TPA023, a GABA(A) alpha2,3 alphasubtype-selective partial agonist, is expected to have comparable anxiolytic efficacy as benzodiazepines with reduced sedating effects. The compound lacks efficacy at the alpha1 subtype, which is believed to mediate these effects. This study investigated the effects of 0.5 and 1.5 mg TPA023 and compared them with placebo and lorazepam 2 mg (therapeutic anxiolytic dose). Twelve healthy male volunteers participated in this placebo-controlled, double-blind, double-dummy, four-way, cross-over study. Saccadic eye movements and visual analogue scales (VAS) were used to assess the sedative properties of TPA023. The effects on posturaL stability and cognition were assessed using body sway and a standardized battery of neurophysiological memory tests. Lorazepam caused a significant reduction in saccadic peak velocity, the VAS alertness score and impairment of memory and body sway. TPA023 had significant dose dependent effects on saccadic peak velocity (85 deg/sec maximum reduction at the higher dose) that approximated the effects of lorazepam. In contrast to lorazepam, TPA023 had no detectabLe effects on saccadic latency or inaccuracy. Also unlike lorazepam, TPA023 did not affect VAS alertness, memory or body sway. These results show that the effect profile of TPA023 differs markedly from that of lorazepam, at doses that were equipotent with regard to effects on saccadic peak veLocity. Contrary to lorazepam, TPA023 caused no detectable memory impairment or postural imbalance. These differences reflect the selectivity of TPA023 for different GABA(A) receptor subtypes.
The potential use of rapid eye movement (REM) sleep effects as a biomarker for the therapeutic effects of antidepressants in healthy volunteers is reviewed. A literature search was performed to select studies investigating the effects of antidepressants on REM sleep. To assess the specificity of REM sleep effects as a biomarker, the effects of other central nervous system drugs on REM sleep were also investigated. A significant REM sleep reduction was shown for 16 of 21 investigated antidepressants after single-dose (mean reduction 34.1%) and for 11/13 drugs after multiple-dose administration (mean reduction 29.2%). The median increase in REM latency was approximatety 60% after single- or multiple-dose administration. REM sleep effects were linearly normalized to therapeutic doses, by dividing the REM sleep effect by the investigated dose and multiplying by the therapeutic dose. Normalized REM sleep effects were highly variable (range -27.0% to 81.8% for REM sleep; range -17.0% to 266.3% for REM latency) and demonstrated no relationship with relevant pharmacological properties of the investigated drugs. No quantifiable dose-response relationship could be constructed after single and multiple dose administration. REM sleep effects were not specific for antidepressants. Benzodiazepines, for example, caused an average dose normalized REM sleep reduction of 8.7% and a median 8.6% increase of REM latency. This review demonstrates that although REM sleep effects occur with most of the antidepressants, it is by itself of limited value as a biomarker for antidepressant action. The specificity for antidepressants is limited, and it does not show a quantitative dose-response relationship to antidepressant agents. This is at least partly due to the complex relationships between drug pharmacokinetics and the variable time course of REM and other sleep stages throughout the night. Models that take these complex relationships into account may provide more comprehensive and quantifiable results.
Sinhibitory effect were not significantly different between hetEMs and homEMs, although there was a trend towards an increased AUC and acid-inhibitory effect in hetEMs. Therefore we compared the acid-inhibitory effect of LPZ and OPZ to baseline.Compared with baseline median 24 h pH and % of time pH > 4 at day 1 were significantly increased in hetEMs, but not in homEMs for both LPZ and OPZ. At day 6 the differences in acid-inhibitory effect between hetEMs and homEMs were not significant.At day 1 of administration acid inhibitory effect of LPZ 15 mg and OPZ 10 mg is affected by CYP2C19 polymorphism. Compared with baseline, there was at day 1 a significant acid-inhibitory effect in hetEMs, but not in homEMs. Lansoprazole (LPZ) and omeprazole (OPZ) are metabolized by CYP2C19 and CYP3A4. The major metabolic pathway for OPZ is hydroxylation by CYP2C19. The aim of the study was to compare the effect of CYP2C19 genotype status on pharmacokinetics and acid-inhibitory effects of LPZ with that of OPZ.A randomized three-way crossover study was performed in 12 H. pylori-negative healthy Caucasian subjects. Subjects received OPZ 10 mg o.d. and LPZ 15 mg o.d. for 7 days with a 2-week washout period. Plasma concentrations of LPZ and OPZ were measured at day 1, and gastric pH was monitored at day 1 and 6 of drug administration. CYP2C19 genotype was determined by a PCR-RFLP method.CYP2C19 status was determined in 11 subjects; six were homozygous extensive metabolizers (homEMs) and five were heterozygous extensive metabolizers (hetEMs). There were no significant differences between hetEMs and homEMs in median 24 h gastric pH and % of time pH > 4 during the baseline period. At day 1 of OPZ administration area under the concentration time curve (AUC) and acid-inhibitory effect (median 24 h pH) were significantly greater in hetEMs than in homEMs (Table 1). At day 1 of LPZ administration AUC and acid-
4045 Poster Board III-980 Introduction CNTO328 is a chimeric monoclonal antibody against the inflammatory cytokine, IL-6, which is currently being studied in hematologic and solid malignancies. IL-6 is reported to play a key role in the etiology and symptoms of Anemia of Cancer (AOC). Increased IL-6 during cancer associated inflammation up-regulates the hepatic production of hepcidin, which is the iron-regulatory hormone that may be responsible for most of the features of this disorder. CNTO328 treatment has previously been shown to be associated with Hb increases in Castleman's Disease (a disorder caused by deregulated IL-6 production) and Renal Cell Carcinoma (RCC). We retrospectively undertook this assessment in the RCC patients, to assess whether there was an associated decrease in hepcidin. Patients and Methods Serum Hb, IL-6 and CRP (a surrogate for IL-6 activity) levels were prospectively studied in RCC patients selected from two 6 mg/kg CNTO328 treatment cohorts (IV Q2W or Q3W) in a phase 1/2 study. Free and total IL-6 could not be measured due to interference of the drug with assay performance which prevents accurate measurement. Serum hepcidin levels were retrospectively measured using a hepcidin C-ELISA. The change from baseline in Hb, hepcidin and CRP levels was calculated at multiple time points. The association between Hb response (defined as max Hb increase of ≥1 g/dL) and change in hepcidin and CRP levels was evaluated by Pearson Correlation Coefficient (r). Results 38 RCC patients with a median baseline Hb of 13.2 g/dL (10.1-17.1) were studied. All patients had normal renal function throughout the study. Two patients were excluded from analysis because of blood transfusions at baseline. None of the patients studied received ESAs or blood transfusions during screening or treatment. Treatment with CNTO328 resulted in an Hb increase during study in 35 (92%) of the 38 patients starting on Day 8, with 25 (66%) achieving a max Hb increase of 31 g/dL (median 2.0; range 1.0-3.5). Hb responses were not due to tumor response, were independent of dosing schedule (Q2W vs Q3W) and were even seen in 6 (86%) out of 7 patients with a baseline Hb <12 g/dL. As expected, a marked reduction in day 8 hepcidin was noted (median decrease of 61.1%, range -90%-53.9%). A moderate correlation was found between Hb response and the Day 8 percent change in hepcidin (r = -0.56, n=19) but not between baseline hepcidin and Hb response (r = 0.056, n=21). A sustained suppression of serum CRP levels from baseline was evident in all patients and Hb responses were moderately correlated with the Day 8 absolute change in CRP (r = -0.41, n=24) and less well correlated with baseline CRP (r = 0.31, n=25) levels. Max Hb levels (median 14.9 g/dl, range 11.1-17.7) did not exceed the upper limit of normal for any patient, and no thromboembolic events were observed. Conclusion CNTO328 was associated with normalization of Hb in this moderately anemic RCC population, presumably due to reduction of hepcidin via IL-6 blockade. This mechanism may provide a physiologic alternative to transfusions in AOC and warrants further evaluation with prospective mechanistic studies in more anemic patients. A possible Hb response correlation with hepcidin and CRP levels is of particular interest and will be actively pursued in prospective trials. Disclosures: Rijnbeek: Johnson & Johnson: Employment. Reddy:Johnson & Johnson: Employment. Qin:Johnson & Johnson: Employment. Cornfeld:Johnson & Johnson: Employment, Equity Ownership.
5150 Introduction: Siltuximab is a chimeric monoclonal antibody with high affinity for the inflammatory cytokine, IL-6, which is currently being studied in hematologic, solid malignancies and multicentric Castleman's disease (MCD). In addition to representing a therapeutic target, IL-6 is reported to play a key role in the etiology and symptoms of anemia of cancer. A possible mechanism is through up-regulation of hepatic production of hepcidin, the central iron-regulatory hormone. Siltuximab treatment has previously been shown to be associated with clinically significant Hb increases in MCD (a disorder caused by deregulated IL-6 production) and renal cell carcinoma. We have prospectively studied the Hb response in the context of a phase I study with siltuximab in patients with advanced solid tumors. Patients and Methods Siltuximab was administered intravenously to patients with any advanced solid tumor at increasing dose levels (2.8 or 5.5 mg/kg every 2 weeks, 11 or 15 mg/kg every 3 weeks). Hepcidin (C-ELISA), Hb, CRP (marker for inflammation) and iron status (serum iron, ferritin, transferrin saturation, total iron binding capacity) were measured at baseline and serially during treatment. IL-6 was not measured since interference of the drug with assay performance prevents accurate measurement of bioactive IL-6. The relationships between these biomarkers and Hb response (defined as a maximum Hb increase of ≥1 g/dL during treatment) were evaluated. Results: Forty-four pts (18 colorectal, 12 ovarian, 5 pancreatic, 9 other) received a median of 3 siltuximab cycles (range 1 – 25). Eight patients were excluded from analysis because they received blood transfusions or ESAs. There were no objective tumor responses (CR or PR). Baseline Hb ranged from 9.4–15.3 g/dL (median 12.2). All 36 evaluable patients had an increase in Hb (median 1.35 g/dL; range 0.1–3.2). Eleven (31%) patients had a maximum increase of ≥2 g/dL. Maximum Hb levels did not exceed the upper limit of normal. Baseline hepcidin (median 118.6 ng/mL; range 9.5–493.3) was positively correlated with baseline CRP (median 13.6 mg/L; range 0.42–152.0) (p<0.05) and ferritin (median 346 pmol/L; range 74.2–8543.1) (p<0.05) but not with baseline Hb or Hb response. For subjects with a Hb response of more than 2 g/dL an association was found with Day 8 hepcidin (p = 0.03) when controlled for baseline serum iron. Early hepcidin percentage change was not correlated with Hb response. Conclusion: Siltuximab treatment was associated with clinically meaningful Hb response in this moderately anemic refractory cancer population. The exact mechanism of action remains uncertain, however correlation with additional markers (e.g., soluble transferrin receptor, inflammatory markers such as IL-6) might also be important to identify patients most likely to respond to treatment and should be evaluated further in randomized trials. Disclosures: Kurzrock: Johnson & Johnson: Research Funding. Angévin:Johnson & Johnson: Research Funding. Cohen:Johnson & Johnson: Research Funding. Van Laethem:Johnson & Johnson: Research Funding. Rijnbeek:Johnson & Johnson: Employment. Vermeulen:Johnson & Johnson: Employment. Tromp:Johnson & Johnson: Employment. Li:Johnson & Johnson: Employment. Reddy:Johnson & Johnson: Employment. Cornfeld:Johnson & Johnson: Employment. Tabernero:Johnson & Johnson: Research Funding.
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