TY - JOUR
T1 - Pharmacokinetics and Safety of Olaparib in Patients with Advanced Solid Tumours and Renal Impairment
AU - Rolfo, Christian
AU - de Vos-Geelen, Judith
AU - Isambert, Nicolas
AU - Molife, L. Rhoda
AU - Schellens, Jan H. M.
AU - De Greve, Jacques
AU - Dirix, Luc
AU - Grundtvig-Sorensen, Peter
AU - Jerusalem, Guy
AU - Leunen, Karin
AU - Mau-Sorensen, Morten
AU - Plummer, Ruth
AU - Learoyd, Maria
AU - Bannister, Wendy
AU - Fielding, Anitra
AU - Ravaud, Alain
N1 - Funding Information:
The authors thank the patients, their families, and all investigators and study personnel involved. Ruth Plummer and L. Rhoda Molife acknowledge that The Royal Marsden Hospital and Northern Centre of Cancer Care are funded by Cancer Research UK and the Department of Health (England) as Experimental Cancer Medicine Centres. Medical writing assistance was provided by Kristin Luehders PhD and Claire Routley PhD from Mudskipper Business Ltd, funded by AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD).
Funding Information:
Funding This study was sponsored by AstraZeneca and is part of an alliance between AstraZeneca and MSD. AstraZeneca was involved in the study design, data collection, data analysis and data interpretation. MSD also provided input into data interpretation. Medical writing support was funded by AstraZeneca and MSD.
Funding Information:
Acknowledgements The authors thank the patients, their families, and all investigators and study personnel involved. Ruth Plummer and L. Rhoda Molife acknowledge that The Royal Marsden Hospital and Northern Centre of Cancer Care are funded by Cancer Research UK and the Department of Health (England) as Experimental Cancer Medicine Centres. Medical writing assistance was provided by Kristin Luehders PhD and Claire Routley PhD from Mudskipper Business Ltd, funded by AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD).
Publisher Copyright:
© 2019, Springer Nature Switzerland AG.
PY - 2019/9
Y1 - 2019/9
N2 - BackgroundOlaparib, a potent oral poly(ADP-ribose) polymerase inhibitor, is partially renally cleared. We investigated the pharmacokinetics and safety of olaparib in patients with mild or moderate renal impairment to provide dosing recommendations.MethodsThis phase I open-label study assessed the pharmacokinetics, safety and tolerability of single-dose, oral 300-mg olaparib tablets in adults (aged 18-75years) with solid tumours. Patients had normal renal function, or mild or moderate renal impairment (estimated creatinine clearance >= 81, 51-80 or 31-50mL/min, respectively). Blood was collected for 96h, and urine samples collected for 24h post-dose. Patients could continue taking olaparib 300mg twice daily for a long-term safety assessment.ResultsOverall, 44 patients received one or more doses of olaparib and 38 were included in the pharmacokinetic assessment. Patients with mild renal impairment had an area under the curve geometric least-squares mean ratio of 1.24 (90% confidence interval 1.06-1.47) and a geometric least-squares mean maximum plasma concentration ratio of 1.15 (90% confidence interval 1.04-1.27) vs. those with normal renal function. In patients with moderate renal impairment, the geometric least-squares mean ratio for the area under the curve was 1.44 (90% confidence interval 1.10-1.89) and for the maximum plasma concentration was 1.26 (90% confidence interval 1.06-1.48) vs. those with normal renal function. No new safety signals were detected in patients with mild or moderate renal impairment.ConclusionsIn patients with mild renal impairment, the small increase in exposure to olaparib was not considered clinically relevant. In patients with moderate renal impairment, exposure to olaparib increased by 44%; thus, these patients should be carefully monitored and the tablet dose should be adjusted to 200mg twice daily.Clinical Trials RegistrationNCT01894256.
AB - BackgroundOlaparib, a potent oral poly(ADP-ribose) polymerase inhibitor, is partially renally cleared. We investigated the pharmacokinetics and safety of olaparib in patients with mild or moderate renal impairment to provide dosing recommendations.MethodsThis phase I open-label study assessed the pharmacokinetics, safety and tolerability of single-dose, oral 300-mg olaparib tablets in adults (aged 18-75years) with solid tumours. Patients had normal renal function, or mild or moderate renal impairment (estimated creatinine clearance >= 81, 51-80 or 31-50mL/min, respectively). Blood was collected for 96h, and urine samples collected for 24h post-dose. Patients could continue taking olaparib 300mg twice daily for a long-term safety assessment.ResultsOverall, 44 patients received one or more doses of olaparib and 38 were included in the pharmacokinetic assessment. Patients with mild renal impairment had an area under the curve geometric least-squares mean ratio of 1.24 (90% confidence interval 1.06-1.47) and a geometric least-squares mean maximum plasma concentration ratio of 1.15 (90% confidence interval 1.04-1.27) vs. those with normal renal function. In patients with moderate renal impairment, the geometric least-squares mean ratio for the area under the curve was 1.44 (90% confidence interval 1.10-1.89) and for the maximum plasma concentration was 1.26 (90% confidence interval 1.06-1.48) vs. those with normal renal function. No new safety signals were detected in patients with mild or moderate renal impairment.ConclusionsIn patients with mild renal impairment, the small increase in exposure to olaparib was not considered clinically relevant. In patients with moderate renal impairment, exposure to olaparib increased by 44%; thus, these patients should be carefully monitored and the tablet dose should be adjusted to 200mg twice daily.Clinical Trials RegistrationNCT01894256.
KW - INHIBITOR
KW - CANCER
U2 - 10.1007/s40262-019-00754-4
DO - 10.1007/s40262-019-00754-4
M3 - Article
C2 - 30877569
SN - 0312-5963
VL - 58
SP - 1165
EP - 1174
JO - Clinical Pharmacokinetics
JF - Clinical Pharmacokinetics
IS - 9
ER -