Use of Quantitative Pharmacology in the Development of HAE1, a High-Affinity Anti-IgE Monoclonal Antibody

HAE1, a high-affinity anti-IgE monoclonal antibody, is discussed here as a case study in the use of quantitative pharmacology in the development of a second-generation molecule. In vitro, preclinical, and clinical data from the first-generation molecule, omalizumab, were heavily leveraged in the HAE1 program. A preliminary mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for HAE1 was developed using an existing model for omalizumab, together with in vitro binding data for HAE1 and omalizumab. When phase I data were available, the model was refined by simultaneously modeling PK/PD data from omalizumab studies with the available HAE1 phase I data. The HAE1 clinical program was based on knowledge of the quantitative relationship between a pharmacodynamic biomarker, suppression of free IgE, and clinical response (e.g., lower exacerbation rates) obtained in pivotal studies with omalizumab. A clinical trial simulation platform was developed to predict free IgE levels and clinical responses following attainment of a target free IgE level (≤10 IU/ml). The simulation platform enabled selection of four doses for the phase II dose-ranging trial by two independent methods: dose-response non-linear fitting and linear mixed modeling. Agreement between the two methods provided confidence in the doses selected. Modeling and simulation played a large role in supporting acceleration of the HAE1 program by enabling data-driven decision-making, often based on confirmation of projections and/or learning from incoming new data

Catalytic Methanol Synthesis via Black Liquor Gasification

Biofuel production from gasified black liquor is an interesting route to decrease green house gas emissions. The only pressurised black liquor gasifier currently in pilot operation is located in Sweden. In this work, synthesis gas was taken online directly from this gasifier, purified from hydrocarbons and sulphur compounds and for the first time catalytically converted to methanol in a bench scale equipment. Methanol was successfully synthesised during 45 h in total and the space time yield of methanol produced at 25 bar pressure was 0.16-0.19 g methanol/(g catalyst h). The spent catalyst exposed to gas from the gasifier was slightly enriched in calcium and sodium at the inlet of the reactor and in boron and nickel at the outlet of the reactor. Calcium, sodium and boron likely stem from black liquor whereas nickel probably originates from the stainless steel in the equipment. A slight deactivation, reduced surface area and mesoporosity of the catalyst exposed to gas from the gasifier were observed but it was not possible to reveal the origin of the deactivation. In addition to water, the produced methanol contained traces of hydrocarbons up to C4, ethanol and dimethyl ether

Metabolic syndrome and risk of bladder cancer: prospective cohort study in the metabolic syndrome and cancer project (Me-Can)

There are little data on the putative association between factors in the metabolic syndrome (MetS) and risk of bladder cancer. In the Metabolic Syndrome and Cancer project (Me-Can), measurements of height, weight, blood pressure and circulating levels of glucose, cholesterol, and triglycerides had been collected from 578,700 subjects in cohorts in Norway, Austria, and Sweden. We used Cox proportional hazard models to calculate relative risks (RRs) of bladder cancer by exposures divided into quintiles, in categories according to the World Health Organisation (WHO) and as a continuous standardized variable (z-score with mean = 0 and standard deviation = 1) for each separate component and its standardized sum, a composite MetS score. RRs were corrected for random error in measurements. During a mean follow-up of 11.7 years (SD = 7.6), 1,587 men and 327 women were diagnosed with bladder cancer. Significant associations with risk were found among men per one unit increment of z-score for blood pressure, RR 5 1.13 (95% CI 1.03-1.25), and the composite MetS score, RR = 1.10 (95% CI 1.01-1.18). Among women, glucose was nonsignificantly associated with risk, RR = 1.41 (95% CI 0.97-2.06). No statistically significant interactions were found between the components in the MetS in relation to bladder cancer risk. Hypertension and a composite MetS score were significantly but modestly associated with an increased risk of bladder cancer among men and elevated glucose was associated with a nonsignificant increase in risk among women. Epidemiolog

Metabolic Syndrome and Breast Cancer in the Me-Can (Metabolic Syndrome and Cancer) Project

Background: Few studies have assessed the metabolic syndrome (MetS) as an entity in relation to breast cancer risk, and results have been inconsistent. We aimed to examine the association between MetS factors (individually and combined) and risk of breast cancer incidence and mortality. Methods: Two hundred ninety thousand women from Austria, Norway, and Sweden were enrolled during 1974-2005, with measurements of height, weight, blood pressure, and levels of glucose, cholesterol, and triglycerides. Relative risks (RR) of breast cancer were estimated using Cox proportional hazards regression for each MetS factor in quintiles and for standardized levels (z-scores) and for a composite z-score for the MetS. Results: There were 4,862 incident cases of breast cancer and 633 deaths from breast cancer identified. In women below age 50, there was a decreased risk of incident cancer for the MetS (per 1-unit increment of z-score; RR, 0.83; 95% confidence interval, 0.76-0.90) as well as for the individual factors (except for glucose). The lowest risks were seen among the heaviest women. In women above age 60, there was an increased risk of breast cancer mortality for the MetS (RR, 1.23; 95% confidence interval, 1.04-1.45) and for blood pressure and glucose. The strongest association with mortality was seen for increased glucose concentrations. Conclusions: The MetS was associated with a decreased risk of incident breast cancer in women below age 50 with high body mass index, and with an increased risk of breast cancer mortality in women above 60. Impact: Lifestyle interventions as recommended for cardiovascular disease prevention may be of value to prevent breast cancer mortality in postmenopausal women. Cancer Epidemiol Biomarkers Prev; 19(7); 1737-45. (C) 2010 AACR

Prospective cohort study of metabolic risk factors and gastric adenocarcinoma risk in the Metabolic Syndrome and Cancer Project (Me-Can)

Little is known about the association between the metabolic syndrome (MetS) and the risk of gastric adenocarcinoma. The aim of this study was to investigate whether metabolic risk factors, together or combined, were associated with the risk of gastric adenocarcinoma. The Metabolic Syndrome and Cancer Project (Me-Can) is a pooling of prospective cohorts in Austria, Norway, and Sweden with information on blood pressure, lipids, glucose, and BMI available in 578,700 individuals. Cox proportional hazards analysis was used to calculate hazard ratio (HR) of gastric adenocarcinoma using metabolic risk factors categorized into quintiles and transformed into z-scores (with mean = 0 and SD = 1). The standardized sum of all z-scores created a composite MetS score. In total, 1,210 incident cases of gastric adenocarcinoma were identified. Glucose was significantly associated with the risk of gastric adenocarcinoma [calibrated HR 1.58 (1.14-2.20) per one unit increment in z-score] in women. There was a statistically significant association between triglycerides and risk of gastric adenocarcinoma per mmol increment in triglycerides [HR 1.20 (1.06-1.36) per mmol] but not for the adjusted z-score in women. There were no significant association between any metabolic factors and gastric cancer among men. The composite MetS score was associated with the risk of gastric adenocarcinoma in women [HR 1.18 (1.00-1.38) per one unit increment in z-score] but not in men. Glucose and high levels of the composite MetS score were associated with an increased risk of gastric adenocarcinoma in women but not in men

Metabolic syndrome and rare gynecological cancers in the Metabolic syndrome and Cancer project (Me-Can)

Background: Risk factors for rare gynecological cancers are largely unknown. Initial research has indicated that the metabolic syndrome (MetS) or individual components could play a role. Materials and methods: The Metabolic syndrome and Cancer project cohort includes 288 834 women. During an average follow-up of 11 years, 82 vulvar, 26 vaginal and 43 other rare gynecological cancers were identified. Hazard ratios (HRs) were estimated fitting Cox proportional hazards regression models for tertiles and standardized z-scores [with a mean of 0 and a standard deviation (SD) of 1] of body mass index (BMI), blood pressure, glucose, cholesterol, triglycerides and MetS. Risk estimates were corrected for random error in the measurement of metabolic factors. Results: The MetS was associated with increased risk of vulvar [HR 1.78, 95% confidence interval (CI) 1.30-2.41) and vaginal cancer (HR 1.87, 95% CI 1.07-3.25). Among separate MetS components, 1 SD increase in BMI was associated with overall risk (HR 1.43, 95% CI 1.23-1.66), vulvar (HR 1.36, 95% CI 1.11-1.69) and vaginal cancer (HR 1.79, 95% CI 1.30-2.46). Blood glucose and triglyceride concentrations were associated with increased risk of vulvar cancer (HR 1.98, 95% CI 1.10-3.58 and HR 2.09, 95% CI 1.39-3.15, respectively). Conclusion: The results from this first prospective study on rare gynecological cancers suggest that the MetS and its individual components may play a role in the development of these tumors

Serum triglycerides and cancer risk in the metabolic syndrome and cancer (Me-Can) collaborative study

To assess the association between serum triglyceride levels and cancer risk. The metabolic syndrome and cancer project (Me-Can) includes cohorts from Norway, Austria, and Sweden; the current study included data on 257,585 men and 256,512 women. The mean age at study entry was 43.8 years for men and 44.2 years for women. The mean follow-up time was 13.4 years (SD = 8.5) for men and 11.9 years (SD = 7.2) for women. Excluding the first year of follow-up, 23,060 men and 15,686 women were diagnosed with cancer. Cox regression models were used to calculate relative risk (RR) of cancer for triglyceride levels in quintiles and as a continuous variable. RRs were corrected for random error by use of regression dilution ratio. Relative risk for top quintile versus bottom quintile of triglycerides of overall cancer was 1.16 (95% confidence interval 1.06-1.26) in men and 1.15 (1.05-1.27) in women. For specific cancers, significant increases for top quintile versus bottom quintile of triglycerides among men were found for cancers of the colon, respiratory tract, the kidney, melanoma and thyroid and among women, for respiratory, cervical, and non-melanoma skin cancers. Data from our study provided evidence for a possible role of serum triglycerides in cancer development

Metabolic risk factors and primary liver cancer in a prospective study of 578,700 adults

Initial studies have indicated diabetes and obesity to be risk factors for hepatocellular carcinoma; but the association between other metabolic risk factors and primary liver cancer (PLC) has not been investigated. The metabolic syndrome and cancer project (Me-Can) includes cohorts from Norway, Austria and Sweden with data on 578,700 subjects. We used Cox proportional hazard models to calculate relative risks (RRs) of PLC by body mass index (BMI), blood pressure and plasma levels of glucose, cholesterol and triglycerides as continuous standardized variables (z-score with mean = 0 and standard deviation (SD) = 1) and their standardized sum of metabolic syndrome (MetS) z-score. RRs were corrected for random error in measurements. During an average follow-up of 12.0 years (SD = 7.8), 266 PLCs were diagnosed among cohort members. RR of liver cancer per unit increment of z-score adjusted for age, smoking status and BMI and stratified by birth year, sex and sub-cohorts, was for BMI 1.39 (95% confidence interval (CI) 1.241.58), mid blood pressure 2.08 (0.954.73), blood glucose 2.13 (1.552.94) cholesterol 0.62 (0.510.76) and serum triglycerides 0.85 (0.651.10). The RR per one unit increment of the MetS z-score was 1.35 (1.121.61). BMI, glucose and a composite MetS score were positively and cholesterol negatively associated with risk of liver cancer