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Barbara Poulsen Nautrup - One of the best experts on this subject based on the ideXlab platform.
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Equipotent doses of transdermal fentanyl and transdermal buprenorphine in patients with cancer and noncancer pain results of a retrospective cohort study
Clinical Therapeutics, 2005Co-Authors: Reinhard Sittl, Rudolf Likar, Barbara Poulsen NautrupAbstract:Abstract Background: The equipotency ratio of transdermal (TD) fentanyl to oral morphine has been established as 1:100; for buprenorphine TD, a ratio of 1:75 has been proposed, although this ratio has not been confirmed in clinical studies. Growing evidence from clinical practice, in which much lower doses of buprenorphine are used, suggests that this conversion ratio may be too high. Objective: The aim of this study was to comparecalculated Equipotent oral morphine doses of fentanyl TD with Equipotent oral morphine doses of buprenorphine TD prescribed in clinical practice. Methods: This retrospective study identified patientswith cancer and noncancer pain who had received ≥1 prescription for fentanyl TD or buprenorphine TD (the all-patients groups) from the German IMS Disease Analyzer-mediplus database, which contains all relevant data concerning drug prescriptions from 400 practices in Germany. Also identified were subgroups of the all-patients groups who had received long-term treatment with fentanyl TD or buprenorphine TD and were considered to have similar pain intensity, as they had previously received similar analgesic medication (the identical-cohort groups). Mean prescribed daily doses for the all-patients and identical-cohort groups were calculated based on the distribution of prescribed patch strengths. Because patients could have applied >1 patch, mean prescribed daily doses were also calculated based on an assumption of double application when appropriate. Equipotent oral morphine doses were estimated using equipotency ratios of 1:100 for fentanyl TD and 1:75 for buprenorphine TD. Results: The all-patients groups consisted of 2198 patients with noncancer pain and 2544 patients with cancer pain; the identical-cohort groups consisted of 380 patients with noncancer pain and 496 patients with cancer pain (529 women, 347 men; mean age, 74 years [range, 25–101 years]). Equipotent doses of oral morphine were significantly lower in patients receiving buprenorphine TD compared with those receiving fentanyl TD (P Conclusions: The fact that this retrospective analysis conducted in identical cohorts showed lower calculated Equipotent oral morphine doses in the buprenorphine TD groups compared with the fentanyl TD groups calls into question the proposed 1:75 ratio for conversion of buprenorphine TD to Equipotent oral morphine doses. Based on the findings of the present study, an equipotency ratio of 1:110 to 1:115 may be more appropriate. However, confirmative data from prospective randomized clinical trials are needed.
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Equipotent doses of transdermal fentanyl and transdermal buprenorphine in patients with cancer and noncancer pain: results of a retrospective cohort study.
Clinical therapeutics, 2005Co-Authors: Reinhard Sittl, Rudolf Likar, Barbara Poulsen NautrupAbstract:The equipotency ratio of transdermal (TD) fentanyl to oral morphine has been established as 1:100; for buprenorphine TD, a ratio of 1:75 has been proposed, although this ratio has not been confirmed in clinical studies. Growing evidence from clinical practice, in which much lower doses of buprenorphine are used, suggests that this conversion ratio may be too high. The aim of this study was to compare calculated Equipotent oral morphine doses of fentanyl TD with Equipotent oral morphine doses of buprenorphine TD prescribed in clinical practice. This retrospective study identified patients with cancer and noncancer pain who had received > or =1 prescription for fentanyl TD or buprenorphine TD (the all-patients groups) from the German IMS Disease Analyzer-mediplus database, which contains all relevant data concerning drug prescriptions from 400 practices in Germany. Also identified were subgroups of the all-patients groups who had received long-term treatment with fentanyl TD or buprenorphine TD and were considered to have similar pain intensity, as they had previously received similar analgesic medication (the identical-cohort groups). Mean prescribed daily doses for the all-patients and identical-cohort groups were calculated based on the distribution of prescribed patch strengths. Because patients could have applied >1 patch, mean prescribed daily doses were also calculated based on an assumption of double application when appropriate. Equipotent oral morphine doses were estimated using equipotency ratios of 1:100 for fentanyl TD and 1:75 for buprenorphine TD. The all-patients groups consisted of 2198 patients with noncancer pain and 2544 patients with cancer pain; the identical-cohort groups consisted of 380 patients with noncancer pain and 496 patients with cancer pain (529 women, 347 men; mean age, 74 years [range, 25-101 years]). Equipotent doses of oral morphine were significantly lower in patients receiving buprenorphine TD compared with those receiving fentanyl TD (P < 0.001). In cancer patients, the Equipotent oral morphine doses of fentanyl TD and buprenorphine TD were 130.9 to 138.9 mg and 85.2 to 88.8 mg, respectively; in noncancer patients, the corresponding values were 117.0 to 118.3 mg and 80.2 to 80.9 mg. Based on these results, an equipotency ratio of 1:110 to 1:115 for buprenorphine TD would appear to be more appropriate than the proposed ratio of 1:75. The fact that this retrospective analysis conducted in identical cohorts showed lower calculated Equipotent oral morphine doses in the buprenorphine TD groups compared with the fentanyl TD groups calls into question the proposed 1:75 ratio for conversion of buprenorphine TD to Equipotent oral morphine doses. Based on the findings of the present study, an equipotency ratio of 1:110 to 1:115 may be more appropriate. However, confirmative data from prospective randomized clinical trials are needed.
Rowena Callis - One of the best experts on this subject based on the ideXlab platform.
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azd8931 an Equipotent reversible inhibitor of signaling by epidermal growth factor receptor erbb2 her2 and erbb3 a unique agent for simultaneous erbb receptor blockade in cancer
Clinical Cancer Research, 2010Co-Authors: Mark D Hickinson, Judith Anderton, Teresa Klinowska, Georgina Speake, John Vincent, Cath Trigwell, Sarah Beck, Gayle Marshall, Sara Davenport, Rowena CallisAbstract:Purpose: To test the hypothesis that simultaneous, Equipotent inhibition of epidermal growth factor receptor (EGFR; erbB1), erbB2 (human epidermal growth factor receptor 2), and erbB3 receptor signaling, using the novel small-molecule inhibitor AZD8931, will deliver broad antitumor activity in vitro and in vivo . Experimental Design: A range of assays was used to model erbB family receptor signaling in homodimers and heterodimers, including in vitro evaluation of erbB kinase activity, erbB receptor phosphorylation, proliferation in cells, and in vivo testing in a human tumor xenograft panel, with ex vivo evaluation of erbB phosphorylation and downstream biomarkers. Gefitinib and lapatinib were used to compare the pharmacological profile of AZD8931 with other erbB family inhibitors. Results: In vitro , AZD8931 showed Equipotent, reversible inhibition of EGFR (IC 50 , 4 nmol/L), erbB2 (IC 50 , 3 nmol/L), and erbB3 (IC 50 , 4 nmol/L) phosphorylation in cells. In proliferation assays, AZD8931 was significantly more potent than gefitinib or lapatinib in specific squamous cell carcinoma of the head and neck and non–small cell lung carcinoma cell lines. In vivo , AZD8931 inhibited xenograft growth in a range of models while significantly affecting EGFR, erbB2, and erbB3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation. Conclusions: AZD8931 has a unique pharmacologic profile providing Equipotent inhibition of EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models. AZD8931 provides the opportunity to investigate whether simultaneous inhibition of erbB receptor signaling could be of utility in the clinic, particularly in the majority of solid tumors that do not overexpress erbB2. Clin Cancer Res; 16(4); 1159–69
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AZD8931, an Equipotent, reversible inhibitor of signaling by epidermal growth factor receptor, ERBB2 (HER2), and ERBB3: a unique agent for simultaneous ERBB receptor blockade in cancer.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2010Co-Authors: D. Mark Hickinson, Judith Anderton, Teresa Klinowska, Georgina Speake, John Vincent, Cath Trigwell, Sarah Beck, Gayle Marshall, Sara Davenport, Rowena CallisAbstract:To test the hypothesis that simultaneous, Equipotent inhibition of epidermal growth factor receptor (EGFR; erbB1), erbB2 (human epidermal growth factor receptor 2), and erbB3 receptor signaling, using the novel small-molecule inhibitor AZD8931, will deliver broad antitumor activity in vitro and in vivo. A range of assays was used to model erbB family receptor signaling in homodimers and heterodimers, including in vitro evaluation of erbB kinase activity, erbB receptor phosphorylation, proliferation in cells, and in vivo testing in a human tumor xenograft panel, with ex vivo evaluation of erbB phosphorylation and downstream biomarkers. Gefitinib and lapatinib were used to compare the pharmacological profile of AZD8931 with other erbB family inhibitors. In vitro, AZD8931 showed Equipotent, reversible inhibition of EGFR (IC(50), 4 nmol/L), erbB2 (IC(50), 3 nmol/L), and erbB3 (IC(50), 4 nmol/L) phosphorylation in cells. In proliferation assays, AZD8931 was significantly more potent than gefitinib or lapatinib in specific squamous cell carcinoma of the head and neck and non-small cell lung carcinoma cell lines. In vivo, AZD8931 inhibited xenograft growth in a range of models while significantly affecting EGFR, erbB2, and erbB3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation. AZD8931 has a unique pharmacologic profile providing Equipotent inhibition of EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models. AZD8931 provides the opportunity to investigate whether simultaneous inhibition of erbB receptor signaling could be of utility in the clinic, particularly in the majority of solid tumors that do not overexpress erbB2.
John Dingley - One of the best experts on this subject based on the ideXlab platform.
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Equipotent subanesthetic concentrations of sevoflurane and xenon preventing cold stimulated vocalization of neonatal rats
Anesthesiology, 2014Co-Authors: Hannah Gill, Marianne Thoresen, Sarah A. Bishop, Elisa Smit, Xun Liu, Lars Walløe, John DingleyAbstract:BACKGROUND The effects of inhaled anesthetics on the developing brain are studied using neonatal rodents exposed to fractions of minimum alveolar concentration (to avoid cardiorespiratory compromise). However, these fractions cannot be assumed to be Equipotent. Xenon's anesthetic and neuroprotective properties warrant investigation in these models. Therefore, Equipotent, subanesthetic concentrations of inhaled anesthetics are needed. METHODS Forty-eight Wistar rats (Charles River Laboratories, Kent, United Kingdom) on postnatal day 9 were randomized to eight concentrations of inhaled anesthetics: isoflurane, sevoflurane, or xenon. Exposure was closely monitored in individual metal-based chambers resting on a 35°C mat to maintain normothermia. A 25°C mat was used to stimulate vocalization and a sound recording made (1 min, 1 to 100 kHz). Rectal temperature or partial pressure of carbon dioxide and pH of mixed arteriovenous blood were measured immediately after the exposure. Concentration-response models were constructed using logistic regression (dependent variable: vocalization and explanatory variable: concentration). The effects of all other explanatory variables were assessed by inserting them individually into the model. RESULTS The effective inhaled concentrations preventing cold-stimulated vocalization in 50 and 95% of neonatal rats (EiC50 and EiC95) on postnatal day 9 were 0.46 and 0.89% sevoflurane and 20.15 and 34.81% xenon, respectively. The effect on the EiC50 of all other explanatory variables, including duration, was minimal. Stability of EiC50 isoflurane was not achieved over three durations (40, 80, and 120 min exposure). Partial pressure of carbon dioxide and pH in mixed arteriovenous blood appeared normal. CONCLUSIONS The authors report Equipotent subanesthetic concentrations of sevoflurane and xenon in neonatal rats with preserved cardiopulmonary function. This may be useful in designing neonatal rodent models of anesthesia.
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Equipotent subanesthetic concentrations of sevoflurane and xenon preventing cold-stimulated vocalization of neonatal rats.
Anesthesiology, 2014Co-Authors: Hannah Gill, Marianne Thoresen, Sarah A. Bishop, Elisa Smit, Xun Liu, Lars Walløe, John DingleyAbstract:The effects of inhaled anesthetics on the developing brain are studied using neonatal rodents exposed to fractions of minimum alveolar concentration (to avoid cardiorespiratory compromise). However, these fractions cannot be assumed to be Equipotent. Xenon's anesthetic and neuroprotective properties warrant investigation in these models. Therefore, Equipotent, subanesthetic concentrations of inhaled anesthetics are needed. Forty-eight Wistar rats (Charles River Laboratories, Kent, United Kingdom) on postnatal day 9 were randomized to eight concentrations of inhaled anesthetics: isoflurane, sevoflurane, or xenon. Exposure was closely monitored in individual metal-based chambers resting on a 35°C mat to maintain normothermia. A 25°C mat was used to stimulate vocalization and a sound recording made (1 min, 1 to 100 kHz). Rectal temperature or partial pressure of carbon dioxide and pH of mixed arteriovenous blood were measured immediately after the exposure. Concentration-response models were constructed using logistic regression (dependent variable: vocalization and explanatory variable: concentration). The effects of all other explanatory variables were assessed by inserting them individually into the model. The effective inhaled concentrations preventing cold-stimulated vocalization in 50 and 95% of neonatal rats (EiC50 and EiC95) on postnatal day 9 were 0.46 and 0.89% sevoflurane and 20.15 and 34.81% xenon, respectively. The effect on the EiC50 of all other explanatory variables, including duration, was minimal. Stability of EiC50 isoflurane was not achieved over three durations (40, 80, and 120 min exposure). Partial pressure of carbon dioxide and pH in mixed arteriovenous blood appeared normal. The authors report Equipotent subanesthetic concentrations of sevoflurane and xenon in neonatal rats with preserved cardiopulmonary function. This may be useful in designing neonatal rodent models of anesthesia.
Reinhard Sittl - One of the best experts on this subject based on the ideXlab platform.
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Equipotent doses of transdermal fentanyl and transdermal buprenorphine in patients with cancer and noncancer pain results of a retrospective cohort study
Clinical Therapeutics, 2005Co-Authors: Reinhard Sittl, Rudolf Likar, Barbara Poulsen NautrupAbstract:Abstract Background: The equipotency ratio of transdermal (TD) fentanyl to oral morphine has been established as 1:100; for buprenorphine TD, a ratio of 1:75 has been proposed, although this ratio has not been confirmed in clinical studies. Growing evidence from clinical practice, in which much lower doses of buprenorphine are used, suggests that this conversion ratio may be too high. Objective: The aim of this study was to comparecalculated Equipotent oral morphine doses of fentanyl TD with Equipotent oral morphine doses of buprenorphine TD prescribed in clinical practice. Methods: This retrospective study identified patientswith cancer and noncancer pain who had received ≥1 prescription for fentanyl TD or buprenorphine TD (the all-patients groups) from the German IMS Disease Analyzer-mediplus database, which contains all relevant data concerning drug prescriptions from 400 practices in Germany. Also identified were subgroups of the all-patients groups who had received long-term treatment with fentanyl TD or buprenorphine TD and were considered to have similar pain intensity, as they had previously received similar analgesic medication (the identical-cohort groups). Mean prescribed daily doses for the all-patients and identical-cohort groups were calculated based on the distribution of prescribed patch strengths. Because patients could have applied >1 patch, mean prescribed daily doses were also calculated based on an assumption of double application when appropriate. Equipotent oral morphine doses were estimated using equipotency ratios of 1:100 for fentanyl TD and 1:75 for buprenorphine TD. Results: The all-patients groups consisted of 2198 patients with noncancer pain and 2544 patients with cancer pain; the identical-cohort groups consisted of 380 patients with noncancer pain and 496 patients with cancer pain (529 women, 347 men; mean age, 74 years [range, 25–101 years]). Equipotent doses of oral morphine were significantly lower in patients receiving buprenorphine TD compared with those receiving fentanyl TD (P Conclusions: The fact that this retrospective analysis conducted in identical cohorts showed lower calculated Equipotent oral morphine doses in the buprenorphine TD groups compared with the fentanyl TD groups calls into question the proposed 1:75 ratio for conversion of buprenorphine TD to Equipotent oral morphine doses. Based on the findings of the present study, an equipotency ratio of 1:110 to 1:115 may be more appropriate. However, confirmative data from prospective randomized clinical trials are needed.
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Equipotent doses of transdermal fentanyl and transdermal buprenorphine in patients with cancer and noncancer pain: results of a retrospective cohort study.
Clinical therapeutics, 2005Co-Authors: Reinhard Sittl, Rudolf Likar, Barbara Poulsen NautrupAbstract:The equipotency ratio of transdermal (TD) fentanyl to oral morphine has been established as 1:100; for buprenorphine TD, a ratio of 1:75 has been proposed, although this ratio has not been confirmed in clinical studies. Growing evidence from clinical practice, in which much lower doses of buprenorphine are used, suggests that this conversion ratio may be too high. The aim of this study was to compare calculated Equipotent oral morphine doses of fentanyl TD with Equipotent oral morphine doses of buprenorphine TD prescribed in clinical practice. This retrospective study identified patients with cancer and noncancer pain who had received > or =1 prescription for fentanyl TD or buprenorphine TD (the all-patients groups) from the German IMS Disease Analyzer-mediplus database, which contains all relevant data concerning drug prescriptions from 400 practices in Germany. Also identified were subgroups of the all-patients groups who had received long-term treatment with fentanyl TD or buprenorphine TD and were considered to have similar pain intensity, as they had previously received similar analgesic medication (the identical-cohort groups). Mean prescribed daily doses for the all-patients and identical-cohort groups were calculated based on the distribution of prescribed patch strengths. Because patients could have applied >1 patch, mean prescribed daily doses were also calculated based on an assumption of double application when appropriate. Equipotent oral morphine doses were estimated using equipotency ratios of 1:100 for fentanyl TD and 1:75 for buprenorphine TD. The all-patients groups consisted of 2198 patients with noncancer pain and 2544 patients with cancer pain; the identical-cohort groups consisted of 380 patients with noncancer pain and 496 patients with cancer pain (529 women, 347 men; mean age, 74 years [range, 25-101 years]). Equipotent doses of oral morphine were significantly lower in patients receiving buprenorphine TD compared with those receiving fentanyl TD (P < 0.001). In cancer patients, the Equipotent oral morphine doses of fentanyl TD and buprenorphine TD were 130.9 to 138.9 mg and 85.2 to 88.8 mg, respectively; in noncancer patients, the corresponding values were 117.0 to 118.3 mg and 80.2 to 80.9 mg. Based on these results, an equipotency ratio of 1:110 to 1:115 for buprenorphine TD would appear to be more appropriate than the proposed ratio of 1:75. The fact that this retrospective analysis conducted in identical cohorts showed lower calculated Equipotent oral morphine doses in the buprenorphine TD groups compared with the fentanyl TD groups calls into question the proposed 1:75 ratio for conversion of buprenorphine TD to Equipotent oral morphine doses. Based on the findings of the present study, an equipotency ratio of 1:110 to 1:115 may be more appropriate. However, confirmative data from prospective randomized clinical trials are needed.
Judith Anderton - One of the best experts on this subject based on the ideXlab platform.
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Discovery of AZD8931, an Equipotent, Reversible Inhibitor of Signaling by EGFR, HER2, and HER3 Receptors.
ACS medicinal chemistry letters, 2013Co-Authors: Barlaam Bernard Christophe, Judith Anderton, Peter Ballard, Robert Hugh Bradbury, Laurent Francois Andre Hennequin, D. Mark Hickinson, Jason G. Kettle, George Kirk, Teresa Klinowska, Christine Lambert-van Der BremptAbstract:Deregulation of HER family signaling promotes proliferation and tumor cell survival and has been described in many human cancers. Simultaneous, Equipotent inhibition of EGFR-, HER2-, and HER3-mediated signaling may be of clinical utility in cancer settings where the selective EGFR or HER2 therapeutic agents are ineffective or only modestly active. We describe the discovery of AZD8931 (2), an Equipotent, reversible inhibitor of EGFR-, HER2-, and HER3-mediated signaling and the structure-activity relationships within this series. Docking studies based on a model of the HER2 kinase domain helped rationalize the increased HER2 activity seen with the methyl acetamide side chain present in AZD8931. AZD8931 exhibited good pharmacokinetics in preclinical species and showed superior activity in the LoVo tumor growth efficacy model compared to close analogues. AZD8931 is currently being evaluated in human clinical trials for the treatment of cancer.
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azd8931 an Equipotent reversible inhibitor of signaling by epidermal growth factor receptor erbb2 her2 and erbb3 a unique agent for simultaneous erbb receptor blockade in cancer
Clinical Cancer Research, 2010Co-Authors: Mark D Hickinson, Judith Anderton, Teresa Klinowska, Georgina Speake, John Vincent, Cath Trigwell, Sarah Beck, Gayle Marshall, Sara Davenport, Rowena CallisAbstract:Purpose: To test the hypothesis that simultaneous, Equipotent inhibition of epidermal growth factor receptor (EGFR; erbB1), erbB2 (human epidermal growth factor receptor 2), and erbB3 receptor signaling, using the novel small-molecule inhibitor AZD8931, will deliver broad antitumor activity in vitro and in vivo . Experimental Design: A range of assays was used to model erbB family receptor signaling in homodimers and heterodimers, including in vitro evaluation of erbB kinase activity, erbB receptor phosphorylation, proliferation in cells, and in vivo testing in a human tumor xenograft panel, with ex vivo evaluation of erbB phosphorylation and downstream biomarkers. Gefitinib and lapatinib were used to compare the pharmacological profile of AZD8931 with other erbB family inhibitors. Results: In vitro , AZD8931 showed Equipotent, reversible inhibition of EGFR (IC 50 , 4 nmol/L), erbB2 (IC 50 , 3 nmol/L), and erbB3 (IC 50 , 4 nmol/L) phosphorylation in cells. In proliferation assays, AZD8931 was significantly more potent than gefitinib or lapatinib in specific squamous cell carcinoma of the head and neck and non–small cell lung carcinoma cell lines. In vivo , AZD8931 inhibited xenograft growth in a range of models while significantly affecting EGFR, erbB2, and erbB3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation. Conclusions: AZD8931 has a unique pharmacologic profile providing Equipotent inhibition of EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models. AZD8931 provides the opportunity to investigate whether simultaneous inhibition of erbB receptor signaling could be of utility in the clinic, particularly in the majority of solid tumors that do not overexpress erbB2. Clin Cancer Res; 16(4); 1159–69
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AZD8931, an Equipotent, reversible inhibitor of signaling by epidermal growth factor receptor, ERBB2 (HER2), and ERBB3: a unique agent for simultaneous ERBB receptor blockade in cancer.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2010Co-Authors: D. Mark Hickinson, Judith Anderton, Teresa Klinowska, Georgina Speake, John Vincent, Cath Trigwell, Sarah Beck, Gayle Marshall, Sara Davenport, Rowena CallisAbstract:To test the hypothesis that simultaneous, Equipotent inhibition of epidermal growth factor receptor (EGFR; erbB1), erbB2 (human epidermal growth factor receptor 2), and erbB3 receptor signaling, using the novel small-molecule inhibitor AZD8931, will deliver broad antitumor activity in vitro and in vivo. A range of assays was used to model erbB family receptor signaling in homodimers and heterodimers, including in vitro evaluation of erbB kinase activity, erbB receptor phosphorylation, proliferation in cells, and in vivo testing in a human tumor xenograft panel, with ex vivo evaluation of erbB phosphorylation and downstream biomarkers. Gefitinib and lapatinib were used to compare the pharmacological profile of AZD8931 with other erbB family inhibitors. In vitro, AZD8931 showed Equipotent, reversible inhibition of EGFR (IC(50), 4 nmol/L), erbB2 (IC(50), 3 nmol/L), and erbB3 (IC(50), 4 nmol/L) phosphorylation in cells. In proliferation assays, AZD8931 was significantly more potent than gefitinib or lapatinib in specific squamous cell carcinoma of the head and neck and non-small cell lung carcinoma cell lines. In vivo, AZD8931 inhibited xenograft growth in a range of models while significantly affecting EGFR, erbB2, and erbB3 phosphorylation and downstream signaling pathways, apoptosis, and proliferation. AZD8931 has a unique pharmacologic profile providing Equipotent inhibition of EGFR, erbB2, and erbB3 signaling and showing greater antitumor activity than agents with a narrower spectrum of erbB receptor inhibition in specific preclinical models. AZD8931 provides the opportunity to investigate whether simultaneous inhibition of erbB receptor signaling could be of utility in the clinic, particularly in the majority of solid tumors that do not overexpress erbB2.