Comprehensive biomarker and modeling approach to support dose finding for BI 836880, a VEGF/Ang-2 inhibitor.

BACKGROUND: BI 836880 is a humanized bispecific nanobody® that binds to and blocks vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2). A comprehensive biomarker and modeling approach is presented here that supported dose finding for BI 836880. METHODS: Two Phase I dose-escalation studies (1336.1 [NCT02674152], 1336.6 [NCT02689505]) assessed BI 836880 in adults with confirmed locally advanced or metastatic solid tumors, refractory to standard therapy or for which standard therapy was not reliably effective. Two dosing schedules were investigated, 3 weeks (q3w) or once weekly (qw), starting at a dose of 40 mg. In a comprehensive biomarker approach, soluble pharmacodynamic markers (free and total plasma VEGF-A and Ang-2), as well as circulating angiogenic factors (soluble VEGF3, soluble Tie2 and placenta growth factor, amongst others) were analyzed to assess target engagement in peripheral blood for q3w doses. A Population based pharmacokinetics/pharmacodynamics (PopPK/PD) model was built using the limited Phase I dataset to support dose finding by simulations. In order to demonstrate drug activity in the tumor, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was applied. RESULTS: DCE-MRI scans supported target engagement in the tumor. Free VEGF-A was depleted at all doses, whereas free Ang-2 decreased dose-dependently, reaching depletion in most patients from 360 mg q3w onwards. While total VEGF-A levels increased in a dose-dependent manner, reaching saturation at 360 mg q3w, total Ang-2 levels increased, but did not plateau. Angiogenic biomarkers showed changes from doses ≥ 360 mg q3w. PopPK/PD modeling showed that doses ≥ 360 mg q3w led to > 90% inhibition of free Ang-2 at steady-state in most patients. By increasing the dose to ≥ 500 mg q3w, > 90% of patients are expected to achieve this level. CONCLUSIONS: The comprehensive analyses of multiple target engagement markers support BI 836880 720 mg q3w as a biologically relevant monotherapy dose schedule. TRIAL REGISTRATION: NCT02674152 and NCT02689505.

Exposure-safety analyses of nintedanib in patients with chronic fibrosing interstitial lung disease.

BACKGROUND: Nintedanib reduces the rate of decline in forced vital capacity in patients with idiopathic pulmonary fibrosis (IPF), other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype and systemic sclerosis-associated ILD (SSc-ILD). The recommended dose of nintedanib is 150 mg twice daily (BID). METHODS: Data from Phase II and III trials in IPF and Phase III trials in SSc-ILD and progressive fibrosing ILDs other than IPF were analyzed to investigate the relationship between nintedanib plasma concentrations (exposure) and safety (liver enzyme elevations [defined as transaminase elevations equal or greater than 3 times the upper limit of normal] and diarrhea). RESULTS: Using data from 1403 subjects with IPF treated with 50-150 mg nintedanib BID, a parametric time-to-first-event model for liver enzyme elevations was established. Besides exposure, gender was a significant covariate, with a three-fourfold higher exposure-adjusted risk in females than males. Subsequent analysis of combined data from IPF, SSc-ILD (n = 576) and progressive fibrosing ILD (n = 663) studies suggested a consistent exposure-liver enzyme elevation relationship across studies. No exposure-diarrhea relationship was found using data from the various fibrosing ILDs, but diarrhea risk was dependent on dose administered. CONCLUSIONS: The positive correlation between exposure and risk of liver enzyme elevations was consistent across nintedanib studies in IPF, SSc-ILD and progressing fibrosing ILDs other than IPF. The effect size does not warrant a priori dose adjustment in patients with altered plasma exposure (excluding hepatic impairment patients, where there are specific labelling recommendations). For diarrhea, dose administered was a better predictor than exposure.

Study design of a randomised, placebo-controlled trial of nintedanib in children and adolescents with fibrosing interstitial lung disease.

Childhood interstitial lung disease (chILD) comprises >200 rare respiratory disorders, with no currently approved therapies and variable prognosis. Nintedanib reduces the rate of forced vital capacity (FVC) decline in adults with progressive fibrosing interstitial lung diseases (ILDs). We present the design of a multicentre, prospective, double-blind, randomised, placebo-controlled clinical trial of nintedanib in patients with fibrosing chILD (1199-0337 or InPedILD; ClinicalTrials.gov: NCT04093024). Male or female children and adolescents aged 6-17 years (≥30; including ≥20 adolescents aged 12-17 years) with clinically significant fibrosing ILD will be randomised 2:1 to receive oral nintedanib or placebo on top of standard of care for 24 weeks (double-blind), followed by variable-duration nintedanib (open-label). Nintedanib dosing will be based on body weight-dependent allometric scaling, with single-step dose reductions permitted to manage adverse events. Eligible patients will have evidence of fibrosis on high-resolution computed tomography (within 12 months of their first screening visit), FVC ≥25% predicted, and clinically significant disease (Fan score of ≥3 or evidence of clinical progression over time). Patients with underlying chronic liver disease, significant pulmonary arterial hypertension, cardiovascular disease, or increased bleeding risk are ineligible. The primary endpoints are pharmacokinetics and the proportion of patients with treatment-emergent adverse events at week 24. Secondary endpoints include change in FVC% predicted from baseline, Pediatric Quality of Life Questionnaire, oxygen saturation, and 6-min walk distance at weeks 24 and 52. Additional efficacy and safety endpoints will be collected to explore long-term effects.

Exposure-efficacy analyses of nintedanib in patients with chronic fibrosing interstitial lung disease.

BACKGROUND: The tyrosine kinase inhibitor nintedanib reduces the rate of decline in forced vital capacity (FVC) in patients with idiopathic pulmonary fibrosis (IPF), other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype and systemic sclerosis-associated ILD (SSc-ILD). The recommended dose of nintedanib is 150 mg twice daily (BID). METHODS: Data from Phase II and III trials in IPF, SSc-ILD and progressive fibrosing ILDs other than IPF were analyzed to investigate the relationship between nintedanib plasma concentrations (exposure) and efficacy. RESULTS: Using data from 1403 patients with IPF treated with 50-150 mg nintedanib BID in Phase II and III studies, a linear disease progression model with a maximum drug effect on the rate of decline in FVC was established. Age, height and gender were pre-specified covariates on baseline FVC. Stepwise analysis revealed no other covariates with a distinct effect on the exposure-efficacy relationship. The estimated plasma concentration producing 80% of the maximum drug effect was 10-13 ng/mL, close to the median exposure at 150 mg BID (10 ng/mL). The model in IPF was adapted using Phase III data from 575 patients with SSc-ILD and 663 patients with progressive fibrosing ILDs other than IPF. Besides differences in the natural decline in FVC without treatment, data were consistent with the exposure-efficacy relationship in IPF. CONCLUSIONS: For most patients with chronic fibrosing ILDs, the 150 mg nintedanib BID dose provides exposure levels associated with a therapeutic effect close to the maximum nintedanib effect independent of disease condition or baseline demographics.

Two first-in-human studies of xentuzumab, a humanised insulin-like growth factor (IGF)-neutralising antibody, in patients with advanced solid tumours.

BACKGROUND: Xentuzumab, an insulin-like growth factor (IGF)-1/IGF-2-neutralising antibody, binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling. Two first-in-human trials assessed the maximum-tolerated/relevant biological dose (MTD/RBD), safety, pharmacokinetics, pharmacodynamics, and activity of xentuzumab in advanced/metastatic solid cancers. METHODS: These phase 1, open-label trials comprised dose-finding (part I; 3 + 3 design) and expansion cohorts (part II; selected tumours; RBD [weekly dosing]). Primary endpoints were MTD/RBD. RESULTS: Study 1280.1 involved 61 patients (part I: xentuzumab 10-1800 mg weekly, n = 48; part II: 1000 mg weekly, n = 13); study 1280.2, 64 patients (part I: 10-3600 mg three-weekly, n = 33; part II: 1000 mg weekly, n = 31). One dose-limiting toxicity occurred; the MTD was not reached for either schedule. Adverse events were generally grade 1/2, mostly gastrointestinal. Xentuzumab showed dose-proportional pharmacokinetics. Total plasma IGF-1 increased dose dependently, plateauing at ~1000 mg/week; at ≥450 mg/week, IGF bioactivity was almost undetectable. Two partial responses occurred (poorly differentiated nasopharyngeal carcinoma and peripheral primitive neuroectodermal tumour). Integration of biomarker and response data by Bayesian Logistic Regression Modeling (BLRM) confirmed the RBD. CONCLUSIONS: Xentuzumab was well tolerated; MTD was not reached. RBD was 1000 mg weekly, confirmed by BLRM. Xentuzumab showed preliminary anti-tumour activity. CLINICAL TRIAL REGISTRATION: NCT01403974; NCT01317420.

Model-Informed Dose Selection for Xentuzumab, a Dual Insulin-Like Growth Factor-I/II-Neutralizing Antibody.

Over the past decade, the insulin-like growth factor (IGF)-signaling pathway has gained substantial interest as potential therapeutic target in oncology. Xentuzumab, a humanized IgG1 monoclonal antibody, binds to IGF-I and IGF-II thereby inhibiting the downstream signaling essential for survival and tumor growth. This pathway is further regulated by circulating IGF binding proteins (IGFBPs). In this work, a mechanistic model characterizing the dynamics and interactions of IGFs, IGFBPs, and Xentuzumab has been developed to guide dose selection. Therefore, in vitro and in vivo literature information was combined with temporal IGF-I, IGF-II, and IGFBP-3 total plasma concentrations from two phase I studies. Based on the established quantitative framework, the time-course of free IGFs as ultimate drug targets not measured in clinics was predicted. Finally, a dose of 1000 mg/week-predicted to reduce free IGF-I and free IGF-II at steady-state by at least 90% and 64%, respectively-was suggested for phase II.

Clinical Pharmacokinetics and Pharmacodynamics of Nintedanib.

Nintedanib is an oral, small-molecule tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis and patients with advanced non-small cell cancer of adenocarcinoma tumour histology. Nintedanib competitively binds to the kinase domains of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF). Studies in healthy volunteers and in patients with advanced cancer have shown that nintedanib has time-independent pharmacokinetic characteristics. Maximum plasma concentrations of nintedanib are reached approximately 2-4 h after oral administration and thereafter decline at least bi-exponentially. Over the investigated dose range of 50-450 mg once daily and 150-300 mg twice daily, nintedanib exposure increases are dose proportional. Nintedanib is metabolised via hydrolytic ester cleavage, resulting in the formation of the free acid moiety that is subsequently glucuronidated and excreted in the faeces. Less than 1% of drug-related radioactivity is eliminated in urine. The terminal elimination half-life of nintedanib is about 10-15 h. Accumulation after repeated twice-daily dosing is negligible. Sex and renal function have no influence on nintedanib pharmacokinetics, while effects of ethnicity, low body weight, older age and smoking are within the inter-patient variability range of nintedanib exposure and no dose adjustments are required. Administration of nintedanib in patients with moderate or severe hepatic impairment is not recommended, and patients with mild hepatic impairment should be monitored closely and the dose adjusted accordingly. Nintedanib has a low potential for drug-drug interactions, especially with drugs metabolised by cytochrome P450 enzymes. Concomitant treatment with potent inhibitors or inducers of the P-glycoprotein transporter can affect the pharmacokinetics of nintedanib. At an investigated dose of 200 mg twice daily, nintedanib does not have proarrhythmic potential.

Population pharmacokinetics of nintedanib in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Nintedanib is a potent intracellular inhibitor of tyrosine kinases, including the receptor kinases vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor. A previous model assessed the population pharmacokinetics of nintedanib and its main metabolite BIBF 1202 in patients with non-small cell lung cancer and idiopathic pulmonary fibrosis (IPF). The objective of this analysis was to further characterise the population pharmacokinetics of nintedanib in patients with IPF by including data from the Phase III trials. METHODS: We pooled data from 933 patients with IPF participating in the Phase II TOMORROW trial and the two Phase III INPULSIS trials. Plasma concentrations of nintedanib (n = 3501) were analysed using nonlinear mixed-effects modelling. RESULTS: Pharmacokinetics of nintedanib was described by a one-compartment model with linear elimination, first-order absorption and an absorption lag time. The population estimates of absorption rate, lag time, apparent total clearance and apparent volume of distribution at steady state for a typical IPF patient were 0.0814 h-1, 0.689 h, 994 L/h, and 265 L. The model confirmed age, body weight, smoking and Asian race (with different effect sizes in different Asian subpopulations) as statistically significant covariates influencing nintedanib exposure. Serum lactate dehydrogenase levels were identified as another factor significantly influencing nintedanib plasma concentrations. No individual covariate at extreme values (5th and 95th percentiles of baseline for continuous covariates) resulted in changes in exposure of more than 50% relative to a typical patient. CONCLUSIONS: The developed model provides further details about the pharmacokinetics of nintedanib in patients with IPF and can be used for simulations exploring covariate effects and exposure-response analyses in this patient population.

Pharmacokinetics of Nintedanib in Subjects With Hepatic Impairment.

Nintedanib is an intracellular inhibitor of tyrosine kinases used in the treatment of non-small cell lung cancer and idiopathic pulmonary fibrosis (IPF). This phase 1 open-label study investigated the influence of mild and moderate hepatic impairment on the pharmacokinetics (PK), safety, and tolerability of nintedanib following oral administration of a single 100-mg dose. Subjects with hepatic impairment classified as Child-Pugh A (mild hepatic impairment) or Child-Pugh B (moderate hepatic impairment) were eligible. The control group comprised healthy matched subjects. Primary end points were Cmax and AUC0-∞ of nintedanib. Thirty-three subjects received nintedanib (8 in each of the Child-Pugh A and Child-Pugh B groups and 17 controls). The shape of the plasma concentration-time curve for nintedanib was similar between Child-Pugh A or B and healthy subjects. Nintedanib exposure was ∼2-fold higher in Child-Pugh A subjects and ∼8-fold higher in Child-Pugh B subjects than in healthy subjects. Adverse events were reported in 3 Child-Pugh B subjects (37.5%), no Child-Pugh A subjects, and 3 healthy subjects (17.6%). In conclusion, exposure to nintedanib was higher in Child-Pugh A and B subjects than in matched healthy subjects. A single dose of nintedanib 100 mg had an acceptable safety and tolerability profile in subjects with hepatic impairment. Results of this dedicated phase 1 study are in line with exploratory investigations into the PK of nintedanib in patients with advanced solid tumors or IPF and hepatic impairment.

Population pharmacokinetics of nintedanib, an inhibitor of tyrosine kinases, in patients with non-small cell lung cancer or idiopathic pulmonary fibrosis.

PURPOSE: A population pharmacokinetic model was developed for nintedanib in patients with non-small cell lung cancer (NSCLC) or idiopathic pulmonary fibrosis (IPF). The effects of intrinsic and extrinsic patient factors on exposure of nintedanib and its main metabolite BIBF 1202 were studied. METHODS: Data from 1191 patients with NSCLC (n = 849) or IPF (n = 342) treated with oral nintedanib (once- or twice-daily, dose range 50-250 mg) in 4 Phase II or III studies were combined. Plasma concentrations of nintedanib (n = 5611) and BIBF 1202 (n = 5376) were analyzed using non-linear mixed-effects modeling. RESULTS: Pharmacokinetics of nintedanib were described by a one-compartment model with linear elimination, first-order absorption, and absorption lag time. For a typical patient, the absorption rate was 0.0827 h-1, apparent total clearance was 897 L/h, apparent volume of distribution at steady state was 465 L, and lag time was 25 min. Age, weight, smoking, and Asian race were statistically significant covariates influencing nintedanib exposure, but no individual covariate at extreme values (5th and 95th percentiles of baseline values for continuous covariates) resulted in a change of more than 33% relative to a typical patient. Pharmacokinetics and covariate effects for BIBF 1202 were similar to nintedanib. Mild or moderate renal impairment and mild hepatic impairment (classified by transaminase or bilirubin increase above the upper limit of normal) or underlying disease had no significant effects on nintedanib pharmacokinetics. CONCLUSIONS: This model adequately described the pharmacokinetic profile of nintedanib in NSCLC and IPF populations and can be used for simulations exploring covariate effects and exposure-response analyses.

Population pharmacokinetics of afatinib, an irreversible ErbB family blocker, in patients with various solid tumors.

PURPOSE: This population pharmacokinetic model was developed to characterize the pharmacokinetics of the oral irreversible ErbB family blocker afatinib in patients with solid tumors and to investigate the impact of selected intrinsic and extrinsic factors. METHODS: Data from 927 patients (4,460 plasma concentrations) with advanced solid tumors in 7 Phase II or III studies were analyzed. Afatinib was administered orally in continuous 3 or 4 week cycles (starting dose 20, 40 or 50 mg once-daily). Plasma concentration-time data for up to 7 months dosing were analyzed using nonlinear mixed-effects modeling. RESULTS: The pharmacokinetic profile of afatinib was best described by a two-compartment disposition model with first-order absorption and linear elimination. There was a slightly more than proportional increase in exposure with increasing dose, accounted for by a dose-dependent relative bioavailability. For the therapeutic dose of 40 mg, the estimated apparent total clearance and distribution volume at steady state were 734 mL/min and 2,370 L, respectively. While food intake, body weight, gender, Eastern Cooperative Oncology Group performance score, renal function, and the level of alkaline phosphatase, lactate dehydrogenase or total protein were statistically significant covariates influencing afatinib exposure, none resulted in a proportional change in exposure of more than 27.8 % in a typical patient at model extremes (2.5th and 97.5th percentiles of baseline values for continuous covariates). In simulations of the individual covariate effects, none caused a change in the typical profile exceeding the observed variability range (90 % prediction interval) of afatinib. CONCLUSION: This population pharmacokinetic model adequately described the pharmacokinetics of afatinib in different cancer patient populations and therefore can be used for simulations exploring covariate effects and possible dose adaptations. The effect size for each of the individual covariates is not considered clinically relevant.

3-year prevalence of alcohol-related disorders in German patients treated with high-potency opioids.

PURPOSE: In November 2010, the European Medicines Agency's Committee for Medicinal Products for Human Use completed a review of the safety and effectiveness of modified-release oral high-potency opioids (HPO). The reason for this referral procedure was the concern that some of these controlled-release systems may be unstable when co-ingested with alcohol and that the active substance would be released too quickly. The aim of this study was to estimate the prevalence of alcohol-related disorders (ARD) in German patients treated with HPO approved for pain therapy. METHODS: The source of data was the German Pharmacoepidemiological Research Database including more than 14 million members of four statutory health insurances. The age and sex standardized 3-year prevalence of ARD in patients treated with any type of HPO and in patients receiving modified-release oral HPO was compared with the prevalence of ARD in the general population excluding HPO-treated patients. RESULTS: The age and sex standardized prevalence of ARD was significantly higher in patients treated with any type of HPO (5.5%, 95%confidence interval [CI]: 5.2%-5.9%) or with modified-release HPO (5.4%, 95%CI: 4.8%-5.9%) than in persons belonging to the general population (2.2%, 95%CI: 2.2-2.2%). CONCLUSIONS: Interactions with alcohol in patients receiving modified-release HPO may be of relevance in a substantial number of patients. Physicians should be aware of this potentially dangerous interaction.

Utilisation of transdermal fentanyl in Germany from 2004 to 2006.

PURPOSE: Oral morphine is the first-choice opioid for moderate to severe cancer pain. Transdermal fentanyl is an alternative in patients with stable requirements of high-potency opioids (HPO) or if drugs cannot be taken orally. Drug regulatory authorities have issued several alerts to use transdermal fentanyl only for chronic pain and in HPO-tolerant patients to minimise the risk of severe opioid side effects. The aim of this study was to characterise utilisation of transdermal fentanyl in Germany. METHODS: The analysis was based on data from four German statutory health insurances from the years 2004-2006. Descriptive analyses were performed in new users of transdermal fentanyl to assess HPO-naïvety, potential difficulties with the oral route in HPO-naïve patients and the number of transdermal fentanyl dispensations. The initial dose in new users was assessed in 2005-2006 after marketing of transdermal fentanyl 12.5 µg/hour. RESULTS: Of 35 262 patients with new use of transdermal fentanyl, 29 793 (84.5%) were assessed as HPO-naïve. Of those, 21 596 (72.5%) did not have diagnoses indicating difficulties with the oral route. For 71.2% of the HPO-naïve new users of transdermal fentanyl, the first dose exceeded the recommended dose of 12.5 µg/hour, and 49.3% of them received only one prescription of the drug. CONCLUSIONS: Transdermal fentanyl was used as a first-choice opioid, which may increase the risk of serious opioid side effects, in a substantial number of HPO-naïve patients. Inappropriate prescribing included also high initial doses in HPO-naïve patients and possible prescription for acute pain in a considerable proportion of patients.

Linkage of mother-baby pairs in the German Pharmacoepidemiological Research Database.

PURPOSE: Administrative healthcare databases are increasingly being used to investigate potential drug risks in pregnancy. Our study aimed to develop an algorithm for linkage of mother-baby pairs (MBPs) in the German Pharmacoepidemiological Research Database (GePaRD) as a prerequisite for such studies. METHODS: GePaRD contains sociodemographic data, drug dispensations, ambulatory, and hospital information on more than 14 million insurants from four German statutory health insurances (SHIs) covering all regions in Germany. Linkage was based on co-insurance information of the newborn with the potential mother (direct linkage) or of both potential mother and newborn with the potential father (indirect linkage). Linkage is not possible if the baby is co-insured with the father and the mother is self-insured. Further information on birth or childbed was used to validate the potential mother as true mother in MBP. Descriptive comparisons between linked and unlinked mothers were conducted. RESULTS: Of 323,993 newborns identified between 2004 and 2006, 250,355 (77.3%) could be linked in MBP. Of those, 189,702 (75.8%) MBP were based on direct linkage. Mean age was similar in linked (31.1 years, standard deviation (SD = 5.4) and unlinked (31.8 years, SD = 5.5) mothers as was the proportion of caesarean sections in both groups (28.9% vs. 29.3%). CONCLUSIONS: The developed algorithm permits linkage of a great number of newborns with their mothers and creates a potential data source for investigation of drug risks in pregnancy. Further validation studies are needed also including information on pregnancies not resulting in live births.

Towards a detailed understanding of bacterial metabolism--spectroscopic characterization of Staphylococcus epidermidis.

Bacteria are a major cause of infection. To fight disease and growing resistance, research interest is focused on understanding bacterial metabolism. For a detailed evaluation of the involved mechanisms, a precise knowledge of the molecular composition of the bacteria is required. In this article, various vibrational spectroscopic techniques are applied to comprehensively characterize, on a molecular level, bacteria of the strain Staphylococcus epidermidis, an opportunistic pathogen which has evolved to become a major cause of nosocomial infections. IR absorption spectroscopy reflects the overall chemical composition of the cells, with major focus on the protein vibrations. Smaller sample volumes-down to a single cell-are sufficient to probe the overall chemical composition by means of micro-Raman spectroscopy. The nucleic-acid and aromatic amino-acid moieties are almost exclusively explored by UV resonance Raman spectroscopy. In combination with statistical evaluation methods [hierarchical cluster analysis (HCA), principal component analysis (PCA), linear discriminant analysis (LDA)], the protein and nucleic-acid components that change during the different bacterial growth phases can be identified from the in vivo vibrational spectra. Furthermore, tip-enhanced Raman spectroscopy (TERS) provides insight into the surface structures and follows the dynamics of the polysaccharide and peptide components on the bacterial cells with a spatial resolution below the diffraction limit. This might open new ways for the elucidation of host-bacteria and drug-bacteria interactions.

Phospholipid-based microemulsions suitable for use in foods.

The preparation of nonaqueous microemulsions using food-acceptable components is reported. The effect of oil on the formation of microemulsions stabilized by lecithin (Epikuron 200) and containing propylene glycol as immiscible solvent was investigated. When the triglycerides were used as oil, three types of phase behavior were noted, namely, a two-phase cloudy region (occurring at low lecithin concentrations), a liquid crystalline (LC) phase (occurring at high surfactant and low oil concentrations), and a clear monophasic microemulsion region. The extent of this clear one-phase region was found to be dependent upon the molecular volume of the oil being solubilized. Large molecular volume oils, such as soybean and sunflower oils, produced a small microemulsion region, whereas the smallest molecular volume triglyceride, tributyrin, produced a large, clear monophasic region. Use of the ethyl ester, ethyl oleate, as oil produced a clear, monophasic region of a size comparable to that seen with tributyrin. Substitution of some of the propylene glycol with water greatly reduced the extent of the clear one-phase region and increased the extent of the liquid crystalline region. In contrast, ethanol enhanced the clear, monophasic region by decreasing the LC phase. Replacement of some of the lecithin with the micelle-forming nonionic surfactant Tween 80 to produce mixed lecithin/Tween 80 mixtures of weight ratios (Km) 1:2 and 1:3 did not significantly alter the phase behavior, although there was a marginal increase in the area of the two-phase, cloudy region of the phase diagram. The use of the lower phosphatidylcholine content lecithin, Epikuron 170, in place of Epikuron 200 resulted in a reduction in the LC region for all of the systems investigated. In conclusion, these studies show that it is possible to prepare one-phase, clear lecithin-based microemulsions over a wide range of compositions using components that are food-acceptable.

A new protocol for the one-pot synthesis of symmetrical biaryls.

Biaryls play an important role in modern organic chemistry. Although a large number of protocols for the synthesis of symmetrical and unsymmetrical biaryls already exist, most of them are not generally applicable. In our studies toward the total synthesis of the secalonic acids, we were interested in bis(pinacolato)diboron as a reagent for transforming haloarenes into arylboronic esters. By optimizing the reaction conditions, we were able to obtain biaryls containing various functional groups in good to excellent yields.