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Fostamatinib is a prodrug that undergoes gastrointestinal tract dephosphorylation to form the active metabolite, R406. Here we report its cytochrome P450-inducing potential. In vitro, R406 3 and 10 μM induced CYP2C8 to levels representing 53% and 75%, respectively, of the level achieved by the positive control, rifampicin. Induction of other enzymes was minor. The effect of fostamatinib (100 mg twice daily) on the pharmacokinetics of a single oral 30-mg dose of the CYP2C8 substrate pioglitazone and its metabolite, hydroxy pioglitazone, was then investigated (open-label, nonrandomized, 2-period phase I study [n = 15]). Coadministration of fostamatinib and pioglitazone (vs pioglitazone alone) was associated with lower mean maximum plasma concentration values for pioglitazone (geometric least-squares mean ratio, 82.8; 90% confidence interval, 64.2-106.8) and hydroxy pioglitazone (90.9; 78.6-105.1), an increase in pioglitazone AUC (117.8; 108.4-128.0), a decrease in hydroxy pioglitazone AUC(0-t) (89.7; 78.9-101.9), and an increase in pioglitazone geometric mean t1/2λz (9.4-12.8 hours). No tolerability concerns were identified upon coadministration. These data suggest that although clinical significance has not been formally evaluated, fostamatinib is unlikely to have a clinically significant effect on the pharmacokinetics of pioglitazone (which may be extrapolated to other CYP2C8 substrates). However, vigilance is advised should these agents be prescribed together.

Cachexia occurs in up to 80% of patients with advanced cancer and is characterized by involuntary weight loss, frequently accompanied by anorexia and altered metabolism.1–5 It is associated with poorer survival, a decline in physical functioning and quality of life, increased risk of treatment failure and toxicity, and a greater symptom burden.2,6,7 Despite the negative impact of cachexia on cancer patients, the syndrome is under-recognized and often left untreated.8 Cancer cachexia is a complex syndrome that is not fully understood, but the underlying mechanisms are thought to include the metabolic, endocrine and central nervous systems.3,7 Treatments for cancer cachexia are unfortunately lacking. With no standard effective therapies available worldwide, cachexia remains a critically unmet need in cancer supportive care.9,10 Ghrelin and ghrelin receptor agonists are being explored for their potential impact on clinical conditions such as anorexia and cancer cachexia. These compounds have been found to have clinical attributes which make them well-suited for the treatment of cachexia. Ghrelin plays an important role in stimulating appetite and encouraging food intake. Activation of the ghrelin receptor (otherwise called the growth hormone [GH] secretagogue receptor) increases lean body mass and fat mass through the secretion of GH.11,12 Anamorelin (RC-1291) is an orally-active ghrelin receptor agonist which may assist in the treatment of cancer cachexia through its appetite-enhancing, anabolic effects.13–16 It is rapidly absorbed whilst experiments with radio-labeled (14C) anamorelin have shown that it is primarily eliminated in the feces (92%; urine 8%).13,17 In a phase I study in healthy volunteers, 5–6 days treatment with anamorelin HCl, hereafter referred to as anamorelin, led to dose-related increases in body weight with no dose-limiting adverse effects; 25 and 50 mg anamorelin also produced a significant increase in appetite (VAS–Hunger scores) at virtually every pre-prandial timepoint assessed. Food intake at the 4-hour timepoint was increased on average by 18.4% compared to placebo (P

Osimertinib (AZD9291) 80 mg once daily is approved by the US FDA for the treatment of patients with metastatic EGFR T790M-positive NSCLC whose disease has previously progressed on EGFR-TKI therapy. Osimertinib PK was evaluated to define the dose and dosing interval, whether a fixed-dosing approach can be used globally, and the impact of formulation and food on exposure.AURA (NCT01802632): single- and multiple-dose PK of osimertinib (20-240 mg daily) was determined in patients with advanced NSCLC. Bioavailability study (NCT01951599): single-dose PK of osimertinib (20 mg) was determined in healthy volunteers with administration of capsule, solution, or tablet formulations fasted, and as a tablet in the fed and fasted state.Osimertinib was slowly absorbed and displayed dose-proportional increases in exposure from 20 to 240 mg. Distribution was extensive and clearance low to moderate, resulting in a mean half-life of 48.3 h. Steady state was achieved by 15 days of dosing, consistent with single-dose PK, with a peak-to-trough ratio of 1.6. Two active metabolites circulated at ~10 % of osimertinib exposure. Ethnicity did not appear to affect exposure. Osimertinib PK profiles in healthy volunteers were similar to those in patients and were unaffected by formulation. Food caused a clinically insignificant increase in exposure.Osimertinib PK supports once-daily dosing; the same dose for Asian and non-Asian populations; a fixed-dosing approach; a minimal effect of food on exposure; and a switch to tablet formulation without alteration to dose or schedule. Osimertinib plasma concentrations are sustained throughout the dosing period, which is considered optimal for efficacy.

The effects of supratherapeutic dosages of duloxetine, a serotonin and norepinephrine reuptake inhibitor, on blood pressure and pulse rate were assessed in a multicenter, double-blind, randomized, placebo-controlled, crossover study in 117 healthy women aged 19 to 74 years. Dosages were escalated from 60 mg twice daily (BID) to 200 mg BID over 16 days. Vital signs were monitored at baseline, before morning dosing, and sequentially at steady state. Duloxetine produced increases in supine systolic and diastolic blood pressures, which reached maximums of approximately 12 mm Hg and approximately 7 mm Hg above baseline, respectively, during dosing at 120 mg BID and then stabilized. Supine pulse rate increased gradually with dose, reaching 10 to 12 bpm above baseline after 4 days of dosing at 200 mg BID. Duloxetine caused changes in orthostatic blood pressures and pulse rate that reached plateau values after 3 to 4 days of dosing at 160 mg BID and were generally not associated with subjectively reported orthostatic-related adverse events. All vital signs normalized by 1 to 2 days after study drug discontinuation. Prehypertensive subjects may become hypertensive upon initial duloxetine dosing, but this can be predicted from predose blood pressure. Short-term supratherapeutic duloxetine dosages up to 200 mg BID are not well tolerated but are generally not associated with severe, clinically important adverse events. Overall, the types of adverse events reported in this study were similar to those in other studies of duloxetine in healthy subjects.

The electrophysiological effects of duloxetine at supratherapeutic exposures were evaluated to ensure compliance with regulatory criteria and to assess the QT prolongation potential.Electrocardiograms were collected in a multicenter, double-blind, randomized, placebo-controlled, crossover study that enrolled 117 healthy female subjects aged 19 to 74 years. Duloxetine dosages escalated from 60 mg twice daily to 200 mg twice daily; a single moxifloxacin 400 mg dose was used as a positive control. Data were analyzed using 3 QT interval correction methods: mixed-effect analysis of covariance model with RR interval change from baseline as the covariate, the QT Fridericia's correction method, and the individual QT correction method. Concentrations of duloxetine and its 2 major metabolites were measured.Compared with placebo, the mean change from baseline in QTc decreased with duloxetine 200 mg twice daily. The upper limits of the 2-sided 90% confidence intervals for duloxetine vs. placebo were0 msec at each time point by any correction method. No subject had absolute QT Fridericia's correction values445 msec with duloxetine, and the change in QT Fridericia's correction from baseline with duloxetine did not exceed 36 msec. No relationship was detected between QTc change and plasma concentrations of duloxetine or its metabolites even though average duloxetine concentrations ranged to more than 5 times those achieved at therapeutic doses. Moxifloxacin significantly prolonged QTc at all time points, regardless of correction method.Duloxetine does not affect ventricular repolarization as assessed by both mean changes and outliers in QT corrected by any method.

P2Y(12) receptors participate in ADP-induced activation and aggregation of human platelets. INS50589, a selective P2Y(12) receptor antagonist, is being developed for use where controlled, reversible modulation of the platelet hemostatic function is needed. The tolerability, pharmacokinetics, and pharmacodynamics of INS50589 were tested in healthy human volunteers. Thirty-six subjects received intravenous infusions of placebo or INS50589 at 0.1-3 mg/kg/h for four hours. Platelet function, clotting parameters, bleeding time, safety assessments, and plasma concentrations of INS50589 and its major metabolite were monitored for 24 hours. Near-steady state plasma concentrations of INS50589 and effects on platelet function were achieved rapidly. The average maximal plasma concentration of INS50589 was linearly related to the dose administered. Intravenous INS50589 produced dose-dependent inhibition of platelet activation and aggregation in response to ADP in vitro until nearly full inhibition was achieved at the higher doses. Bleeding time was correspondingly increased, without any effect on activated clotting time, prothrombin time, or activated partial thromboplastin time. Platelet response to ADP had returned to at least 75% of the baseline value within 0.25-4 h after cessation of the intravenous infusion of INS50589, depending upon the dose and ADP challenge concentration. Infusions were well tolerated up to the highest dose tested. There was no evidence that the principal metabolite (INS51088) contributed to these effects. INS50589 is a well-tolerated, reversible, competitive antagonist of ADP at the P2Y(12) human platelet receptor, and its potential therapeutic utility in various cardiovascular settings is discussed.

The effects of the new cyclooxygenase (COX)-2 selective inhibitor, valdecoxib (40 mg bid; n = 17), on platelet function were evaluated, along with ibuprofen (800 mg tid; n = 15) and placebo (n = 15), in healthy elderly subjects (65-85 years) in this 7.5-day, randomized, single-center, double-blind study. Platelet aggregation (to sodium arachidonate, collagen, and adenosine diphosphate), bleeding time, and serum thromboxane B2 (TxB2) concentrations were measured up to 8 hours postdose on Days 1 and 8. Valdecoxib had no platelet effects, while ibuprofen significantly decreased platelet aggregation, significantly increased bleeding time (2-4 h postdose on each day), and significantly decreased TxB2 levels at all time points. In conclusion, unlike ibuprofen, valdecoxib 40 mg bid spares platelet COX-1 function in healthy elderly subjects. Valdecoxib's lack of effect on platelet aggregation and bleeding time suggests that it will have an improved clinical profile over nonselective NSAIDs, particularly in patients for whom bleeding complications are a concern.

The platelet effects of a supratherapeutic dose of the new cyclooxygenase (COX)-2 specific inhibitor, valdecoxib (40 mg twice a day), naproxen 500 mg twice a day, diclofenac 75 mg twice a day, and placebo were compared in 62 healthy adult subjects in this 7½ day single-center, randomized, placebo-controlled trial. Platelet aggregation responses (to arachidonate [AA], collagen, and adenosine diphosphate [ADP]), bleeding time, and serum thromboxane B2 (TxB2) concentrations were measured at baseline and at regular intervals on days 1 and 8. Valdecoxib had no effect on platelet function. Naproxen and diclofenac significantly reduced the platelet aggregation response to AA and to a lesser extent collagen and ADP at most assessments compared with placebo. Naproxen significantly lowered serum TxB2 levels. In contrast to standard doses of 2 nonsteroidal antiinflammatory drugs (NSAIDs), a supratherapeutic valdecoxib dosage does not impair platelet function (COX-1). Valdecoxib may be a safer analgesic option than conventional NSAIDs in patients for whom bleeding complications are a concern. (Am J Emerg Med 2002;20:275-281. Copyright 2002, Elsevier Science (USA). All rights reserved.)

SummaryThis 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 (

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.

The primary objective of this open-label study was to determine the pharmacokinetics of norelgestromin (NGMN) and ethinyl estradiol (EE)following two consecutive applications of a contraceptive patch (ORTHO EVRA/EVRA). Twelve healthy women wore the first patch on their abdomen for 7 days and, after removal at 168 hours (day 7), wore a second patch for 10 days (i.e., 3 days beyond the intended 7-day wear period). Blood samples were collected before and at various times up to 456 hours (day 19) after application of the first patch for analysis of NGMN and EE. Mean serum concentrations of NGMN and EE remained within the reference ranges, 0.6 to 1.2 ng/ml and 25 to 75 pg/ml, respectively, during the entire 7-day wear period after application of the first patch and for 10 days after application of the second patch; reference ranges are based on studies with ORTHO-CYCLEN/ Cilest. No patch detached spontaneously. No subject discontinued or experienced a serious adverse event.

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 (s.c.) 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 s.c. 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.

To determine the single- and multiple-dose pharmacokinetics of atrasentan, a highly selective endothelin-A receptor antagonist that is currently being investigated for the treatment of prostate cancer and cardiovascular disorders. Phase I, randomised, placebo-controlled, double-blind, single-and multiple-dose study of orally administered atrasentan. Single daily oral doses of 1, 5, 10, 15, 20, 25, 30 or 40mg of atrasentan or placebo were administered to healthy male volunteers (n = 72; six active and three placebo per drug administration group) on study day 1 and days 3 to 9. Atrasentan plasma concentration-time profiles for day 1 and day 9 were used to assess atrasentan pharmacokinetics. Except for the 1mg group, atrasentan plasma concentrations increased rapidly after single and multiple administration, declining thereafter biexponentially with a study-wide harmonic mean (pseudo-SD) half-life of 21 (12) hours and mean (SD) apparent total body clearance (CL/F) of 28 (9.8) L/h. For the 1mg group, there was no apparent distribution phase and the absorption was slower. Drug administration in the 40mg group was discontinued prematurely because of adverse events. Except for lower-than-predicted maximum plasma concentration (Cmax) values for the 1mg group, drug exposure (Cmax, trough concentration and area under the concentration-time curve) increased linearly with dose, and CL/F values were similar across groups, after single- and multiple-dose administration. Steady state was reached within 4 days of drug administration. The pharmacokinetics of atrasentan are dose- and time-independent after single-and multiple-dose administration over the range of 1 to 30 mg/day.

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.

Brivaracetam (BRV) is a new anticonvulsant under development. Although BRV is an analog of levetiracetam (LEV), in addition to being an SV2A ligand, it also inhibits sodium channels in a voltage-dependent manner. The cognitive effects of BRV are uncertain.A randomized, double-blind, placebo-controlled, four-way cross-over design was employed in 16 healthy volunteers comparing acute dosing (i.e., two doses) of BRV 10 mg, LEV 500 mg, lorazepam (LZP) 2 mg, and placebo. The primary outcome was the summary score from the cognitive neurophysiologic test (CNT), which combines electrophysiologic and performance measures. Secondary outcomes included CNT cognitive and electrophysiologic subscores, traditional neuropsychological measures, and treatment-emergent adverse events (TEAEs).Compared to BRV, LEV, and placebo, LZP adversely affected the CNT summary score and the majority of CNT subscores and neuropsychological measures. In contrast, BRV did not differ from placebo or LEV on any measure. More TEAEs occurred with LZP compared to each of the other treatment conditions.The differential pattern of drug effects was consistent across multiple electrophysiologic, cognitive, and subjective measures. The profile of cognitive, subjective, and electrophysiologic effects for BRV was similar to the analog compound LEV and to placebo. The findings suggest that BRV should be tolerated well from a neuropsychological perspective, but additional studies are needed.

Purpose Brivaracetam (BRV) is a new anticonvulsant under development. Although BRV is an analog of levetiracetam (LEV), in addition to being an SV2A ligand, it also inhibits sodium channels in a voltage-dependent manner. The cognitive effects of BRV are uncertain. Methods A randomized, double-blind, placebo-controlled, four-way cross-over design was employed in 16 healthy volunteers comparing acute dosing (i.e., two doses) of BRV 10 mg, LEV 500 mg, lorazepam (LZP) 2 mg, and placebo. The primary outcome was the summary score from the cognitive neurophysiologic test (CNT), which combines electrophysiologic and performance measures. Secondary outcomes included CNT cognitive and electrophysiologic subscores, traditional neuropsychological measures, and treatment-emergent adverse events (TEAEs). Results Compared to BRV, LEV, and placebo, LZP adversely affected the CNT summary score and the majority of CNT subscores and neuropsychological measures. In contrast, BRV did not differ from placebo or LEV on any measure. More TEAEs occurred with LZP compared to each of the other treatment conditions. Discussion The differential pattern of drug effects was consistent across multiple electrophysiologic, cognitive, and subjective measures. The profile of cognitive, subjective, and electrophysiologic effects for BRV was similar to the analog compound LEV and to placebo. The findings suggest that BRV should be tolerated well from a neuropsychological perspective, but additional studies are needed.

T Cell Modulatory Peptide (TCMP-80), L-lysine-L-serine, is a synthetic dipeptide structurally related to a selected amino acid sequence in human immunoglobulin G. Based on in vitro and preclinical in vivo testing, TCMP-80 has immunomodulatory properties. This report describes the first administration of TCMP-80 to man in a randomized, double-blind, placebo-controlled, single rising-dose tolerability trial. Healthy male volunteers received TCMP-80 or placebo as a 10-minute intravenous infusion. At weekly intervals, two of four subjects were given TCMP-80; the remaining two received placebo. Each subject could receive only one dose during the study. Dosing started at 0.01 mg/kg and was increased to 0.03, 0.1, 0.3, 1, 3, 6.5, and 10 mg/kg. CBCs, blood chemistries, urinalyses, and lymphocyte subset populations were monitored predose and postdose on Days 1, 5, and 14. Three placebo and three TCMP-80 subjects reported adverse events. Adverse events reported after TCMP-80 administration were mild in nature (headache, dizziness, hematoma at injection site), appeared to be independent of dose, and resolved without medical intervention. No clinically significant alterations in vital signs, physical examination parameters, or clinical laboratory values were observed. Based on the results of this study, TCMP-80 is safe and well-tolerated within the dose range studied when administered as single intravenous infusions. Additionally, this study design represents an approach to assess the safety of an investigational immunomodulatory drug.

Osteoporosis is a metabolic bone disease resulting from increased bone resorption and characterized by low bone mass that leads to increased bone fragility and risk of fracture, particularly of the hip, spine and wrist. Bone resorption is dependent on receptor activator of NF-kappa B ligand (RANKL), which binds to RANK receptor on preosteoclasts to initiate osteoclastogenesis and maintains osteoclast function and survival. To neutralize the effects of RANKL, the body naturally produces the protein osteoprotegerin (OPG), which acts as a decoy receptor for RANKL and contributes to bone homeostasis. We describe the piecewise development of a three-compartment pharmacokinetic model with both linear and Michaelis–Menten eliminations, and an indirect pharmacodynamic response model to describe the pharmacokinetics and pharmacodynamics, respectively, of the fusion protein, Fc-osteoprotegerin (Fc-OPG), in healthy postmenopausal women. Subsequently, model verification was performed and used to address study design questions via simulation. The model was developed using data from eight cohorts (n = 13 subjects/cohort; Fc-OPG:placebo = 10:3) classified by dose level (0.1, 0.3, 1.0, or 3.0 mg/kg) and route of administration (intravenous [IV] or subcutaneous [SC]). Fc-OPG serum concentrations and urinary N-telopeptide/creatinine ratios (NTX) following both IV and SC administration were available. The model provided an adequate fit to the observed data and physiologically plausible parameter estimates. Model robustness was tested via a posterior predictive check with the model performing well in most cases. Subsequent clinical trial simulations demonstrated that a single 3.0-mg/kg SC dose of Fc-OPG would be expected to produce, at 14 days post-dose, a median NTX percentage change from baseline of −45% (with a 95% prediction interval ranging from −34% to −60%). Lastly, model ruggedness was evaluated using local and global sensitivity analysis methods. In conclusion, the model selection and simulation strategies we applied were rigorous, useful, and easily generalizable.

This clinical delivery system bridging study evaluated the performance of a single-use disposable, commercial prototype device (designated ND 5.5) 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 ND 5.5 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 ND 5.5 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 ND 5.5. 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 ND 5.5 device.

The safety and bone antiresorptive effect of a single subcutaneous dose of AMG 162. a human monoclonal antibody to RANKI,, 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:l 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 mgkg 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 mgkg dose group, but returned toward baseline with follow-up. Albumin-adjusted serum calcium did not decrease >lo% 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. J Bone Miner Res 2004:19:1059-1066. Puhlished online on March I. 2004: doi: 10.13S9/JBMR.04030S

The effects of the new cyclooxygenase (COX)-2 selective inhibitor, valdecoxib (40 mg bid; n = 17), on platelet function were evaluated, along with ibuprofen (800 mg tid; n = 15) and placebo (n = 15), in healthy elderly subjects (65-85 years) in this 7.5-day, randomized, single-center, double-blind study. Platelet aggregation (to sodium arachidonate, collagen, and adenosine diphosphate), bleeding time, and serum thromboxane B2 (TxB2) concentrations were measured up to 8 hours postdose on Days 1 and 8. Valdecoxib had no platelet effects, while ibuprofen significantly decreased platelet aggregation, significantly increased bleeding time (2-4 h postdose on each day), and significantly decreased TxB2 levels at all time points. In conclusion, unlike ibuprofen, valdecoxib 40 mg bid spares platelet COX-1 function in healthy elderly subjects. Valdecoxib's lack of effect on platelet aggregation and bleeding time suggests that it will have an improved clinical profile over nonselective NSAIDs, particularly in patients for whom bleeding complications are a concern.

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.

Background: Macrolide antibiotics such as clarithromycin are potent inhibitors of the cytochrome P450 (CYP)3A4 isozyme and have the potential to attenuate the metabolism and increase blood concentrations of drugs metabolized by this pathway. In vitro studies have suggested that sumatriptan is metabolized primarily by the monoamine oxidase-A isozyme and not by CYP3A4. Objective: This study sought to determine the effect of coadministration of clarithromycin dosed to steady state on the pharmacokinetics of a single dose of sumatriptan. A secondary objective was to assess the safety and tolerability of combining these agents. Methods: This was an open-label, randomized, 2-way crossover study in healthy volunteers. During treatment period 1, subjects received either a single oral dose of sumatriptan 50 mg (sumatriptan alone) or clarithromycin 500 mg orally every 12 hours on days 1 to 3 and a single oral dose of sumatriptan 50 mg plus a single oral dose of clarithromycin 500 mg on the morning of day 4 (combination treatment). During treatment period 2, they received the alternative regimen. Equivalence between sumatriptan alone and combination treatment was concluded if the 90% CI for the ratio of reference to test means of log e -transformed data for area under the plasma concentration-time curve extrapolated to infinity (AUC ∞ ) and maximum plasma concentration (C max ) fell within the interval from 0.8 to 1.25. Results: In the 24 evaluable subjects (12 men, 12 women) included in the pharmacokinetic analysis, mean sumatriptan AUC ∞ and C max values after administration of combination treatment were 9% and 14% higher, respectively, than the corresponding values after administration of sumatriptan alone. The 90% CI for the ratio of reference to test means for AUC ∞ was 1.03 to 1.15. The 90% CI for the ratio of reference to test means for C max was 1.03 to 1.26, above the traditional bioequivalence criterion. All other pharmacokinetic parameters tested, including nonparametric analysis of the time to C max , met the criterion for equivalence between treatments. Both treatments were well tolerated in the 27 subjects (13 men, 14 women) included in the safety analysis. Conclusions: The extent of absorption of sumatriptan was similar after oral administration alone and in combination with clarithromycin dosed to steady state. These data are consistent with previous reports that sumatriptan is unaffected by coadministration with the potent CYP3A4 inhibitor clarithromycin, supporting concomitant administration of these agents without the need for dose adjustment of sumatriptan in the acute treatment of migraine.

The objectives of this randomized, open-label, three-period, incomplete block design study were to evaluate the pharmacokinetics of norelgestromin (NGMN) and ethinyl estradiol (EE) delivered by the contraceptive patch, Ortho Evra/Evra, and to evaluate patch adhesion under conditions of heat, humidity, and exercise. During each treatment period, 30 healthy women wore Ortho Evra on the abdomen for 7 days under one of six conditions (normal activity, sauna, whirlpool, treadmill, cool water immersion, or a combination of activities). Blood samples were collected before and several times to 240 hours after patch application. Mean serum concentrations of NGMN and EE generally remained within the reference ranges, 0.6 to 1.2 ng/ml and 25 to 75 pg/ml, respectively, during the 7-day wearperiodfor all activities. Only 1 (1.1%) of 87 patches completely detached spontaneously. Peel force measurements were comparable for all activities. Ortho Evra was well tolerated. In conclusion, Ortho Evra delivers efficacious concentrations of NGMN and EE and maintains adhesive reliability through 7 days of wear even under conditions of heat, humidity, and exercise.

Aim: AZD9291 is a selective, 3rd generation EGFR-TKI, effective against EGFR-TKI-sensitising and resistance T790M mutations preclinically. In a Phase I study of AZD9291 in pts with EGFRm+ NSCLC (NCT01802632) performed in the West and Asia, all dose levels (20–240 mg daily) resulted in tumour shrinkage. This study also provided capsule PK data at all doses and tablet PK at 80 mg. A relative bioavailability study in HV (NCT01951599) has provided single 20 mg dose data for capsule, solution and tablet formulations and will provide initial fed/fasted data. Methods: In pts, plasma concentrations of AZD9291 (and potentially active metabolites AZ5104 and AZ7550) were determined up to 168 h following single dose and after 8 or 22 days of once daily dosing fasted. 197 pts received the capsule and 12 received the tablet. In HV, single dose PK were determined up to 504 h in a 3-period cross-over study. The impact of a high fat meal on PK will be investigated in a separate cohort. PK parameters were calculated using non-compartmental methods and nominal sample times. Results: AZD9291 was slowly absorbed with a median (range) tmax of 6 (3–24) h across doses. Exposure was dose proportional across the 20–240 mg dose range. AZD9291 steady state appeared to be achieved by 22 days of dosing. The geomean accumulation of AZD9291 in plasma in pts was ∼4.5-fold, consistent with the dosing frequency and observed mean (range) half-life of 55 (30–145) h. AZD9291 PK appeared to be time independent. Initial assessment of key demographic factors (body weight, Asian/Caucasian ethnicity, sex and age) indicated no relationship between any demographic factor and PK. The tablet produced similar exposure to the capsule. Exposures of AZ5104 and AZ7550 were ∼10-fold lower than AZD9291. The PK in pts and HV were consistent. Conclusions: PK results support once daily dosing, the same dose for all ethnic populations and switching from capsule to tablet in future studies. Plasma concentrations are sustained through the dosing period, which is considered optimal for efficacy and is supported by the tumour responses observed. Updated information will be provided. Disclosure: D. Planchard: Advisory boards: AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Pfizer, Roche, BMS; P.A. Dickinson, K.H. Brown and M. Cantarini: Employment and stock ownership: AstraZeneca; E. Felip: Advisory boards: Boehringer Ingelheim, Novartis, Roche, BMS, Lilly; P. Leese: Employment: Quintiles (the CRO contracted to do the study); M. Ranson: Advisory board: AstraZeneca. All other authors have declared no conflicts of interest.

The pharmacokinetics, safety, and tolerability of oral moxifloxacin, a new 8-methoxy quinolone, were assessed in a randomized, double-blind, placebo-controlled study in which healthy male and female volunteers received either 400 mg of moxifloxacin once daily ( n = 10) or a placebo once daily ( n = 5) for 10 days. Plasma moxifloxacin concentrations on days 1 and 10 were measured by high-performance liquid chromatography and fluorometric detection. Standard pharmacokinetic parameters were estimated by noncompartmental methods. Natural logarithmic estimates for each pharmacokinetic variable of each subject were analyzed by a two-way analysis of variance. Hematology, blood chemistry, vital signs, and adverse events were monitored, and electrocardiograms (ECG) were performed. Plasma moxifloxacin concentrations of predicted therapeutic relevance were achieved in this study. For day 1, the mean maximum concentration of drug in serum ( C max ) and the area under the concentration-time curve from 0 to 24 h (AUC 0–24 ) were 3.4 mg/liter and 30.2 mg · h/liter, respectively. Corresponding means on day 10 were 4.5 mg/liter and 48 mg · h/liter, respectively. On day 10, the mean elimination half-life was approximately 12 h. Plasma moxifloxacin concentrations exceeded the MIC for Streptococcus pneumoniae throughout the 24-h dosing period. The day 1 and day 10 mean AUC/MIC ratios were 121 and 192, respectively, and the mean C max /MIC ratios were 13 and 18, respectively. Moxifloxacin was well tolerated; no clinically relevant changes in the standard laboratory tests, vital signs, or ECG were observed. Pharmacokinetic parameters demonstrated linearity, and estimates of pharmacokinetic/pharmacodynamic ratios (AUC/MIC and C max /MIC) indicate that the regimen of 400-mg once daily should be effective for treating a variety of infections. Moxifloxacin was found to be safe and well tolerated in healthy volunteers when it was given as a single daily 400-mg dose for 10 days.

To evaluate the potential need for modification of dose regimens of intravenous amiodarone in patients with left ventricular dysfunction, the pharmacokinetics of amiodarone and its active metabolite, desethylamiodarone (DEA), were examined after a single 15-minute intravenous infusion of amiodarone 5 mg/kg. Three parallel groups of otherwise healthy volunteers with normal (n = 12), moderately impaired (ejection fraction > 30 but < or = 45%; n = 6), or severely impaired (ejection fraction < or = 30%; n = 6) left ventricular function were enrolled in the study. Serial blood samples were obtained over a 76-day period for estimation of pharmacokinetic parameters. With the exception of the half-life (t1/2) of DEA, statistical comparisons revealed no significant between-group differences in pharmacokinetic parameters or correlations between pharmacokinetic parameters and ejection fractions. The t1/2 of DEA was increased by approximately 60% in patients with severe left ventricular dysfunction compared with that in patients with moderately impaired and normal left ventricular function. The rate of DEA formation is slow, however, and its concentration relative to amiodarone is low. Therefore, it is unlikely that concentrations of DEA in serum would reach levels that contribute significantly to the pharmacologic activity of amiodarone during short-term (up to 2 weeks) intravenous amiodarone therapy. Single doses of amiodarone were well tolerated. The results of this study suggest that intravenous amiodarone can be used with appropriate observation to control arrhythmias, regardless of the degree of left ventricular dysfunction.

The first human MR imaging results for the hepatobiliary contrast agent manganese(II)N,N'-dipyridoxylethylenediamine-N,N'-diacetate 5,5'-bis(phosphate) (MnDPDP) are reported. MnDPDP is a paramagnetic contrast agent specific for hepatobiliary imaging. An imaging study was performed to investigate the presence of contrast enhancement or facilitated visualization of normal structures. Twelve healthy subjects receiving MnDPDP at doses of 3, 10, or 15 mumol/kg were imaged after injection for approximately 30 minutes at 1-5-minute intervals. Transaxial abdominal images were obtained at 1.5 T in a single breath-hold interval of 21 seconds with use of a spin-echo pulse sequence (repetition time = 150 msec, echo time = 20 msec). Liver parenchyma enhancement was observed 1 minute after injection and persisted for at least 30 minutes. Clearance into the gallbladder was visualized within 15 minutes. Enhancement was dose-dependent; a dose of 10 mumol/kg produced a 75%-100% signal enhancement of the liver at 10 minutes after injection.

The tolerance of a low molecular weight heparin (Fraxiparine, Choay, Paris, France) in normal individuals was determined using a two part investigation. Study 1 consisted of administering escalating doses of Fraxiparine in a single blinded, placebo controlled, rising dose tolerance evaluation. The daily doses tested were 3750 U AXA IC, 7500 U AXa IC, 11250 U AXa IC, 15000 U AXa IC, and 22500 U AXa IC Fraxiparine subcutaneously for 5 consecutive days. In study 2, we compared the tolerance of unfractionated heparin (UH) administered as 5000 IU every 8 hours, to that of 7500 U AXa IC/day or 15000 U AXa IC/day of Fraxiparine administered once daily. Our results indicated very good tolerance to this low molecular weight heparin (LMWH) at doses up to and including 22500 U AXa IC/day. We observed significantly elevated increases in transaminases following LMWH administration. In our second study we observed that the increase in serum transaminases seen after 15000 U AXa IC/day Fraxiparine was without significant difference from that observed following UH (5000 IU every 8 hours). AXa examination revealed an accumulation of AXa effect after 5 days of administration at doses greater than 15000 U AXa IC, and there was good correlation between AXa and APTT at Fraxiparine doses greater than 15000 U AXa IC/day. No thrombocytopenia was associated with Fraxiparine. We conclude that Fraxiparine is relatively well tolerated and shows accumulation after daily dosing with greater than 15000 U AXa IC.

Objectives: To assess the safety and immunogenicity of two vaccines, MSP142-FVO/Alhydrogel and MSP142-3D7/Alhydrogel, targeting blood-stage Plasmodium falciparum parasites. Design: A Phase 1 open-label, dose-escalating study. Setting: Quintiles Phase 1 Services, Lenexa, Kansas between July 2004 and November 2005. Participants: Sixty healthy malaria-naïve volunteers 18–48 y of age. Interventions: The C-terminal 42-kDa region of merozoite surface protein 1 (MSP142) corresponding to the two allelic forms present in FVO and 3D7 P. falciparum lines were expressed in Escherichia coli, refolded, purified, and formulated on Alhydrogel (aluminum hydroxide). For each vaccine, volunteers in each of three dose cohorts (5, 20, and 80 μg) were vaccinated at 0, 28, and 180 d. Volunteers were followed for 1 y. Outcome Measures: The safety of MSP142-FVO/Alhydrogel and MSP142-3D7/Alhydrogel was assessed. The antibody response to each vaccine was measured by reactivity to homologous and heterologous MSP142, MSP119, and MSP133 recombinant proteins and recognition of FVO and 3D7 parasites. Results: Anti-MSP142 antibodies were detected by ELISA in 20/27 (74%) and 22/27 (81%) volunteers receiving three vaccinations of MSP142-FVO/Alhydrogel or MSP142-3D7/Alhydrogel, respectively. Regardless of the vaccine, the antibodies were cross-reactive to both MSP142-FVO and MSP142-3D7 proteins. The majority of the antibody response targeted the C-terminal 19-kDa domain of MSP142, although low-level antibodies to the N-terminal 33-kDa domain of MSP142 were also detected. Immunofluorescence microscopy of sera from the volunteers demonstrated reactivity with both FVO and 3D7 P. falciparum schizonts and free merozoites. Minimal in vitro growth inhibition of FVO or 3D7 parasites by purified IgG from the sera of the vaccinees was observed. Conclusions: The MSP142/Alhydrogel vaccines were safe and well tolerated but not sufficiently immunogenic to generate a biologic effect in vitro. Addition of immunostimulants to the Alhydrogel formulation to elicit higher vaccine-induced responses in humans may be required for an effective vaccine., Editorial Commentary Background: Generally, adults living in parts of the world where malaria is common develop protective immunity against the parasite. This means they may get infected but not become ill as a result. However, there are individuals, such as pregnant women and children under the age of five, who are more likely to develop symptoms of malaria due to no (or reduced) natural immunity. A successful malaria vaccine would stimulate an individual's immune system to respond to the malaria parasite and prevent serious clinical disease. Many different groups are currently developing potential vaccines. Several candidates are based on a protein called MSP1 (merozoite surface protein 1) which is found on the surface of the blood-stage form of the malaria parasite. However, in nature parasites carry different versions of the MSP1 protein, and ideally a successful vaccine would bring about immune responses against these different versions. The researchers carrying out this trial wanted to compare the safety and immune responses against candidate vaccines representing two different MSP1 proteins, which covered many different parasite lines. As a phase 1 trial, the study was carried out in healthy adult volunteers. Sixty individuals were assigned to receive an injection of the vaccines, either containing a recombinant protein analogous to the FVO parasite line (termed MSP142-FVO) or the 3D7 parasite line (termed MSP142-3D7) at three different dose levels. The trial's primary objective was to assess safety, which was done by collecting data on any abnormal signs or symptoms up to 14 d after each of three vaccinations. These outcomes were graded and then defined as related to the vaccine or not. The researchers also looked at antibody levels in participants' blood against different variants of the MSP1 protein, as well as using in vitro tests to see whether antibodies from vaccinated individuals could prevent malaria parasites from growing in lab culture. What the trial shows: The safety outcomes of the trial showed that the most common type of side effect experienced by the volunteers was pain at the injection site. The vast majority of such events were graded as mild, although there was one single case of a severe event (high levels of pain experienced by one volunteer at the injection site). There was no significant association between the chance of side effects and the vaccine dosage that an individual received. Following vaccination, antibody levels against the protein on which the vaccine was based were detected, although these levels dropped over time. The researchers did not see a strong association between the vaccine dosage that individuals received and the level of antibody response. However, the two vaccines when compared seemed to be equally good at raising an immune response and both caused antibodies to be raised corresponding to different variants of the MSP1 protein. However, the antibodies raised did not seem to be particularly effective at preventing malaria parasites from growing in lab culture. Strengths and limitations: Strengths of this study include a comparison of three different dosage levels of the vaccines under study, as well as a comparison of two vaccines based on the same protein, representing different parasite lines. Limitations to the study include the small number of participants, which makes the trial underpowered to detect all but large differences in side effects between the groups being compared. A placebo arm was not included in the trial, so it is not possible to be sure that the numbers of side effects observed here can be attributed to the vaccines or not. Finally, the procedure for assigning individuals to the two different vaccines involved alternation, rather than true randomization, which could have minimized the risk of bias. Contribution to the evidence: The trial reported here is an essential step in vaccine development. The results provide the first evidence relating to safety for these two vaccines, and do not raise any safety concerns at this stage. Although the vaccines raised an immune response, the antibodies raised did not seem to have much of an effect on malaria parasites in vitro. While these vaccines are safe, alternative MSP1 vaccine formulations anticipated to bring about a greater immune response will likely be studied before proceeding to field studies.

The utility of existing methods for the evaluation of hemostatic agents has been limited. The purpose of this study was to evaluate and optimize the use of a standardized punch biopsy to investigate the effects of hemostatic agents in healthy subjects. Recombinant FVIIa (rFVIIa) is licensed for the treatment of bleeding episodes in patients with hemophilia A or B with inhibitors. Recent reports (anecdotal and from randomized clinical trials) have described the successful use of rFVIIa in patients with liver disease, intracerebral hemorrhage, congenital and acquired coagulation factor deficiency, warfarin-induced bleeding, thrombocytopenia, traumatic brain injury, spinal cord surgery, and platelet disorders using a wide range of doses and dosing regimens. This variety of clinical situations, suggests a need to determine the optimal dose and dosing regime of rFVIIa for use in these potentially new therapeutic areas. A study was designed to evaluate the dose-response of rFVIIa in a controlled manner using a punch biopsy procedure in healthy volunteers that consented to participate in an IRB approved protocol. The study was designed as a three-part trial. Part A (6 subjects) optimized the size of the biopsy needed to create bleeding times and durations appropriate for study purposes. Part B (10 subjects) determined the feasibility of evaluating rFVIIa efficacy and safety in this bleeding model. Part C (48 subjects) examined, in an ascending dose escalation paradigm, the effect of a single dose of rFVIIa on bleeding time, blood loss volume, coagulation parameters and coagulation status in healthy volunteers. In Part C, all patients underwent three punch biopsies: the first (baseline biopsy) with no treatment, the second with either a low or high rFVIIa dose administered prior to biopsy, the third with either a low or high dose of rFVIIa administered prior to biopsy. The treatment pair sequences were placebo/10, 10/20, 20/40, 40/80, 80/120, and 120/160 μg/kg. Blood samples were drawn 15 minutes pre-, 15 minutes post-, and 1 hour post-biopsy to monitor coagulation and conduct ex-vivo assessments of hemostasis [Hemodyne Hemostasis Analyzer (HHA)]. Safety evaluations were conducted by an Independent Safety Officer after each dose tier, and subjects were permitted to enroll in the next higher dose tier only if no significant safety issues were observed. In healthy subjects with no pre-existing coagulopathies, regression analyses indicated that increasing doses of rFVIIa did not have a dose-related linear effect on blood loss volume or duration of bleeding. However, it is of interest that with HHA, a statistically significant impact was noted on the time to 20 mm clot strength, platelet contractile force, and clot elastic modulus, suggesting that rFVIIa does have a measureable and perhaps meaningful effect in individuals with normal coagulation systems. No safety issues were detected during this study. Thus in this model system, designed to evaluate hemostasis, interesting effects were seen with the HHA instrument which suggest that increasing doses of rFVIIa may impact clot stability, but these observations are limited by the significant hetereogeneity which may benefit from improved experimental controls.

The generation of thrombin is a critical step in clot formation and securing hemostasis. Inadequate thrombin generation may result in excessive bleeding, while uncontrolled thrombin production has the potential to induce thromboses. Recombinant FVIIa has been shown to control bleeding in hemophilia patients with inhibitors to coagulation factors VIII and IX, and several other clinical conditions in which life- and limb-threatening bleeding may occur. However, for non-hemophilia patients the dose and dosing regimen still require refinement. The use of ex-vivo assessment systems (Thromboelastograph assay, Hemodyne Hemostasis Analyzer) to generate an in vitro model of hemostasis may be useful to determine the effect of rFVIIa on the dynamics of clot formation, particularly in a patient population where clinical trials are difficult. A series of pilot studies were performed to establish an optimal punch biopsy location and biopsy size to create an effective bleeding site for further study. The current study (48 subjects consented for an IRB approved protocol) examined, in an ascending dose-escalation manner, the effect of an individual dose of rFVIIa on bleeding time, blood loss volume, coagulation parameters and coagulation status in healthy volunteers. All patients underwent three punch biopsies: the first (baseline biopsy) with no treatment, the second and third biopsy with either a low or high rFVIIa dose administered prior to biopsy. The treatment pair sequences were placebo/10, 10/20, 20/40, 40/80, 80/120, and 120/160 μg/kg. Blood samples were drawn 15 minutes pre-, 15 minutes post-, 1 hour and 5 hours post-biopsy to conduct ex-vivo assessments of hemostasis. The results indicate that overall there was a trend towards an increase in platelet contractile force and clot elastic modulus with an apparent maximal effect at 1 hour post-biopsy. At the higher doses this effect, although reduced, does not return to pre-treatment values by 5 hours post-biopsy. For the lower doses these values decreased to levels comparable to those at pre-treatment. These observations are consistent with the reports of a dose-related half-life of rFVIIa. These data imply that the administration of rFVIIa may have an effect in non-coagulopathic individuals. Although the heterogenity observed in this sample of patients may limit interpretations, it is proposed that this ex-vivo model with further refinements may be useful for evaluating the effects of future pro-hemostatic agents. Figure Figure

Mucositis is a frequent and debilitating complication experienced by patients receiving high-dose chemotherapy and/or radiotherapy significantly impacting patient-reported outcomes (Spielberger et al, ASCO 2003) and healthcare resources (Emmanouilides, ASH 2003) for its management. Palifermin has been shown in hematological cancer patients to reduce the duration, incidence, and severity of mucositis and its related clinical sequelae following 3-consecutive daily doses of 60 mcg/kg before and after TBI and chemotherapy with HSCT (Spielberger et al, ASCO 2003). In this phase 1, randomized, double-blind, placebo-controlled, dose escalation study, the PK and PD of palifermin were evaluated in healthy subjects. A single IV bolus of palifermin or placebo was administered at 6 dose levels ranging from 60 to 250 mcg/kg. Blood samples for PK assessments were collected through 120 hours post administration, and PK analysis was conducted using noncompartmental methods. PD measurements (using Ki67 staining on buccal mucosa biopsies) assessing the proliferation of buccal mucosal epithelium were performed on all subjects at baseline and 48 or 72 hours following administration of palifermin or placebo. Seventy-nine subjects received study drug (n=16 placebo and n=63 palifermin). Most subjects were white (76%) and men (96%). The mean age was 25.8 years (range 18 to 53). A sharp decrease in palifermin concentrations occurred during the first 1 to 1.5 hours postdose, followed by a slight increase and then a subsequent decay phase. Exposure to palifermin increased approximately proportional to dose (3-fold increase in C0 and AUC for a 4-fold increase in dose). Table 1. Mean (SD) PK Data Dose (mcg/kg) n C0 AUC0-∞ (ng*hr/mL) t1/2,z (hr) CL (mL/hr/kg) 60 16 891 (661) 134 (40.5) 4.50 (0.580) 494 (171) 90 15 1020 (823) 170 (54.8) 4.92 (0.460) 590 (212) 120 8 1530 (1190) 253 (85.7) 5.22 (0.412) 528 (185) 160 8 1590 (1100) 257 (69.2) 4.89 (0.274) 661 (162) 210 8 1700 (1560) 322 (96.5) 5.89 (0.975) 714 (245) 250 8 2720 (2150) 412 (110) 6.09 (1.20) 645 (172) The PD response also increased with increasing doses of palifermin up to the dose of 160 mcg/kg at which near maximal effect appeared to have been reached. A greater response for Ki67 staining was observed at 48 hours compared with 72 hours. Transient asymptomatic increases in amylase (primarily of salivary origin) and lipase were noted 1 to 3 days postdosing at all palifermin doses. Upper torso, arm, and facial skin erythema and injection site reactions were more frequently noted at the highest doses. In this study, palifermin was safe and generally well tolerated in the dose range examined. In summary, for the dose range examined, exposure to palifermin increased approximately dose-proportionally and an increased PD response was observed with increased dose with a flattening of the dose response relationship at higher doses. Based on the safety and PD profile of palifermin in this study and the results of a phase 3 study (Spielberger et al, ASCO 2003), future trials in oncology patients will be conducted using a single 180 mcg/kg dose in lieu of 3 doses at 60 mcg/kg.

The bioavailability of a new sustained-release potassium chloride (KC1) tablet, designed for once-a-day dosing, was compared to a KC1 elixir using urinary excretion data. The study utilized 25 male volunteers dosed in a crossover design in a dietary/activity-controlled environment. The regimens consisted of a total of 80 mEq of potassium in three equally divided doses of elixir every 6 hr and a single 80-mEq dose using four 20-mEq sustained-release (SR) tablets. The mean time to maximum rate of potassium urinary excretion was 2.2 hr for the first elixir dose and 5.5 hr after the SR tablet (P < 0.01), thereby supporting the prolonged-release properties of this formulation. After correction for baseline urinary potassium excretion, the mean total 24-hr urinary potassium excretion was 42.18 mEq for the elixir and 40.41 mEq for the SR tablet. The results indicate that the absorption pattern from the SR tablet is equal to three doses of KC1 elixir dosed 6 hr apart.

The effect of cetamolol (an investigational cardioselective beta blocker with intrinsic sympathomimetic activity) on the hypokalemic response to epinephrine infusions in normal subjects was evaluated and compared with placebo and two other beta-adrenergic blocking drugs. After two daily doses of cetamolol 15 mg, atenolol (a cardioselective beta blocker) 50 mg; a long-acting propranolol preparation (a nonselective beta blocker) 80 mg; or placebo, 12 men (mean age, 26.7 years) were infused with epinephrine. The resulting average plasma epinephrine level was 1123 pg/mL, whereas average baseline serum potassium levels for the four treatment groups ranged from 3.94 to 4.07 mEq/L. Epinephrine-induced hypokalemia occurred in the placebo group (maximum potassium decrease of 1.00 mEq/L) and in the atenolol group (maximum potassium decrease of 0.59 mEq/L); potassium levels did not decrease but rose slightly in subjects receiving cetamolol or propranolol. Subjects treated with placebo or atenolol also demonstrated statistically significant prolongation of the QTc interval (0.039 seconds with placebo; 0.023 seconds with atenolol) and frequently developed T-wave flattening and U-wave appearance. After pretreatment with cetamolol or propranolol, however, the QTc interval was unaffected, T-wave abnormalities did not occur, and U waves appeared only rarely. The results of this study indicate that cetamolol blocks epinephrine-induced hypokalemia and associated electrocardiographic changes.

(1985). Recruiting for Post-Operative Pain Studies: Experiences over two Years. Clinical Research Practices and Drug Regulatory Affairs: Vol. 3, No. 4, pp. 451-451.

The preclinical and clinical trial experience with ferrioxamine (S-FDF; Salutar, Inc.) as a contrast agent for magnetic resonance imaging (MRI) is summarized. The results in 44 patients or subjects show that the drug is safe and well tolerated when given intravenously. In certain conditions, early results show that the use of this contrast agent provides more information than can be obtained with MRI alone.