Preeclampsia at delivery is associated with lower serum vitamin D and higher antiangiogenic factors: a case control study.

BACKGROUND: Preeclampsia is characterized by decreased trophoblastic angiogenesis leading to abnormal invasion of spiral arteries, shallow implantation and resulting in compromised placentation with poor uteroplacental perfusion. Vitamin D plays an important role in pregnancy influencing implantation, angiogenesis and placental development. The objective of this study was to determine whether there is an association between serum vitamin D levels, and anti-angiogenic factors at the time of delivery and the occurrence of preeclampsia. METHODS: This nested case control study analyzed frozen serum samples at the time of delivery and related clinical data from women with singleton liveborn pregnancies who had participated in studies of the NICHD Stillbirth Collaborative Research Network. Women with a recorded finding of preeclampsia and who had received magnesium sulfate treatment prior to delivery were considered index cases (N = 56). Women without a finding of preeclampsia were controls (N = 341). RESULTS: Women with preeclampsia had 14.5% lower serum vitamin D levels than women in the control group (16.5 ng/ml vs. 19 ng/ml, p = 0.014) with 64.5% higher sFlt-1 levels (11,600 pg/ml vs. 7050 pg/ml, p < 0.001) and greater than 2 times higher endoglin levels (18.6 ng/ml vs. 8.7 ng/ml, < 0.001). After controlling for gestational age at delivery and maternal BMI, vitamin D levels were 0.88 times lower (P = 0.051), while endoglin levels were 2.5 times higher and sFlt-1 levels were 2.1 times higher than in control pregnancies (P < 0.001). CONCLUSIONS: Women with preeclampsia at time of delivery have higher maternal antiangiogenetic factors and may have lower maternal serum vitamin D levels. These findings may lead to a better understanding of the underlying etiology of preeclampsia as well as possible modifiable treatment options which could include assuring adequate levels of maternal serum vitamin D prior to pregnancy.

Phase I dose-escalation study of the safety, tolerability, and pharmacokinetics of aflibercept in combination with S-1 in Japanese patients with advanced solid malignancies.

Background Aflibercept, a recombinant fusion protein binding VEGF-A, VEGF-B and placental growth factor, inhibits tumor growth by blocking angiogenesis. The aim of this phase I dose-escalation study was to determine the recommended phase II dose (RP2D) of aflibercept in combination with S-1 in Japanese patients with solid tumors. Patients and methods Sequential cohorts of 3-6 patients with metastatic or unresectable solid tumors, who had failed at least one prior line of standard treatment or who were not suitable for such treatment, were to receive escalating doses of aflibercept every 2 weeks, starting at 2 mg/kg, combined with S-1 at 40 mg/m2 twice daily (80 mg/m2/day; 4 weeks on/2 weeks off). Dose-escalation was to be based on the incidence of dose-limiting toxicity (DLT). Blood samples were collected for pharmacokinetic analysis. Results At the first dose level (aflibercept 2 mg/kg plus S-1) 1 of 6 patients experienced a DLT (grade 4 proteinuria). The aflibercept dose was consequently escalated to 4 mg/kg; 1 of 3 patients treated at this dose level had a DLT (grade 2 pleural effusion), and another patient experienced grade 3 reversible posterior leukoencephalopathy syndrome after the DLT assessment period. Additional patients were therefore enrolled into the first dose level to explore safety and tolerability. The study was subsequently terminated prematurely. The maximum tolerated dose was not reached and the RP2D was not determined in Japanese patients. Conclusions The tolerability and safety of aflibercept 2 mg/kg in combination with S-1 was confirmed in Japanese patients with advanced solid tumors.

Possibility for Dose Optimization of Pazopanib from Its Plasma Concentration in Japanese Patients with Cancer.

The currently approved dose of pazopanib (800 mg) is being re-examined owing to its adverse effects. The aim of this study was to evaluate the relationships among starting or maintenance doses of pazopanib, estimated pazopanib Cmin, and other clinical factors, including albumin and α-1 acid glycoprotein levels, in soft-tissue sarcoma and renal cell carcinoma. We also determined whether therapeutic drug monitoring of pazopanib concentrations may be used to improve its therapeutic efficacy and prevent adverse effects. Forty patients who received pazopanib for renal cancer or soft-tissue sarcoma at the Hokkaido Cancer Center were evaluated prospectively. Cmin for pazopanib was calculated based on the measured values from the plasma samples. The efficacy and time to treatment failure were then assessed. The pazopanib maintenance doses were 200 (n = 4), 400 (n = 34), 600 (n = 4), and 800 mg (n = 1). Most patients (65%) who received a 400 mg dose had an effective pazopanib concentration (≧20 µg/mL), whereas 35% of patients who received the 400 mg dose had ineffective concentrations (<20 µg/mL). Logistic regression analysis revealed that only the albumin level was significantly associated with effective pazopanib concentrations (odds ratio: 1.37, p = 0.0234). In conclusion, a dose of 400 mg had been effective and well tolerated in more than half of patients in this study. However, therapeutic drug monitoring is necessary during pazopanib therapy.

Plasma vasohibin-1 and vasohibin-2 are useful biomarkers in patients with esophageal squamous cell carcinoma.

BACKGROUND: Vasohibins (VASH), which are angiogenesis regulators, consist of Vasohibin-1 (VASH1) and Vasohibin-2 (VASH2). VASH1 is an angiogenesis inhibitor, while VASH2 is a proangiogenic factor. Patients with esophageal squamous cell carcinoma (ESCC) with high tumor expression levels of VASH1 and VASH2 have been reported to show a poor prognosis. The clinical significance of VASH concentrations in the blood of patients with ESCC has not yet been investigated. METHODS: Plasma samples from 89 patients with ESCC were analyzed, and the relationships between the plasma VASH concentrations and the clinicopathological factors of the patients were evaluated. Immunohistochemical examination (IHC) of the resected tumor specimens for VASH was performed in 56 patients, and the correlation between the plasma VASH concentrations and tumor expression levels of VASH was analyzed. RESULTS: The patient group with high plasma concentrations of VASH1 showed a higher frequency of lymph node metastasis (P = 0.01) and an invasive growth pattern (P = 0.05). Furthermore, poorly differentiated cancer occurred at a higher frequency in the patient group with high plasma concentrations of VASH2 (P < 0.01). High tumor expression levels of VASH1 were encountered more frequently in the patient group with high plasma concentrations of VASH1 (P = 0.03), and high tumor expression levels of VASH2 were encountered more frequently in the patient group with high plasma concentrations of VASH2 (P = 0.04). CONCLUSIONS: In patients with ESCC, high plasma concentrations were associated with poor clinical outcomes for both VASH1 and VASH2. We propose that results indicate that plasma VASH1 and VASH2 are useful biomarkers in patients with ESCC.

Harnessing soft tissue sarcoma with low-dose pazopanib - a matter of blood levels.

BACKGROUND: Pazopanib is a tyrosine kinase inhibitor indicated for the treatment of renal cell carcinoma and soft tissue sarcoma. Despite the high inter-patient variability in pharmacokinetic exposure, pazopanib is administered at a fixed dose of 800 mg once daily (QD). Pharmacokinetic exposure is linked to both efficacy and toxicity. In this case report, we illustrate the value of therapeutic drug monitoring by describing two patients with adequate pazopanib trough concentrations (Cmin) at an eight times lower than standard dose. CASE PRESENTATION: Patient A is a 69-year-old woman with metastatic leiomyosarcoma who had significant toxicities and a high Cmin on the standard dose. While dose reductions to 200 mg QD and later 200 mg every other day were made, pazopanib Cmin remained above the efficacy threshold. Patient B is a 50-year-old male with metastatic angiosarcoma and a history of Gilbert syndrome. Pazopanib treatment was initiated at the standard dose of 800 mg QD, but was reduced to 200 mg QD 1-week-on - 1-week-off due to total bilirubin elevation. Pazopanib Cmin was adequate in this patient as well. CONCLUSION: It could be valuable to measure pazopanib levels in case of dose reductions due to toxicity, as exposure could still be adequate at considerably lower than standard doses.

Fast and Straightforward Method for the Quantification of Pazopanib in Human Plasma Using LC-MS/MS.

BACKGROUND: Pazopanib is an angiogenesis inhibitor approved for renal cell carcinoma and soft-tissue sarcoma. Studies indicate that treatment with pazopanib could be optimized by adapting the dose based on measured pazopanib plasma concentrations. METHODS: We describe the validation and clinical application of a fast and straightforward method for the quantification of pazopanib in human plasma for the purpose of therapeutic drug monitoring and bioanalytical support of clinical trials. Stable isotopically labeled C,H3-pazopanib was used as internal standard. Plasma samples were prepared for analysis by protein precipitation using methanol and diluted with 10 mmol/L ammonium hydroxide buffer. Chromatographic separation was performed on a C18 column using isocratic elution with ammonium hydroxide in water and methanol. For detection, a tandem mass spectrometer, equipped with a turbo ion spray interface was used in positive ion mode at m/z 438 → m/z 357 for pazopanib and m/z 442 → m/z 361 for the internal standard. RESULTS: Final runtime was 2.5 minutes. All validated parameters were within pre-established limits and fulfilled the FDA and EMA requirements for bioanalytical method validation. After completion of the validation, the routine application of the method was tested by analyzing clinical study samples that were collected for the purpose of therapeutic drug monitoring. CONCLUSIONS: In conclusion, the described method was successfully validated and was found to be robust for routine application to analyze samples from cancer patients treated with pazopanib.

Development and Validation of a Simultaneous Quantification Method of Ruxolitinib, Vismodegib, Olaparib, and Pazopanib in Human Plasma Using Liquid Chromatography Coupled With Tandem Mass Spectrometry.

BACKGROUND: A simple, rapid, and sensitive liquid chromatography coupled with tandem mass spectrometry method has been developed and validated for the quantification of ruxolitinib, olaparib, vismodegib, and pazopanib in human plasma. METHODS: After a simple protein precipitation of plasma samples, the chromatographic separation was performed using an ultraperformance liquid chromatography system coupled with mass tandem spectrometry in a positive ionization mode. The mobile phase consisted of a gradient elution of 10-mmol/L formate ammonium buffer containing 0.1% (vol/vol) formic acid (phase A) and acetonitrile with 0.1% (vol/vol) formic acid (phase B) at a flow rate at 300 µL/min. RESULTS: Analysis time was 5.0 minutes per run, and all analytes and internal standards eluted within 1.5-1.73 minutes. The calibration curves were linear over the range from 10 to 2500 ng/mL for ruxolitinib and from 100 to 100,000 ng/mL for olaparib, vismodegib, and pazopanib with coefficients of correlation above 0.99 for all analytes. The intraday and interday coefficients of variation were below 14.26% and 14.81%, respectively, for lower concentration and below 9.94% and 6.37%, respectively, for higher concentration. CONCLUSIONS: Using liquid chromatography coupled with tandem mass spectrometry, we have developed and validated a simple and rapid assay for the simultaneous quantification of olaparib, vismodegib, pazopanib, and ruxolitinib in human plasma. This method is now part of our therapeutic drug monitoring service provision and is currently used clinically to manage patients prescribed these drugs.

Nonclinical assessments of the potential biosimilar PF-06439535 and bevacizumab.

Bevacizumab, a recombinant humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF), is approved for treatment of metastatic colorectal cancer, nonsquamous non-small-cell lung cancer, metastatic kidney cancer, and glioblastoma. To support clinical development of the potential bevacizumab biosimilar PF-06439535, nonclinical studies evaluated structural, functional, toxicological, and toxicokinetic similarity to bevacizumab sourced from the European Union (bevacizumab-EU) and United States (bevacizumab-US). Peptide mapping demonstrated the amino acid sequence of PF-06439535 was identical to bevacizumab-EU and bevacizumab-US. Biologic activity, measured via inhibition of VEGF-induced cell proliferation in human umbilical vein endothelial cells and binding to VEGF isoforms, was similar across the three drugs. In vivo similarity was demonstrated in cynomolgus monkeys administered intravenous PF-06439535 or bevacizumab-EU (0 or 10 mg/kg/dose twice weekly for 1 month; total of nine doses). Systemic exposure appeared similar and test article-related effects were limited to physeal dysplasia of the distal femur. The potential for non-target-mediated toxicity of PF-06439535 was evaluated in rats administered intravenous PF-06439535 (15 or 150 mg/kg/dose twice weekly for 15 days; total of five doses). Nonadverse higher liver weights and minimal sinusoidal cell hyperplasia were observed. Collectively, these studies demonstrated similarity of PF-06439535 to bevacizumab, supporting entry into clinical development.

Diclofenac sex-divergent drug-drug interaction with Sunitinib: pharmacokinetics and tissue distribution in male and female mice.

Coadministration of diclofenac and sunitinib, tyrosine kinase inhibitor, led to sex-divergent pharmacokinetic drug-drug interaction outcomes. Male and female mice were administered 60 mg/kg PO sunitinib alone (control groups) or with 30 mg/kg PO diclofenac. Sunitinib concentration in plasma, brain, kidney and liver were determined by HPLC and non-compartmental pharmacokinetic parameters calculated. In male mice, diclofenac decreased AUC0→∞ 38% in plasma (p < 0.05) and 24% in liver (p < 0.001) and 23% in kidney (p < 0.001). However, AUC0→∞ remained unchanged in plasma and increased 41% in kidney (p < 0.001) of female mice. In brain, sunitinib exposure decreased 46% (p < 0.001) and 32% (p < 0.001) in male and female brain respectively. Mechanistically, diclofenac increased the liver uptake efficiency in male (27%, p < 0.05) and female (48%, p < 0.001) mice and 30% in kidney (p < 0.05) of male mice, probably owing to effects on efflux transporters. Sunitinib displayed sex-divergent DDI with diclofenac with probable clinical translatability due to potential different effects in male and female patients requiring careful selection of the NSAID and advanced TDM to implement a personalized treatment.

Sunitinib-paracetamol sex-divergent pharmacokinetics and tissue distribution drug-drug interaction in mice.

The sex-divergent pharmacokinetics and interaction of tyrosine kinase inhibitor sunitinib with paracetamol was evaluated in male and female mice. Mice (control groups) were administered 60 mg/kg PO sunitinib alone or with 200 mg/kg PO paracetamol (study groups). Sunitinib concentration in plasma, brain, kidney and liver were determined and non-compartmental pharmacokinetic analysis performed. Female control mice showed 36% higher plasma sunitinib AUC0→∞, 31% and 27% lower liver and kidney AUC0→∞ and 2.2-fold higher AUC0→∞ in brain (all p < 0.001) and had lower liver- and kidney-to-plasma AUC0→∞ ratios (p < 0.001) than male control mice. Paracetamol decreased 29% plasma AUC0→∞ (p < 0.05) in male mice and remained unchanged in female mice. In male and female mice, it decreased liver (15%, 9%), kidney (15%, 20%) and brain (47%, 50%) AUC0→∞ (p < 0.001) respectively owing to 52% brain uptake efficiency reduction in female mice (p < 0.01). Sunitinib displayed sex-divergent pharmacokinetics, tissue distribution and DDI with potential clinical translatability for the treatment of brain tumor and RCC patients.

Angiogenic and Antiangiogenic Markers for Prediction and Risk Classification of Preeclampsia.

Preeclampsia is a pregnancy-specific hypertensive disorder with multisystem involvement and is a significant cause of obstetric morbidity and mortality worldwide. A major issue in the treatment of preeclampsia stems from its still significant rates of misclassification and misdiagnosis. Angiogenic factors have been speculated as a possible diagnostic modality due to a perceived imbalance in angiogenesis in preeclampsia. Factors currently studied include soluble fms-like protein kinase 1 and placental growth factor. Because of significant mortality associated with preeclampsia it is felt that both early and accurate diagnosis of preeclampsia is imperative if this disease process is to be treated.

A functional bioassay to determine the activity of anti-VEGF antibody therapy in blood of patients with cancer.

BACKGROUND: Only a small proportion of patients respond to anti-VEGF therapy, pressing the need for a reliable biomarker that can identify patients who will benefit. We studied the biological activity of anti-VEGF antibodies in patients' blood during anti-VEGF therapy by using the Ba/F3-VEGFR2 cell line, which is dependent on VEGF for its growth. METHODS: Serum samples from 22 patients with cancer before and during treatment with bevacizumab were tested for their effect on proliferation of Ba/F3-VEGFR2 cells. Vascular endothelial growth factor as well as bevacizumab concentrations in serum samples from these patients were determined by enzyme linked immunosorbent assay (ELISA). RESULTS: The hVEGF-driven cell proliferation was effectively blocked by bevacizumab (IC50 3.7 µg ml-1; 95% CI 1.7-8.3 µg ml-1). Cell proliferation was significantly reduced when patients' serum during treatment with bevacizumab was added (22-103% inhibition compared with pre-treatment). Although bevacizumab levels were not related, on-treatment serum VEGF levels were correlated with Ba/F3-VEGFR2 cell proliferation. CONCLUSIONS: We found that the neutralising effect of anti-VEGF antibody therapy on the biological activity of circulating VEGF can be accurately determined with a Ba/F3-VEGFR2 bioassay. The value of this bioassay to predict clinical benefit of anti-VEGF antibody therapy needs further clinical evaluation in a larger randomised cohort.

Serum levels of vascular dysfunction markers reflect disease severity and stage in systemic sclerosis patients.

OBJECTIVE: To improve knowledge of vasculopathy in SSc through the assessment of serum levels of circulating angiogenetic and endothelial dysfunction markers in patients at different stages of the disease. METHODS: Sera from 224 subjects were obtained and concentrations of angiopoietin-2, chemokine (C-X-C motif) ligand (CXCL)-16 (CXCL16), E-selectin, soluble intercellular adhesion molecule-1, IL-8 (CXCL8), soluble vascular adhesion molecule-1 and VEGF were determined by a Luminex assay. Subjects included 43 healthy controls, 47 early SSc patients according to LeRoy and Medsger without other signs and symptoms of evolutive disease, 48 definitive SSc (defSSc) patients according to the 2013 ACR/EULAR criteria without skin or lung fibrosis, 51 lcSSc subjects and 35 dcSSc subjects. RESULTS: The four groups of patients showed well-distinct clinical and laboratory characteristics, with a linear decreasing trend in forced vital capacity and diffusing capacity for carbon monoxide % predicted values from early SSc to defSSc to lcSSc and to dcSSc, and a linear increasing trend in ESR, and in the prevalence of abnormal CRP, serum gamma globulins and lung fibrosis (all P < 0.0001). Highly significant linear trends pointing to an increase in angiopoietin-2 (P < 0.0001), CXCL16 (P < 0.0001), E-selectin (P = 0.001) and soluble intercellular adhesion molecule-1 (P = 0.002) in relation to the different disease subsets were observed. CONCLUSION: Markers characterizing vascular activation are found to be increased in SSc patients from the earliest stages of disease when clinical and laboratory findings of advanced disease cannot yet be detected. These abnormalities progress with the appraisal of the first sclerodermatous manifestation in defSSc and further increase with the onset of fibrotic manifestations.

Phase I study of every 2- or 3-week dosing of ramucirumab, a human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2 in patients with advanced solid tumors.

BACKGROUND: Ramucirumab is a fully human immunoglobulin G1 monoclonal antibody receptor antagonist designed to block the ligand-binding site of vascular endothelial growth factor receptor-2 (VEGFR-2). An initial phase I study evaluated ramucirumab administered weekly in advanced cancer patients. This phase I study of ramucirumab [administered every 2 or 3 weeks (Q2W or Q3W)] examined safety, maximum tolerated dose, pharmacokinetics, immunogenicity, antitumor activity, and pharmacodynamics. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of ramucirumab i.v. over 1 h. Blood was sampled for pharmacokinetics studies throughout treatment; levels of circulating vascular endothelial growth factor-A (VEGF-A) and soluble VEGF receptors (R)-1 and -2 were assessed. RESULTS: Twenty-five patients were treated with ramucirumab: 13 with 6, 8, or 10 mg/kg Q2W, and 12 with 15 or 20 mg/kg Q3W. The median treatment duration was 12 weeks (range 2-81). No dose-limiting toxicities were observed. The most frequently reported adverse events (AEs) included proteinuria and hypertension (n = 6 each), and diarrhea, fatigue and headache (n = 4 each). Treatment-related grade 3/4 AEs were: two grade 3 hypertension (10 and 20 mg/kg), one each grade 3 vomiting, fatigue (20 mg/kg), atrial flutter (15 mg/kg), and one each grade 4 duodenal ulcer hemorrhage (6 mg/kg) and grade 4 pneumothorax (20 mg/kg). Pharmacokinetic analysis revealed low clearance and half-life of ∼110-160 h. Analysis of serum biomarkers indicated considerable patient-to-patient variability, but trends toward elevated VEGF-A and a transient decline in soluble VEGFR-2. Fifteen patients (60%) had best response of stable disease, with a median duration of 13 months (range 2-18 months) in tumor types including colorectal, renal, liver, and neuroendocrine cancers. CONCLUSION: Ramucirumab was well tolerated. Study results led to recommended phase II doses of 8 mg/kg Q2W and 10 mg/kg Q3W. Prolonged stable disease was observed, suggesting ramucirumab efficacy in various solid tumors. CLINICALTRIALSGOV: NCT00786383.

Therapeutic drug monitoring to individualize the dosing of pazopanib: a pharmacokinetic feasibility study.

BACKGROUND: Patients treated with the standard dose of pazopanib show a large interpatient variability in drug exposure defined as the area under the plasma concentration-time curve (AUC0-24h). The primary objective of this study was to evaluate the feasibility of pharmacokinetics (PK)-guided individualized dosing to reduce the interpatient variability in pazopanib exposure. METHODS: Thirteen patients were treated with pazopanib for 3 consecutive periods of 2 weeks. During the first period, all patients received 800 mg of pazopanib once daily to reach steady-state exposure. During the second period, the patients either received a PK-guided individualized pazopanib dose or the registered fixed 800-mg dose. During the third period, these 2 dosing regimens were switched. RESULTS: The interpatient variability in pazopanib AUC0-24h during fixed dosing (27.3 coefficient of variation) was not significantly different when compared with the variability in AUC0-24h during PK-guided dosing (24.8 coefficient of variation). The percentage of patients within the target window during PK-guided dosing (53.9%) was not significantly different from the percentage during fixed dosing (46.2%). Both Ctrough and C24 were significantly (P < 0.001) correlated to pazopanib AUC0-24h (R = 0.596 and R = 0.940, respectively). Pazopanib AUC0-24h decreased 17% over time. CONCLUSIONS: PK-guided dosing did not reduce the interpatient variability in pazopanib exposure. In this study, the intrapatient variability in pazopanib exposure was relatively large compared with interpatient variability. This makes it challenging to achieve a target exposure within a predefined window. The causes of intrapatient variability must first be better understood and controlled, before PK-guided dosing can reduce the interpatient variability.

Circulating pro- and anti-angiogenic mediators in patients infected with hepatitis C at different stages of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a hypervascular tumor characterized by neovascularization. The objective of the current study was to determine circulating proangiogenic [vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), and tumor necrosis factor (TNF-α)] and antiangiogenic [IL-4, IL-12, interferon gamma-induced protein 10 (IP-10), and angiostatin] factors in Egyptian patients with different stages of HCC. Enzyme-linked immunosorbent assay (ELISA) was used to detect the concentrations of these mediators in plasma of 135 HCC patients (57 Child-Pugh A, 24 Child-Pugh B, and 54 Child-Pugh C stage) and 50 healthy subjects. Results showed a significant increase in plasma levels of VEGF (P < 0.001), PDGF (P < 0.001), TNF-α (P < 0.01), angiostatin (P < 0.01), and IP-10 (P < 0.001) and a significant reduction in IL-12 (P < 0.001) in HCC patients in relation to normal controls. Classifying HCC patients based on their Child-Pugh's score revealed that the maximum production of proangiogenic mediators (VEGF and TNF-α) was present in HCC patients with Child-Pugh C score which coincides with maximum reduction in antiangiogenic mediators (IL-4, IL-12, and angiostatin). Taken together, these results indicated that the determination of these factors in different Child-Pugh's scores of HCC might be an important guide in clinical decision making regarding therapy and outcome.

A higher maternal choline intake among third-trimester pregnant women lowers placental and circulating concentrations of the antiangiogenic factor fms-like tyrosine kinase-1 (sFLT1).

This study investigated the influence of maternal choline intake on the human placental transcriptome, with a special interest in its role in modulating placental vascular function. Healthy pregnant women (n=26, wk 26-29 gestation) were randomized to 480 mg choline/d, an intake level approximating the adequate intake of 450 mg/d, or 930 mg/d for 12 wk. Maternal blood and placental samples were retrieved at delivery. Whole genome expression microarrays were used to identify placental genes and biological processes impacted by maternal choline intake. Maternal choline intake influenced a wide array of genes (n=166) and biological processes (n=197), including those related to vascular function. Of special interest was the 30% down-regulation (P=0.05) of the antiangiogenic factor and preeclampsia risk marker fms-like tyrosine kinase-1 (sFLT1) in the placenta tissues obtained from the 930 vs. 480 mg/d choline intake group. Similar decreases (P=0.04) were detected in maternal blood sFLT1 protein concentrations. The down-regulation of sFLT1 by choline treatment was confirmed in a human trophoblast cell culture model and may be related to enhanced acetylcholine signaling. These findings indicate that supplementing the maternal diet with extra choline may improve placental angiogenesis and mitigate some of the pathological antecedents of preeclampsia.

Population pharmacokinetic analysis of axitinib in healthy volunteers.

AIMS: Axitinib is a potent and selective second generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3 approved for second line treatment of advanced renal cell carcinoma. The objectives of this analysis were to assess plasma pharmacokinetics and identify covariates that may explain variability in axitinib disposition following single dose administration in healthy volunteers. METHODS: Plasma concentration-time data from 337 healthy volunteers in 10 phase I studies were analyzed, using non-linear mixed effects modelling (nonmem) to estimate population pharmacokinetic parameters and evaluate relationships between parameters and food, formulation, demographic factors, measures of renal and hepatic function and metabolic genotypes (UGT1A1*28 and CYP2C19). RESULTS: A two compartment structural model with first order absorption and lag time best described axitinib pharmacokinetics. Population estimates for systemic clearance (CL), central volume of distribution (Vc ), absorption rate constant (ka ) and absolute bioavailability (F) were 17.0 l h(-1) , 45.3 l, 0.523 h(-1) and 46.5%, respectively. With axitinib Form IV, ka and F increased in the fasted state by 207% and 33.8%, respectively. For Form XLI (marketed formulation), F was 15% lower compared with Form IV. CL was not significantly influenced by any of the covariates studied. Body weight significantly affected Vc , but the effect was within the estimated interindividual variability for Vc . CONCLUSIONS: The analysis established a model that adequately characterizes axitinib pharmacokinetics in healthy volunteers. Vc was found to increase with body weight. However, no change in plasma exposures is expected with change in body weight; hence no dose adjustment is warranted.

A limited sampling model to estimate exposure to lenalidomide in multiple myeloma patients.

BACKGROUND: The aim of this study was to develop a model able to predict the area under the lenalidomide plasma concentration-time curve (AUC) in multiple myeloma (MM) patients using a limited sampling strategy. METHODS: Forty-six hospitalized Japanese MM patients (25 men and 21 women) participated in this study. On days 3-10 of lenalidomide therapy, whole-blood samples were collected just before oral lenalidomide administration, and 1, 2, 4, 8, 12, and 24 hours thereafter. Plasma concentrations of lenalidomide were analyzed using liquid chromatography-tandem mass spectrometry. RESULTS: The AUC0-24 predicted from a single lenalidomide plasma concentration measured 8 hours after the administration (C8h) showed the highest correlation with the measured AUC0-24 of lenalidomide (AUC0-24 = 13.0 × C8h + 1305.0; r = 0.832). To enhance the correlation between the predicted and the actual AUC0-24 of lenalidomide, we included information regarding lenalidomide elimination by entering creatinine clearance (CCr) data in the predictive formula of lenalidomide AUC0-24. Predicting the AUC0-24 of lenalidomide using data from 2 time points, C0h and C4h, along with CCr data further strengthened the correlation with the measured AUC0-24 of lenalidomide [AUC0-24 = 37.1 × C0h + 6.4 × C4h - 32.1 × CCr + 3265.6; r = 0.842]. CONCLUSIONS: The AUC0-24 of lenalidomide can be predicted using plasma concentrations measured at only 2 time points, C0h and C4h, in combination with CCr. Our study also suggests that the limited sampling strategy approach might help to identify patients with renal function impairment and who, despite dose adjustments, accumulate the drug, leading to a high AUC.

[The role of angiogenic factors in preeclampsia]. / Az angiogén faktorok szerepe praeeclampsiában.

Preeclampsia is one of the most common and most serious complications of pregnancy and the management of this condition still challenges obstetricians. Despite intensive research the etiology of preeclampsia still remains unclear. At the beginning of the 2000s preeclampsia-related research was directed towards factors that influence angiogenesis. Most studies have been carried out on the placental growth factor and soluble fms-like tyrosine kinase-1. Most publications confirm the increased concentrations of antiangiogenic factors and decreased concentrations of proangiogenic factors in maternal blood samples in preeclampsia even before the onset of clinical symptoms. According to our current knowledge antiangiogenic proteins are responsible for the endothelial dysfunction in the symptomatic stage of the disease. Placental growth factor and soluble fms-like tyrosine kinase-1 may have important roles in the prediction and treatment of the disease. The point of care detection of placental growth factor and soluble fms-like tyrosine kinase-1 may be used to predict preeclampsia. Rapid tests are available to determine the serum levels of the two proteins. Removal of soluble fms-like tyrosine kinase-1 from maternal circulation is a potential treatment option for early onset preeclampsia.