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Title
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Pharmacokinetic effects and safety of olaparib administered with endocrine therapy : a phase I study in patients with advanced solid tumours
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Author
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Abstract
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| IntroductionThe PARP inhibitor olaparib is efficacious as monotherapy and has potential application in combination with endocrine therapy for the treatment of breast cancer. This phase I study assessed the safety and pharmacokinetic (PK) profiles of olaparib combined with tamoxifen, anastrozole or letrozole in patients with advanced solid tumours.MethodsDuring part A, PK profiles were assessed in three consecutive treatment periods: (1) olaparib (tablet) 300mg bid, days 1-5 followed by a 4-day washout; (2) cohort 1, tamoxifen 60mg loading dose qd days 10-13, 20mg qd days 14-26; cohort 2, anastrozole 1mg qd days 10-19; cohort 3, letrozole 2.5mg qd days 10-38; (3) as for period 2, with concomitant olaparib 300mg bid for 5days. Patients could then enter part B and receive olaparib monotherapy (300mg bid continuously). Safety was assessed in parts A and B until 12months after the last patient entered part B.ResultsSeventy-nine patients (20.3% with breast cancer) received treatment in part A; 72 completed part A and 69 entered part B. Anastrozole and letrozole had no effect on the PK profile of olaparib and vice versa. Co-administration with tamoxifen produced a modest decrease in exposure to olaparib [geometric least-squares mean (GLSmean) C-max,C-ss and AUC(0-) decreased by 20% (90% CI 0.71-0.90) and 27% (0.63-0.84), respectively]. Exposure to tamoxifen was slightly increased when combined with olaparib [GLSmean C-max,C-ss and AUC(0-) increased by 13% (1.06-1.22) and 16% (1.11-1.21), respectively]; however, the 90% CI fell within the 0.7-1.43 boundary and there were no changes in exposure to tamoxifen metabolites. The safety profile for olaparib alone and in combination with the antihormonal therapies was acceptable.ConclusionsThe combination of olaparib and either anastrozole, letrozole or tamoxifen was generally well tolerated, with no clinically relevant PK interactions identified.FundingAstraZeneca.Clinical Trial RegistrationNCT02093351. |
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Language
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English
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Source (journal)
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Advances in therapy : the international journal of drug, device & diagnostic research. - Chester, 1984, currens
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Publication
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Chester
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Springer
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2018
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ISSN
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0741-238X
[print]
1865-8652
[online]
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DOI
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10.1007/S12325-018-0804-Z
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Volume/pages
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35
:11
(2018)
, p. 1945-1964
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ISI
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000449835100018
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Pubmed ID
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30324586
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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