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Background and Objectives: Recombinant factor IX Fc fusion protein (rFIXFc) is a clotting factor developed using monomeric Fc fusion technology to prolong the circulating half-life of factor IX. The objective of this analysis was to elucidate the pharmacokinetic characteristics of rFIXFc in patients with haemophilia B and identify covariates that affect rFIXFc disposition. Methods: Population pharmacokinetic analysis using NONMEM was performed with clinical data from two completed trials in previously treated patients with severe to moderate haemophilia B. Twelve patients from a phase 1/2a study and 123 patients from a registrational phase 3 study were included in this population analysis. Results: A three-compartment model was found to best describe the pharmacokinetics of rFIXFc. For a typical 73 kg patient, the clearance (CL), volume of the central compartment ( V) and volume of distribution at steady state ( V) were 2.39 dL/h, 71.4 dL and 198 dL, respectively. Because of repeat pharmacokinetic profiles at week 26 for patients in a subgroup, inclusion of inter-occasion variability (IOV) on CL and V were evaluated and significantly improved the model. The magnitude of IOV on CL and V were both low to moderate (<20 %) and less than the corresponding inter-individual variability. Body weight (BW) was found to be the only significant covariate for rFIXFc disposition. However, the impact of BW was limited, as the BW power exponents on CL and V were 0.436 and 0.396, respectively. Conclusion: This is the first population pharmacokinetic analysis that systematically characterized the pharmacokinetics of long-lasting rFIXFc in patients with haemophilia B. The population pharmacokinetic model for rFIXFc can be utilized to evaluate and optimize dosing regimens for the treatment of patients with haemophilia B. [ABSTRACT FROM AUTHOR]

Purpose: The goal of this study was to test the hypothesis that by controlling intracellular uptake, organic cation transporter 1, Oct1 is a key determinant of the disposition and toxicity of cis-diammine(pyridine)chloroplatinum(II)(CDPCP) and oxaliplatin. Methods: Pharmacokinetics, tissue accumulation and toxicity of CDPCP and oxaliplatin were compared between Oct1-/- and wild-type mice. Results: After intravenous administration, hepatic and intestinal accumulation of CDPCP was 2.7-fold and 3.9-fold greater in Oct1 wild-type mice ( p < 0.001). Deletion of Oct1 resulted in a significantly decreased clearance (0.444 ± 0.0391 ml/min*kg versus 0.649 ± 0.0807 ml/min*kg in wild-type mice, p < 0.05) and volume distribution (1.90 ± 0.161 L/kg versus 3.37 ± 0.196 L/kg in wild-type mice, p < 0.001). Moreover, Oct1 deletion resulted in more severe off-target toxicities in CDPCP-treated mice. Histologic examination of the liver and measurements of liver function indicated that the level of hepatic toxicity was mild and reversible, but was more apparent in the wild-type mice. In contrast, the effect of Oct1 on the pharmacokinetics and toxicity of oxaliplatin in the mice was minimal. Conclusions: Our study suggests that Oct1 plays an important role in the pharmacokinetics, tissue distribution and toxicity of CDPCP, but not oxaliplatin. [ABSTRACT FROM AUTHOR]

The goal of this study was to determine the effect of a genetic variant in the organic cation transporter 2 (OCT2), OCT2-808G/T, which results in an amino acid change, A270S, on the pharmacokinetics of the antidiabetic drug, metformin.The uptake of metformin was performed in stably transfected HEK-293 cells expressing the empty vector (MOCK), the reference OCT2-808G, and the variant OCT2-808T. Healthy individuals with known OCT2 genotypes [14 homozygous for the OCT2 reference allele (808G/G) and nine heterozygous for the variant allele (808G/T, ∗3D)] were recruited to this study. Metformin concentrations in plasma and urine were measured by liquid chromatography-tandem mass spectrometry method. Creatinine levels were also measured in plasma and urine. Pharmacokinetic parameters were evaluated for both the groups.We observed that in HEK-293 stably transfected cells, OCT2-808T had a greater capacity to transport metformin than did the reference OCT2. Metformin pharmacokinetics was characterized in 23 healthy volunteers of Caucasian and African-American ancestries. We observed that the renal clearance (CLR) and the net secretion (SrCLR) of metformin were significantly different between the volunteers heterozygous for the variant allele (808G/T), and the volunteers homozygous for the reference allele (808G/G) (P<0.005). Multivariate analysis revealed that OCT2 genotype was a significant predictor of CLR and SrCLR of metformin (P<0.01).We conclude that genetic variation in OCT2 plays an important role in the CLR and SrCLR of metformin in healthy volunteers. [ABSTRACT FROM AUTHOR]

The relationships between metallogenic capacity and geochemical features of adakitic rocks along the South Tan-Lu Fault (STLF) remain unclear. In this study, the ore-barren adakitic rocks (Tuncang, Guandian and Wawuliu) exhibit higher K2O/Na2O ratios and lower Sr/Y ratios than the ore-bearing adakitic rocks (Chuzhou and Shangyaopu). These differences strongly suggest that the ore-barren adakitic rocks originated from the thickened lower continental crust (LCC), whereas the ore-bearing adakitic rocks were derived from oceanic slabs. Notably, the Tuncang granite exhibits higher Y/Yb and (Ho/Yb)N ratios than the Guandian granodiorite and Wawuliu intrusion. Accordingly, we suggest that the Tuncang granite likely originated from a delaminated eclogitic LCC, whereas the Guandian and Wawuliu intrusions were derived from a thickened basaltic LCC sources. The occurrence of diorite and gabbro mafic microgranular enclaves (MMEs) within the Tuncang granite strongly suggests a magma-mixing process. Considering their MgO contents and εNd(t) and (87Sr/86Sr)i values, we suggest that the gabbro MMEs were likely derived from an enriched mantle source previously metasomatized by subduction-related components and that the diorite MMEs were subsequently formed by magma mixing. Due to the slightly younger ages of the ore-bearing adakitic rocks, we propose a model in which the ore-barren adakitic rocks formed through LCC delamination at 130 Ma and the ore-bearing adakitic rocks formed through oceanic slab remelting at 125 Ma. Consequently, the exploration of Cu–Au mineralization along the STLF should focus on younger oceanic slab-derived adakitic rocks. [ABSTRACT FROM AUTHOR]

Retinopathy of prematurity is a major cause of childhood blindness worldwide. Hence, exploring the proper treatment methods is a must in tacking this disease. qRT‐PCR and western blot were used to detect the expression of genes and proteins, respectively. The proliferation of human retinal vascular endothelial cells (HRECs) was ensured by MTT assay. The luciferase activity was measured through luciferase assay. The inverted phase‐contrast light microscope was used to observe the formation of a vascular tube. In the present study, our data demonstrated that circPDE4B was downregulated, while hypoxia‐inducible factor‐1α (HIF‐1α) and VEGFA were upregulated in the retinopathy of prematurity model in vitro and in vivo. CircPDE4B increasing remarkably inhibited the expression of HIF‐1α and VEGFA in hypoxia‐induced HRECs and subsequent repressed cell proliferation and pathological angiogenesis. We further found that miR‐181c suppressed the expression of von Hippel–Lindau (VHL), while circPDE4B could promote VHL expression via binding to miR‐181c. Finally, our results revealed that circPDE4B inhibited the expression of VEGFA and pathological angiogenesis via facilitating VHL‐mediated ubiquitin degradation of HIF‐1α. In conclusion, circPDE4B suppressed the expression of VEGFA and pathological angiogenesis via promoting VHL‐mediated ubiquitin degradation of HIF‐1α through binding to miR‐181c. Our study indicated that circPDE4B might be an effective therapeutic target of retinopathy of prematurity. [ABSTRACT FROM AUTHOR]

The Jiuyishan complex massif, located in the northern section of the Nanling region, is a combination of five plutons, namely, the Xuehuading, Jinjiling, Pangxiemu, Shaziling and Xishan plutons. Whole‐rock geochemistry, mineral electron microprobe analysis, zircon U‐Pb dating and Hf isotope analysis were carried out for the Jinjiling and Pangxiemu plutons. The zircon U‐Pb dating yields weighted mean ages of 152.9±0.9 Ma for the Jinjiling pluton and 151.7±1.5 Ma for the Pangxiemu pluton, with a narrow gap between them. The Jinjiling and Pangxiemu plutons both have geochemical characteristics of high SiO2, Al2O3, Na2O, K2O and low TiO2, MgO, CaO, P2O5 contents, with intense depletionS in Sr, Ba, Ti, Eu and enrichments in Ga, FeOT and HFSE, and these characteristics reflect an A‐type affinity. From the Jinjiling to the Pangxiemu plutons, the mineral composition of mica changes from lepidomelane to zinnwaldite, with increases in F, Li2O and Rb2O contents. The mineral composition of zircon changes from low Zr/Hf to high Zr/Hf, with increasing HfO2, P2O5 and UO2+ThO2+Y2O3 contents. The mineral compositions of feldspar indicate that the Pangxiemu pluton contains more alkali feldspar than the Jinjiling pluton. The whole‐rock geochemistry and mineral compositions reveal a higher degree of differentiation for the Pangxiemu pluton. The nearly uniform εHf(t) indicates the same source region for the two plutons: both were derived from partial melting of the lower crust, with small contributions of mantle materials. In addition, higher F, lower Nb/Ta and Zr/Hf ratios in the Pangxiemu Pluton suggest a closer relationship with the rare metal mineralization than for the Jinjiling pluton. [ABSTRACT FROM AUTHOR]

Population pharmacokinetics (PK) of FVIII activity-time profiles following recombinant factor VIII Fc fusion protein (rFVIIIFc) and recombinant factor VIII (rFVIII) dosing were evaluated in previously treated patients with severe hemophilia A (from two clinical trials). Potential covariates that may be determinants of variability in FVIII activity were identified. A 2-compartment model adequately described the PK of both compounds. von Willebrand Factor (VWF) concentration was the major covariate for rFVIIIFc clearance, reflecting its protective role in FVIII activity clearance. The effect of body weight and hematocrit on the central volume of distribution of rFVIIIFc was minor. The results of these analyses confirmed that rFVIIIFc clearance (1.65 dL/h) is much lower than that of rFVIII (2.53 dL/h), while the steady state volumes of distribution were similar. The strong positive correlations between the PK parameters of rFVIIIFc and rFVIII suggest that individuals who have high time-related PK characteristics with rFVIII are likely to have comparable characteristics with rFVIIIFc. Steady-state activity-time profiles for selected rFVIIIFc dosing regimens were simulated accounting for uncertainty in model parameters. These population PK analyses and simulations provide a comprehensive characterization of the PK of rFVIIIFc and rFVIII and may be useful for designing dosing regimens. [ABSTRACT FROM AUTHOR]

In the phase 3 B-LONG (Recombinant Factor IX Fc Fusion Protein [ rFIXFc] in Subjects With Haemophilia B) study, rFIXFc demonstrated a prolonged half-life compared with recombinant factor IX ( rFIX), and safety and efficacy for prophylaxis and treatment of bleeding in subjects with moderately-severe to severe haemophilia B. In this B-LONG sub-analysis, rFIXFc was evaluated for efficacy in subjects requiring major surgery. Dosing was investigator-determined. Assessments included dosing, consumption, bleeding, transfusions and haemostatic response. A population pharmacokinetics model of rFIXFc was used to predict FIX activity. Twelve subjects underwent 14 major surgeries (including 11 orthopaedic surgeries); most subjects (11/12) received rFIXFc prophylaxis before surgery (range, ~2 weeks-12 months). Investigators/surgeons rated haemostatic responses as excellent ( n = 13) or good ( n = 1). In most surgeries (85·7%), haemostasis from the pre-surgical dose until the end of surgery was maintained with a single rFIXFc infusion. Blood loss was consistent with similar surgeries in subjects without haemophilia. The strong correlation ( R2 = 0·9586, P < 0·001) between observed and population pharmacokinetic model-predicted FIX activity suggests surgery did not impact rFIXFc pharmacokinetics. No unique safety concerns or inhibitors were observed. In conclusion, rFIXFc was safe and efficacious, with prolonged dosing intervals and low consumption, when used perioperatively in haemophilia B. Surgery did not appear to alter rFIXFc pharmacokinetics. [ABSTRACT FROM AUTHOR]

In the phase 3 B-LONG [Recombinant Factor IX Fc Fusion Protein ( rFIXFc) in Subjects with Haemophilia B] study, rFIXFc dosed every 1-2 weeks was safe and efficacious in previously treated subjects with haemophilia B. To date, there are no evaluations of transitioning from conventional to long-acting factor IX (FIX) prophylaxis. This post-hoc analysis of B-LONG subjects compared prophylaxis with other FIX products and r FIXFc. Pre- and on-study data were analysed to assess dosing regimen, weekly FIX consumption and annualized bleeding rates (ABRs). Population pharmacokinetics models were used to generate FIX activity profiles with r FIXFc and recombinant FIX prophylaxis. Thirty-nine subjects, previously treated prophylactically, were evaluated. Prior to study, most subjects (69·2%) received twice-weekly FIX infusions; on study, subjects infused r FIXFc once every 1-2 weeks with c. 30-50% reductions in weekly consumption. On-study estimated mean ABRs were lower than pre-study estimated mean ABRs. Models predicted that r FIXFc administered 50 iu/kg weekly and 100 iu/kg every 10 d would maintain steady-state FIX trough levels ≥1 iu/dl in 95·4% and 89·2% of subjects, respectively. These results indicate that patients receiving r FIXFc prophylaxis can markedly reduce infusion frequency and FIX consumption, have a greater likelihood of maintaining FIX activity >1 iu/dl and experience fewer bleeding episodes compared with prior FIX prophylaxis. [ABSTRACT FROM AUTHOR]

Organic cation transporter 1, OCT1 (SLC22A1), is the major hepatic uptake transporter for metformin, the most prescribed antidiabetic drug. However, its endogenous role is poorly understood. Here we show that similar to metformin treatment, loss of Oct1 caused an increase in the ratio of AMP to ATP, activated the energy sensor AMP-activated kinase (AMPK), and substantially reduced triglyceride (TG) levels in livers from healthy and leptin-deficient mice. Conversely, livers of human OCT1 transgenic mice fed high-fat diets were enlarged with high TG levels. Metabolomic and isotopic uptake methods identified thiamine as a principal endogenous substrate of OCT1. Thiamine deficiency enhanced the phosphorylation of AMPK and its downstream target, acetyl-CoA carboxylase. Metformin and the biguanide analog, phenformin, competitively inhibited OCT1-mediated thiamine uptake. Acute administration of metformin to wild-type mice reduced intestinal accumulation of thiamine. These findings suggest that OCT1 plays a role in hepatic steatosis through modulation of energy status. The studies implicate OCT1 as well as metformin in thiamine disposition, suggesting an intriguing and parallel mechanism for metformin and its major hepatic transporter in metabolic function. [ABSTRACT FROM AUTHOR]

Disturbances of angiogenesis have been suggested to result in the impaired healing of skin wounds. Using a murine incisional wound model, we evaluated the effects of SU6668, an inhibitor of the receptors for vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF), on the healing of skin wounds. Mice were administered vehicle, SU6668 (100 or 400 mg/kg/day, b.i.d.), or dexamethasone (1 mg/kg/day, b.i.d.), and wound healing was monitored histologically and using a tensiometer. SU6668 at a fully efficacious dose of 100 mg/kg/day had no significant effect on the healing process, while at a supratherapeutic dose of 400 mg/kg/day, there were subtle transient histologic changes and slight decreases in tensile strength, suggesting a slight delay in the wound healing process. In conclusion, these data indicate that inhibition of the receptors for VEGF, PDGF, and FGF at levels necessary to inhibit tumor growth in mouse xenograft models does not affect the healing of incisional wounds in mice. Redundant pathways likely compensate for inhibition of VEGF, PDGF, and FGF signaling pathways in the skin healing process. [ABSTRACT FROM AUTHOR]

Background We report results of a phase 1/2 open-label, multicenter study of TAK-788 (NCT02716116), an oral investigational EGFR/HER2 inhibitor. Methods Pts with advanced, previously treated NSCLC received daily TAK-788 in dose escalation and expansion cohorts based on tumor genotype. Antitumor activity was determined for pts with EGFR exon 20 insertions who received TAK-788 at the RP2D. Safety is reported for all pts across all doses and at 160 mg. Results As of 14 Sep 2018, 101 pts (median age, 61 y; female, 70%; ≥2 prior anticancer therapies, 76%; brain metastases, 53%) were treated with TAK-788 at 5-180 mg qd. RP2D was determined to be 160 mg. 28 pts with EGFR exon 20 insertions were treated with 160 mg qd during dose escalation or in expansion cohort 1 (3.6 mo on treatment; 3.8 treatment cycles [medians]); 24 pts remain on treatment. At data cutoff, best response (by RECIST v1.1) among 26 pts with ≥1 disease assessment was PR, n = 14; SD, n = 9; and PD, n = 1; 2 pts were not evaluable. 7/14 objective responses (all PR) were confirmed, with 6 awaiting confirmation and 1 unconfirmed PR at 160 mg qd; median time to response in these 14 pts was 56 days. 23/26 pts achieved disease control. 23/24 evaluable pts with EGFR exon 20 insertions treated at 160 mg qd had decreased target lesion measurements (median best percent change, -32.6% [-79.1%, 3.8%]). Most common TEAEs (≥20%) in pts treated with 160 mg qd: diarrhea (85%), rash (43%), nausea (41%), vomiting (30%), decreased appetite (28%), and stomatitis (22%); gr ≥ 3 TEAEs (≥5%): diarrhea (26%); hypokalemia, nausea, and stomatitis (7% each). Among pts treated with 160 mg qd, median dose intensity was 93%, and the rate of treatment discontinuation due to AEs was 10.7%. There is no clear trend that response to TAK-788 is enriched in any single EGFR exon 20 insertion variant. Conclusions In NSCLC pts with EGFR exon 20 insertions, TAK-788 demonstrated antitumor activity and an AE profile consistent with other EGFR TKIs. [ABSTRACT FROM AUTHOR]

We report results of a phase 1/2 open-label, multicenter study of TAK-788 (NCT02716116), an oral investigational EGFR/HER2 inhibitor. Pts with advanced, previously treated NSCLC received daily TAK-788 in dose escalation and expansion cohorts based on tumor genotype. Antitumor activity was determined for pts with EGFR exon 20 insertions who received TAK-788 at the RP2D. Safety is reported for all pts across all doses and at 160 mg. As of 14 Sep 2018, 101 pts (median age, 61 y; female, 70%; ≥2 prior anticancer therapies, 76%; brain metastases, 53%) were treated with TAK-788 at 5-180 mg qd. RP2D was determined to be 160 mg. 28 pts with EGFR exon 20 insertions were treated with 160 mg qd during dose escalation or in expansion cohort 1 (3.6 mo on treatment; 3.8 treatment cycles [medians]); 24 pts remain on treatment. At data cutoff, best response (by RECIST v1.1) among 26 pts with ≥1 disease assessment was PR, n = 14; SD, n = 9; and PD, n = 1; 2 pts were not evaluable. 7/14 objective responses (all PR) were confirmed, with 6 awaiting confirmation and 1 unconfirmed PR at 160 mg qd; median time to response in these 14 pts was 56 days. 23/26 pts achieved disease control. 23/24 evaluable pts with EGFR exon 20 insertions treated at 160 mg qd had decreased target lesion measurements (median best percent change, -32.6% [-79.1%, 3.8%]). Most common TEAEs (≥20%) in pts treated with 160 mg qd: diarrhea (85%), rash (43%), nausea (41%), vomiting (30%), decreased appetite (28%), and stomatitis (22%); gr ≥ 3 TEAEs (≥5%): diarrhea (26%); hypokalemia, nausea, and stomatitis (7% each). Among pts treated with 160 mg qd, median dose intensity was 93%, and the rate of treatment discontinuation due to AEs was 10.7%. There is no clear trend that response to TAK-788 is enriched in any single EGFR exon 20 insertion variant. In NSCLC pts with EGFR exon 20 insertions, TAK-788 demonstrated antitumor activity and an AE profile consistent with other EGFR TKIs. [ABSTRACT FROM AUTHOR]