 6. Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands. 7. Centre Léon Bérard, Lyon, France. 8. Department of hepato-gastroenterology, Université Grenoble-Alpes, CHU Grenoble-Alpes, Institute for Advanced Biosciences, Grenoble, France. 9. The Netherlands Cancer Institute, Amsterdam, and Utrecht University, Utrecht, The Netherlands. 10. APHP, Hôpital La Pitié Salpêtrière, Service d'Hépato-Gastroentérologie, Paris, France. 11. Faculty of Medicine, Department of Pharmacology, Masaryk Memorial Cancer Institute, Masaryk Univerzity, Brno, Czech Republic. 12. The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul, South Korea. 13. Hôpital Saint André, Bordeaux University Hospital, Bordeaux, France. 14. University Hospital in Motol, Charles University, Prague, Czech Republic. 15. AstraZeneca, Cambridge, UK. 16. Phastar, London, UK. 17. AstraZeneca, Gaithersburg, MD, USA. 18. Department of Internal Medicine, Division of Medical Oncology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
Abstract
AIMS: Olaparib, a potent oral poly(ADP-ribose) polymerase inhibitor, is partially hepatically cleared. We investigated the pharmacokinetics (PK) and safety of olaparib in patients with mild or moderate hepatic impairment to provide dosing recommendations. METHODS: This Phase I open-label study assessed the PK, safety and tolerability of single doses of olaparib 300-mg tablets in patients with advanced solid tumours. Patients had normal hepatic function (NHF), or mild (MiHI; Child-Pugh class A) or moderate (MoHI; Child-Pugh class B) hepatic impairment. Blood was collected for PK assessments for 96 hours. Patients could continue taking olaparib 300 mg twice daily for long-term safety assessment. RESULTS: Thirty-one patients received ≥1 dose of olaparib and 30 were included in the PK assessment. Patients with MiHI had an area under the curve geometric least-squares mean (GLSmean) ratio of 1.15 (90% confidence interval 0.72, 1.83) and a GLSmean maximum plasma concentration ratio of 1.13 (0.82, 1.56) vs those with NHF. In patients with MoHI, GLSmean ratio for area under the curve was 1.08 (0.66, 1.74) and for maximum plasma concentration was 0.87 (0.63, 1.22) vs those with NHF. For patients with mild or moderate hepatic impairment, no new safety signals were detected. CONCLUSION: Patients with MiHI or MoHI had no clinically significant changes in exposure to olaparib compared with patients with NHF. The safety profile of olaparib did not differ from a clinically relevant extent between cohorts. No olaparib tablet or capsule dose reductions are required for patients with MiHI or MoHI.
AIMS: Olaparib, a potent oral poly(ADP-ribose) polymerase inhibitor, is partially hepatically cleared. We investigated the pharmacokinetics (PK) and safety of olaparib in patients with mild or moderate hepatic impairment to provide dosing recommendations. METHODS: This Phase I open-label study assessed the PK, safety and tolerability of single doses of olaparib 300-mg tablets in patients with advanced solid tumours. Patients had normal hepatic function (NHF), or mild (MiHI; Child-Pugh class A) or moderate (MoHI; Child-Pugh class B) hepatic impairment. Blood was collected for PK assessments for 96 hours. Patients could continue taking olaparib 300 mg twice daily for long-term safety assessment. RESULTS: Thirty-one patients received ≥1 dose of olaparib and 30 were included in the PK assessment. Patients with MiHI had an area under the curve geometric least-squares mean (GLSmean) ratio of 1.15 (90% confidence interval 0.72, 1.83) and a GLSmean maximum plasma concentration ratio of 1.13 (0.82, 1.56) vs those with NHF. In patients with MoHI, GLSmean ratio for area under the curve was 1.08 (0.66, 1.74) and for maximum plasma concentration was 0.87 (0.63, 1.22) vs those with NHF. For patients with mild or moderate hepatic impairment, no new safety signals were detected. CONCLUSION:Patients with MiHI or MoHI had no clinically significant changes in exposure to olaparib compared with patients with NHF. The safety profile of olaparib did not differ from a clinically relevant extent between cohorts. No olaparib tablet or capsule dose reductions are required for patients with MiHI or MoHI.
Authors: J Mateo; V Moreno; A Gupta; S B Kaye; E Dean; M R Middleton; M Friedlander; C Gourley; R Plummer; G Rustin; C Sessa; K Leunen; J Ledermann; H Swaisland; A Fielding; W Bannister; S Nicum; L R Molife Journal: Target Oncol Date: 2016-06 Impact factor: 4.493
Authors: Christian Rolfo; Judith de Vos-Geelen; Nicolas Isambert; L Rhoda Molife; Jan H M Schellens; Jacques De Grève; Luc Dirix; Peter Grundtvig-Sørensen; Guy Jerusalem; Karin Leunen; Morten Mau-Sørensen; Ruth Plummer; Maria Learoyd; Wendy Bannister; Anitra Fielding; Alain Ravaud Journal: Clin Pharmacokinet Date: 2019-09 Impact factor: 6.447
Authors: Michael Friedlander; Ursula Matulonis; Charlie Gourley; Andreas du Bois; Ignace Vergote; Gordon Rustin; Clare Scott; Werner Meier; Ronnie Shapira-Frommer; Tamar Safra; Daniela Matei; Vadim Shirinkin; Frédéric Selle; Anitra Fielding; Elizabeth S Lowe; Emma L McMurtry; Stuart Spencer; Philip Rowe; Helen Mann; David Parry; Jonathan Ledermann Journal: Br J Cancer Date: 2018-10-24 Impact factor: 7.640
Authors: Christian Rolfo; Nicolas Isambert; Antoine Italiano; L Rhoda Molife; Jan H M Schellens; Jean-Yves Blay; Thomas Decaens; Rebecca Kristeleit; Olivier Rosmorduc; Regina Demlova; Myung-Ah Lee; Alain Ravaud; Katerina Kopeckova; Maria Learoyd; Wendy Bannister; Gershon Locker; Judith de Vos-Geelen Journal: Br J Clin Pharmacol Date: 2020-04-05 Impact factor: 4.335