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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

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.

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.

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.

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

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.

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.