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Pharmacokinetics and safety of olaparib in patients with advanced solid tumours and mild or moderate hepatic impairment

C. Rolfo, N. Isambert, A. Italiano, LR. Molife, JHM. Schellens, JY. Blay, T. Decaens, R. Kristeleit, O. Rosmorduc, R. Demlova, MA. Lee, A. Ravaud, K. Kopeckova, M. Learoyd, W. Bannister, G. Locker, J. de Vos-Geelen

. 2020 ; 86 (9) : 1807-1818. [pub] 20200405

Language English Country Great Britain

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc21026569

Grant support
AstraZeneca - International
Merck Sharp & Dohme Corp. - International
Merck & Co., Inc. - International

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.

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$a Rolfo, Christian $u Marlene and Stewart Greenebaum Comprehensive Cancer Center, Experimental Therapeutics Program, University of Maryland School of Medicine, Baltimore, Maryland, USA
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$a Pharmacokinetics and safety of olaparib in patients with advanced solid tumours and mild or moderate hepatic impairment / $c C. Rolfo, N. Isambert, A. Italiano, LR. Molife, JHM. Schellens, JY. Blay, T. Decaens, R. Kristeleit, O. Rosmorduc, R. Demlova, MA. Lee, A. Ravaud, K. Kopeckova, M. Learoyd, W. Bannister, G. Locker, J. de Vos-Geelen
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$a 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.
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$a Isambert, Nicolas $u Centre Georges François Leclerc, Dijon, France
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$a Italiano, Antoine $u Institut Bergonié, Gironde, France
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$a Molife, L Rhoda $u *Royal Marsden Hospital, London, UK
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$a Schellens, Jan H M $u The Netherlands Cancer Institute, Amsterdam, The Netherlands $u Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands
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$a Blay, Jean-Yves $u Centre Léon Bérard, Lyon, France
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$a Decaens, Thomas $u Department of hepato-gastroenterology, Université Grenoble-Alpes, CHU Grenoble-Alpes, Institute for Advanced Biosciences, Grenoble, France
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$a Kristeleit, Rebecca $u The Netherlands Cancer Institute, Amsterdam, and Utrecht University, Utrecht, The Netherlands
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$a Rosmorduc, Olivier $u APHP, Hôpital La Pitié Salpêtrière, Service d'Hépato-Gastroentérologie, Paris, France
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$a Demlova, Regina $u Faculty of Medicine, Department of Pharmacology, Masaryk Memorial Cancer Institute, Masaryk Univerzity, Brno, Czech Republic
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$a Lee, Myung-Ah $u The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul, South Korea
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$a Ravaud, Alain $u Hôpital Saint André, Bordeaux University Hospital, Bordeaux, France
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$a Kopeckova, Katerina $u University Hospital in Motol, Charles University, Prague, Czech Republic
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$a Learoyd, Maria $u AstraZeneca, Cambridge, UK
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$a Bannister, Wendy $u Phastar, London, UK
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$a Locker, Gershon $u AstraZeneca, Gaithersburg, MD, USA
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$a de Vos-Geelen, Judith $u Department of Internal Medicine, Division of Medical Oncology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
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