The safety and bone antiresorptive effect of a single subcutaneous dose of AMG 162, a human monoclonal antibody to RANKL, was investigated in 49 postmenopausal women. AMG 162 is a potent ...antiresorptive agent for diseases such as osteoporosis.
Introduction: RANKL is an essential osteoclastic differentiation and activation factor.
Materials and Methods: The bone antiresorptive activity and safety of AMG 162, a fully human monoclonal antibody to RANKL, were evaluated in postmenopausal women in this randomized, double‐blind, placebo‐controlled, single‐dose, dose escalation study. Six cohorts of eight to nine women were randomly assigned to receive a single subcutaneous injection of either AMG 162 or placebo (3:1 ratio). AMG 162 doses were 0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg. Subjects were followed up to 6 months in all cohorts and 9 months in the three highest dose cohorts. Second morning void urinary N‐telopeptide/creatinine (NTX; Osteomark), serum NTX, and serum bone‐specific alkaline phosphatase (BALP, Ostase) were assessed as bone turnover markers.
Results and Conclusions: Forty‐nine women were enrolled. A single subcutaneous dose of AMG 162 resulted in a dose‐dependent, rapid (within 12 h), profound (up to 84%), and sustained (up to 6 months) decrease in urinary NTX. At 6 months, there was a mean change from baseline of −81% in the 3.0 mg/kg AMG 162 group compared with −10% in the placebo group; serum NTX changes were −56% and 2%, respectively. BALP levels did not decrease remarkably until after 1 month, indicating that the effect of AMG 162 is primarily antiresorptive. Intact parathyroid hormone (PTH) levels increased up to ∼3‐fold after 4 days in the 3.0 mg/kg dose group, but returned toward baseline with follow‐up. Albumin‐adjusted serum calcium did not decrease >10% on average in any group, and no subject had values below 2 mmol/liter. AMG 162 was well tolerated. No related serious adverse events occurred. No clinically meaningful laboratory changes, other than those described above, were observed. In summary, a single subcutaneous dose of AMG 162 resulted in a dose‐dependent rapid and sustained decrease from baseline in bone turnover and could be an effective and convenient treatment for osteoporosis.
Vandetanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and rearranged during transfection (RET) signalling, indicated for ...the treatment of medullary thyroid cancer. We investigated potential drug-drug interactions between vandetanib and metformin organic cation transporter 2 (OCT2) substrate; NCT01551615; digoxin P-glycoprotein (P-gp) substrate; NCT01561781; midazolam cytochrome P450 (CYP) 3A4 substrate; NCT01544140; omeprazole (proton pump inhibitor) or ranitidine (histamine H2-receptor antagonist; both NCT01539655).
Four open-label, phase I studies were conducted in healthy volunteers: n = 14 (metformin), n = 14 (digoxin), n = 17 (midazolam), n = 16 (omeprazole), n = 18 (ranitidine). Three of these comprised the following regimens: metformin 1000 mg ± vandetanib 800 mg, midazolam 7.5 mg ± vandetanib 800 mg, or digoxin 0.25 mg ± vandetanib 300 mg. The randomized study comprised vandetanib 300 mg alone and then either (i) omeprazole 40 mg (days 1-4), and omeprazole + vandetanib (day 5); or (ii) ranitidine 150 mg (day 1), and ranitidine + vandetanib (day 2). The primary objective assessed metformin, digoxin, midazolam and vandetanib pharmacokinetics.
Vandetanib + metformin increased metformin area under the plasma concentration-time curve from zero to infinity (AUC0-∞) and maximum observed plasma concentration (Cmax) by 74 and 50 %, respectively, and decreased the geometric mean metformin renal clearance (CLR) by 52 % versus metformin alone. Vandetanib + digoxin increased digoxin area under the concentration-time curve from zero to the last quantifiable concentration (AUC0-last) and Cmax by 23 and 29 %, respectively, versus digoxin alone, with only a 9 % decrease in CLR. Vandetanib had no effect on midazolam exposure. Vandetanib exposure was unchanged during co-administration with omeprazole/ranitidine. Treatment combinations were generally well tolerated.
Patients receiving vandetanib with metformin/digoxin may require additional monitoring of metformin/digoxin, with dose adjustments where necessary. Vandetanib with CYP3A4 substrates or omeprazole/ranitidine is unlikely to result in clinically relevant drug-drug interactions.
Osteoprotegerin (OPG), a tumor necrosis factor (TNF) receptor family member, is a critical regulator of bone resorption. It is an important inhibitor of the terminal differentiation and activation of ...osteoclasts. This randomized, double‐blind, placebo‐controlled, sequential dose escalation study was conducted in postmenopausal women to determine the effect of a single subcutaneous (sc) dose of OPG on bone resorption as indicated by the biochemical markers, urinary N‐telopeptide (NTX) and deoxypyridinoline (DPD), which are stable collagen degradation products. NTX levels decreased within 12 h after OPG administration. At the highest dose administered (3.0 mg/kg), a mean percent decrease in NTX of approximately 80% was observed 4 days after dosing. Six weeks after dosing a mean decrease of 14% in NTX was observed. The levels of bone‐specific alkaline phosphatase (BSAP), a marker of bone formation, did not change for approximately 3 weeks after dosing. Thereafter, a modest decrease, reaching approximately 30% at 6 weeks, was observed in the 3.0‐mg/kg dose group. The rapid decrease from baseline in NTX and delayed decrease in BSAP indicated that OPG acted primarily on osteoclasts to decrease bone resorption. OPG injections are well tolerated. This study, for the first time, indicates that a single sc injection of OPG is effective in rapidly and profoundly reducing bone turnover for a sustained period and that OPG therefore may be effective in treatment of bone diseases characterized by increased bone resorption such as osteoporosis.
Conventional nonsteroidal anti‐inflammatory drugs (NSAIDs) nonspecifically inhibit cyclooxygenase‐1 (COX‐1), an enzyme critical to normal platelet function, and COX‐2, which mediates inflammatory ...response mechanisms. Celecoxib, an antiarthritic agent that inhibits COX‐2 but spares COX‐1 at therapeutic doses, is expected to have minimal effects on platelet function. A double‐blind, randomized, placebo‐controlled study of 10 days' duration was conducted in 24 healthy adults to compare the effects on platelet function of a supratherapeutic dose of celecoxib (600 mg bid) with a standard dose of naproxen (500 mg bid), a conventional NSAID. Ex vivo platelet aggregation in response to standard agonists (collagen, arachidonate, or U46619 a thromboxane A2 receptor agonist), bleeding time, and serum thromboxane B2 (TxB2 level were measured. Unlike celecoxib or placebo, naproxen produced statistically significant reductions in platelet aggregation and serum TxB2 levels and increased bleeding time. The results indicate that even at supratherapeutic doses, celecoxib will not interfere with normal mechanisms of platelet aggregation and hemostasis, supporting the premise that celecoxib is COX‐1 sparing relative to conventional NSAIDs.
We have performed a detailed investigation of the photoluminescence features taken at 2
K on a series of Ga
x
In
1−
x
N alloys grown by metal-organic vapour-phase epitaxy through the whole ...composition range. The evolution of the photoluminescence lineshape of GaInN alloys in the indium-rich region is dominated by doping effects rather than by band-gap tailing effects correlated to existence of random chemical crystal inhomogeneities. The lineshape of the photoluminescence indicates a residual electron concentration of about 10
18–10
19
cm
−3 in the bulk part of the epilayers. The value we get for the bowing parameter is
b=2.8
eV.
Background. Vaccinia immune globulin (VIG) administered via the intramuscular route has historically been used for the treatment of complications of smallpox vaccination. Intravenous formulations of ...VIG are required to improve tolerability and pharmacokinetic profile. Methods. We conducted 2 separate studies to evaluate the feasibility of administration of an intravenous formulation of antivaccinia immune globulin (VIGIV). The first study assessed the pharmacokinetics and safety of a newly manufactured lyophilized VIG product for intravenous administration (VIGIV-lyo). Seventy-eight healthy volunteers received an intravenous infusion of VIGIV-lyo at doses of 100 mg/kg, 200 mg/kg, or 500 mg/kg. In the second study, we evaluated the safety of a liquid product of VIGIV (VIGIV-liq) in 33 healthy volunteers receiving an intravenous infusion of 100 mg/kg VIGIV-liq. Results. The geometric mean titer of VIG at the target dose (100 mg/kg) after intravenous administration is 2.5 times higher than the predicted geometric mean titer after intramuscular injection (P < .001). The pharmacokinetics of VIGIV-lyo are linear for doses from 100 mg/kg through 500 mg/kg. Administration of the 200-mg/kg and 500-mg/kg doses of VIGIV-lyo does not result in markedly higher adverse event rates. The adverse event rates observed with the liquid product are comparable to those seen with the lyophilized product. Conclusions. These 2 studies suggest that intravenous administration of VIG is well tolerated and results in a more favorable pharmacokinetic profile than does VIG administered intramuscularly.
This clinical delivery system bridging study evaluated the performance of a single-use disposable, commercial prototype device (designated ND5.5) for particle-mediated epidermal delivery (PMED) of a ...nucleic acid vaccine against Hepatitis B virus (HBV). Healthy adults, previously immunized with licensed HBV vaccine, received a single boost vaccination of HBV nucleic acid vaccine administered by ND5.5 or XR-1, the clinical research device used in previous clinical trials. Similar increases in anti-HBV surface antigen serum antibody titers and cell-mediated immune responses were produced by ND5.5 and XR-1 when delivering comparable effective doses of the vaccine. The overall intensity of the immune response was lower in those subjects vaccinated with two, rather than 4 administrations of vaccine delivered by ND5.5. Skin reactions at sites of vaccine administration were equivalent with both devices. This is the first clinical demonstration of the safe and effective PMED of a nucleic acid vaccine with the ND5.5 device.
This pharmacodynamic study examined weight-based dosing of the low molecular weight heparin (LMWH), tinzaparin, in heavyweight/obese subjects. Single doses (175 and 75 IU/kg) were administered ...subcutaneously (SC) to 37 healthy heavy-weight subjects (101-165 kg; 26-61 kg/m2). AUA and Amax values of anti-Xa and anti-IIa activities were consistent over these body weight and body mass index (BMI) ranges, indicating that tinzaparin pharmacodynamics are not influenced by body weight or BMI. The range of AUA and Amax values in the study population overlapped that of historical control normal-weight subjects (<100 kg), indicating that weight-adjusted tinzaparin dosing yields a predictable response regardless of body weight or BMI. Tinzaparin was well tolerated, although injection site bruising was commonly reported. SC tinzaparin dosing in heavy or obese patients is appropriate based on body weight alone; the dose need not be capped at a maximal absolute dose.
Since a few years, a lot of research efforts have been devoted to InN, the least known of the semiconducting group-III nitrides. Most of the samples available today have been grown using the ...molecular beam epitaxy technique, and fewer using the metal organic vapor phase epitaxy (MOVPE) method. Whatever the method, the growth of InN is extremely challenging, in particular due to the fact that no lattice matched substrate is available.
This paper present results on the improvement of the InN crystal quality in MOVPE. In particular, the use of carbon halides to enhance the lateral growth is demonstrated, leading to extremely smooth InN surfaces. A new process for the realization of InN nanostructures by recrystallization is presented, which allows to obtain a better crystal quality than direct MOVPE growth.
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