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

Christian Rolfo*, Nicolas Isambert, Antoine Italiano, L. Rhoda Molife, Jan Hm 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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Web of Science)

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)vsthose 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)vsthose 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.

Original languageEnglish
Pages (from-to)1807-1818
Number of pages12
JournalBritish Journal of Clinical Pharmacology
Volume86
Issue number9
DOIs
Publication statusPublished - Sep 2020

Keywords

  • advanced solid tumours
  • hepatic impairment
  • liver
  • olaparib
  • pharmacokinetics
  • poly(ADP-ribose) polymerase
  • safety
  • DRUG
  • FORMULATION
  • INHIBITOR
  • DISEASE
  • CANCER

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