PubMed:23315029 JSONTXT

{"project":"Allie","denotations":[{"id":"SS1_23315029_1_0","span":{"begin":204,"end":231},"obj":"expanded"},{"id":"SS2_23315029_1_0","span":{"begin":233,"end":237},"obj":"abbr"},{"id":"SS1_23315029_5_0","span":{"begin":770,"end":786},"obj":"expanded"},{"id":"SS2_23315029_5_0","span":{"begin":788,"end":790},"obj":"abbr"},{"id":"SS1_23315029_5_1","span":{"begin":800,"end":816},"obj":"expanded"},{"id":"SS2_23315029_5_1","span":{"begin":818,"end":820},"obj":"abbr"},{"id":"SS1_23315029_5_2","span":{"begin":836,"end":870},"obj":"expanded"},{"id":"SS2_23315029_5_2","span":{"begin":872,"end":877},"obj":"abbr"}],"relations":[{"id":"AE1_23315029_1_0","pred":"abbreviatedTo","subj":"SS1_23315029_1_0","obj":"SS2_23315029_1_0"},{"id":"AE1_23315029_5_0","pred":"abbreviatedTo","subj":"SS1_23315029_5_0","obj":"SS2_23315029_5_0"},{"id":"AE1_23315029_5_1","pred":"abbreviatedTo","subj":"SS1_23315029_5_1","obj":"SS2_23315029_5_1"},{"id":"AE1_23315029_5_2","pred":"abbreviatedTo","subj":"SS1_23315029_5_2","obj":"SS2_23315029_5_2"}],"text":"Evaluation of the pharmacodynamics and pharmacokinetics of the PARP inhibitor olaparib: a phase I multicentre trial in patients scheduled for elective breast cancer surgery.\nOlaparib (AZD2281) is an oral poly(ADP-ribose) polymerase (PARP) inhibitor with antitumour activity in cancer patients with BRCA1/2 germline mutations and in patients with homologous recombination deficiency. In this dose-finding study, patients were randomized to olaparib 10, 30, 100, 200 or 400 mg (capsule formulation) twice daily for the 4-5 days preceding breast cancer surgery. The primary objective was to identify an effective biological dose of olaparib for future trials. Secondary endpoints included evaluation of PARP-1 inhibition dose/exposure-response, and safety. Olaparib plasma pharmacokinetics (PK) and the pharmacodynamics (PD) in tumour and peripheral blood mononuclear cells (PBMCs) were evaluated. Population PK/PD modelling was performed on pooled data from this study and a previously reported study. Sixty patients were randomized (n = 12, each dose). Dose-dependent increases in exposure to olaparib were observed, but at ~50 % lower plasma exposure levels than seen in advanced disease studies. The mean maximal extent of PARP inhibition in PBMCs and tumour tissue was 50.6 % and 70.0 %, respectively, and was similar to inhibitory levels reported previously. No PARP inhibition-dose relationship was observed. Due to the unexpectedly low olaparib exposure, we were unable to determine an effective biological dose. Common adverse events included procedural pain (n = 31 patients), nausea, asthenia, malaise and increased blood creatinine (n = 6, each); these were of mild-to-moderate intensity, and all were manageable. Despite low olaparib exposure, PARP inhibition was consistent with previous reports. Reasons for the inter-study differences in exposure are unclear. The tolerability profile of olaparib was consistent with previous studies."}

{"project":"PubmedHPO","denotations":[{"id":"T1","span":{"begin":277,"end":283},"obj":"HP_0002664"},{"id":"T2","span":{"begin":536,"end":549},"obj":"HP_0003002"},{"id":"T3","span":{"begin":536,"end":549},"obj":"HP_0100013"},{"id":"T4","span":{"begin":543,"end":549},"obj":"HP_0002664"},{"id":"T5","span":{"begin":825,"end":831},"obj":"HP_0002664"},{"id":"T6","span":{"begin":1253,"end":1259},"obj":"HP_0002664"},{"id":"T7","span":{"begin":1560,"end":1564},"obj":"HP_0012531"},{"id":"T8","span":{"begin":1584,"end":1590},"obj":"HP_0002018"}],"text":"Evaluation of the pharmacodynamics and pharmacokinetics of the PARP inhibitor olaparib: a phase I multicentre trial in patients scheduled for elective breast cancer surgery.\nOlaparib (AZD2281) is an oral poly(ADP-ribose) polymerase (PARP) inhibitor with antitumour activity in cancer patients with BRCA1/2 germline mutations and in patients with homologous recombination deficiency. In this dose-finding study, patients were randomized to olaparib 10, 30, 100, 200 or 400 mg (capsule formulation) twice daily for the 4-5 days preceding breast cancer surgery. The primary objective was to identify an effective biological dose of olaparib for future trials. Secondary endpoints included evaluation of PARP-1 inhibition dose/exposure-response, and safety. Olaparib plasma pharmacokinetics (PK) and the pharmacodynamics (PD) in tumour and peripheral blood mononuclear cells (PBMCs) were evaluated. Population PK/PD modelling was performed on pooled data from this study and a previously reported study. Sixty patients were randomized (n = 12, each dose). Dose-dependent increases in exposure to olaparib were observed, but at ~50 % lower plasma exposure levels than seen in advanced disease studies. The mean maximal extent of PARP inhibition in PBMCs and tumour tissue was 50.6 % and 70.0 %, respectively, and was similar to inhibitory levels reported previously. No PARP inhibition-dose relationship was observed. Due to the unexpectedly low olaparib exposure, we were unable to determine an effective biological dose. Common adverse events included procedural pain (n = 31 patients), nausea, asthenia, malaise and increased blood creatinine (n = 6, each); these were of mild-to-moderate intensity, and all were manageable. Despite low olaparib exposure, PARP inhibition was consistent with previous reports. Reasons for the inter-study differences in exposure are unclear. The tolerability profile of olaparib was consistent with previous studies."}

{"project":"maxiaofeng52_800_3","denotations":[{"id":"T1","span":{"begin":78,"end":86},"obj":"CI"},{"id":"T10","span":{"begin":151,"end":164},"obj":"DP"},{"id":"T11","span":{"begin":536,"end":549},"obj":"DP"},{"id":"T2","span":{"begin":439,"end":447},"obj":"CI"},{"id":"T3","span":{"begin":629,"end":637},"obj":"CI"},{"id":"T4","span":{"begin":1092,"end":1100},"obj":"CI"},{"id":"T5","span":{"begin":1441,"end":1449},"obj":"CI"},{"id":"T6","span":{"begin":1735,"end":1743},"obj":"CI"},{"id":"T7","span":{"begin":1901,"end":1909},"obj":"CI"},{"id":"T8","span":{"begin":174,"end":182},"obj":"CI"},{"id":"T9","span":{"begin":754,"end":762},"obj":"CI"}],"text":"Evaluation of the pharmacodynamics and pharmacokinetics of the PARP inhibitor olaparib: a phase I multicentre trial in patients scheduled for elective breast cancer surgery.\nOlaparib (AZD2281) is an oral poly(ADP-ribose) polymerase (PARP) inhibitor with antitumour activity in cancer patients with BRCA1/2 germline mutations and in patients with homologous recombination deficiency. In this dose-finding study, patients were randomized to olaparib 10, 30, 100, 200 or 400 mg (capsule formulation) twice daily for the 4-5 days preceding breast cancer surgery. The primary objective was to identify an effective biological dose of olaparib for future trials. Secondary endpoints included evaluation of PARP-1 inhibition dose/exposure-response, and safety. Olaparib plasma pharmacokinetics (PK) and the pharmacodynamics (PD) in tumour and peripheral blood mononuclear cells (PBMCs) were evaluated. Population PK/PD modelling was performed on pooled data from this study and a previously reported study. Sixty patients were randomized (n = 12, each dose). Dose-dependent increases in exposure to olaparib were observed, but at ~50 % lower plasma exposure levels than seen in advanced disease studies. The mean maximal extent of PARP inhibition in PBMCs and tumour tissue was 50.6 % and 70.0 %, respectively, and was similar to inhibitory levels reported previously. No PARP inhibition-dose relationship was observed. Due to the unexpectedly low olaparib exposure, we were unable to determine an effective biological dose. Common adverse events included procedural pain (n = 31 patients), nausea, asthenia, malaise and increased blood creatinine (n = 6, each); these were of mild-to-moderate intensity, and all were manageable. Despite low olaparib exposure, PARP inhibition was consistent with previous reports. Reasons for the inter-study differences in exposure are unclear. The tolerability profile of olaparib was consistent with previous studies."}

{"project":"wangzhuo19_800_3","denotations":[{"id":"T1","span":{"begin":78,"end":86},"obj":"CI"},{"id":"T2","span":{"begin":439,"end":447},"obj":"CI"},{"id":"T3","span":{"begin":629,"end":637},"obj":"CI"},{"id":"T4","span":{"begin":1092,"end":1100},"obj":"CI"},{"id":"T5","span":{"begin":1441,"end":1449},"obj":"CI"},{"id":"T6","span":{"begin":1735,"end":1743},"obj":"CI"},{"id":"T7","span":{"begin":1901,"end":1909},"obj":"CI"},{"id":"T8","span":{"begin":174,"end":182},"obj":"CI"},{"id":"T9","span":{"begin":754,"end":762},"obj":"CI"},{"id":"T10","span":{"begin":151,"end":164},"obj":"DP"},{"id":"T11","span":{"begin":536,"end":549},"obj":"DP"}],"text":"Evaluation of the pharmacodynamics and pharmacokinetics of the PARP inhibitor olaparib: a phase I multicentre trial in patients scheduled for elective breast cancer surgery.\nOlaparib (AZD2281) is an oral poly(ADP-ribose) polymerase (PARP) inhibitor with antitumour activity in cancer patients with BRCA1/2 germline mutations and in patients with homologous recombination deficiency. In this dose-finding study, patients were randomized to olaparib 10, 30, 100, 200 or 400 mg (capsule formulation) twice daily for the 4-5 days preceding breast cancer surgery. The primary objective was to identify an effective biological dose of olaparib for future trials. Secondary endpoints included evaluation of PARP-1 inhibition dose/exposure-response, and safety. Olaparib plasma pharmacokinetics (PK) and the pharmacodynamics (PD) in tumour and peripheral blood mononuclear cells (PBMCs) were evaluated. Population PK/PD modelling was performed on pooled data from this study and a previously reported study. Sixty patients were randomized (n = 12, each dose). Dose-dependent increases in exposure to olaparib were observed, but at ~50 % lower plasma exposure levels than seen in advanced disease studies. The mean maximal extent of PARP inhibition in PBMCs and tumour tissue was 50.6 % and 70.0 %, respectively, and was similar to inhibitory levels reported previously. No PARP inhibition-dose relationship was observed. Due to the unexpectedly low olaparib exposure, we were unable to determine an effective biological dose. Common adverse events included procedural pain (n = 31 patients), nausea, asthenia, malaise and increased blood creatinine (n = 6, each); these were of mild-to-moderate intensity, and all were manageable. Despite low olaparib exposure, PARP inhibition was consistent with previous reports. Reasons for the inter-study differences in exposure are unclear. The tolerability profile of olaparib was consistent with previous studies."}