Background Present interferon-based standard of care treatment for chronic hepatitis C virus (HCV) infection is limited by both efficacy and tolerability. We assessed the safety, tolerability, and antiviral activity of an all-oral combination treatment with two experimental anti-HCV drugs-RG7128, a nucleoside polymerase inhibitor; and danoprevir, an NS3/4A protease inhibitor in patients with chronic HCV infection.Methods Patients from six centres in New Zealand and Australia who were chronically infected with HCV genotype 1 received up to 13 days oral combination treatment with RG7128 (500 mg or 1000 mg twice daily) and danoprevir (100 mg or 200 mg every 8 h or 600 mg or 900 mg twice daily) or placebo. Eligible patients were sequentially enrolled into one of seven treatment cohorts and were randomly assigned by interactive voice or web response system to either active treatment or placebo. Patients were separately randomly assigned within each cohort with a block size that reflected the number of patients in the cohort and the ratio of treatment to placebo. The random allocation schedule was computer generated. Dose escalation was started in HCV treatment-naive patients; standard of care treatment-experienced patients, including previous null responders, were enrolled in higher-dose danoprevir cohorts. Investigators, personnel at the study centre, and patients were masked to treatment allocation. However, the pharmacist who prepared the doses, personnel involved in pharmacokinetic sample analyses, statisticians who prepared data summaries, and the clinical pharmacologists who reviewed the data before deciding to initiate dosing in the next cohort were not masked to treatment allocation. The primary outcome was change in HCV RNA concentration from baseline to day 14 in patients who received 13 days of combination treatment. All patients who completed treatment with the study drugs were included in the analyses. This study is registered with ClinicalTrials.gov, NCT00801255.Findings 88 patients were randomly assigned to a study drug treatment regimen (n=74 over seven treatment groups; 73 received at least one dose of study drug) or to placebo (n=14, all of whom received at least one dose). The median change in HCV RNA concentration from baseline to day 14 ranged from -3.7 to -5.2 log(10) IU/mL in the cohorts that received 13 days of combination treatment. At the highest combination doses tested (1000 mg RG7128 and 900 mg danoprevir twice daily), the median change in HCV RNA concentration from baseline to day 14 was -5.1 log(10) IU/mL (IQR -5.6 to -4.7) in treatment-naive patients and -4.9 log(10) IU/mL in previous standard of care null responders (-5.2 to -4.5) compared with an increase of 0.1 log(10) IU/mL in the placebo group. The combination of RG7128 and danoprevir was well tolerated with no treatment-related serious or severe adverse events, no grade 3 or 4 changes in laboratory parameters, and no safety-related treatment discontinuations.Interpretation This oral combination of a nucleoside analogue polymerase inhibitor and protease inhibitor holds promise as an interferon-free treatment for chronic HCV.

E.J. Gane1, S.K. Roberts2, C. Stedman3, P.W. Angus4, B. Ritchie5, R. Elston6, D. Ipe6, L. Baher6, P. Morcos6, I. Najera6, M. Mannino6, B. Brennan6, M. Berrey7, W. Bradford8, E. Yetzer6, N. Shulman6, P.F. Smith6. 1Auckland Clinical Studies, Auckland, New Zealand; 2The Alfred, Melbourne, Australia; 3Christchurch Clinical Studies, Christchurch, New Zealand; 4Austin Hospital, Heidelberg, 5Royal Adelaide Hospital, Adelaide, Australia; 6Roche Palo Alto LLC, Palo Alto, CA, 7Pharmasset, Inc., Princeton, NJ, 8Intermune, Inc., Brisbane, CA, USA E-mail: patrick.smith@roche.com

PURPOSE:AMG 706 is an investigational, orally bioavailable inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor, and stem-cell factor receptor. This phase I, dose-finding study evaluated the safety, pharmacokinetics, and pharmacodynamics of AMG 706 in patients with refractory advanced solid tumors.PATIENTS AND METHODS:AMG 706 was administered at escalating doses of 50 to 175 mg once daily or 25 mg bid for the first 21 days of a 28-day cycle. The 125-mg once-daily dose was also administered continuously. The maximum-tolerated dose (MTD), safety, pharmacokinetics, tumor response, and serum levels of proangiogenic markers were determined.RESULTS:Seventy-one patients received AMG 706. The MTD was 125 mg once daily administered continuously. The most frequent adverse events were fatigue (55%), diarrhea (51%), nausea (44%), and hypertension (42%). Plasma AMG 706 concentrations increased in a dose-proportional manner with no accumulation after multiple doses. Five patients (7%) had a partial response, 35 patients (49%) had stable disease (at least through day 50), and 31 patients (44%) had progressive disease. Changes in tumor size correlated significantly with an increase in placental growth factor (P = .003) and a decrease in soluble kinase domain receptor (P = .001).CONCLUSION:In this study of patients with advanced refractory solid tumors, AMG 706 was well tolerated and displayed favorable pharmacokinetics and evidence of antitumor activity. Additional studies of AMG 706 as monotherapy and in combination with various agents are ongoing.

Background/Aims: To compare the pharmacokinetics, pharmacodynamics, and antiviral activity of peginterferon alfa-2b and peginterferon alfa-2a in patients with chronic hepatitis C virus genotype 1.Methods: Thirty-six patients were randomised to peginterferon alfa-2b (1.5 mu g/kg/week) or peginterferon alfa-2a (180 mu g/week) for 4 weeks, then in combination with ribavirin (13 mg/kg/day) for a further 4 weeks. The pharmacokinetic profile of both peginterferons, mRNA expression of a selected group of interferon-induced gene transcripts, and serum HCV-RNA levels were assessed.Results: Patients receiving peginterferon alfa-2b had significantly greater up-regulation of interferon-alfa response genes compared with those receiving peginterferon alfa-2a. Correspondingly, patients treated with peginterferon alfa-2b also had a significantly greater loglo maximum and loglo time-weighted average decrease in serum HCV-RNA. A greater proportion of peginterferon alfa-2b patients achieved a >=, 2.0 log(10) reduction in serum HCV-RNA levels by week 8 (72% vs 44% of peginterferon alfa-2a patients, P = 0.09). There was an approximately 16-fold greater exposure to peginterferon in the serum of patients treated with peginterferon alfa-2a.Conclusions: These findings suggest that the biological activity, measured by early interferon-induced gene transcripts and early antiviral responsiveness, may have been greater in patients treated with peginterferon alfa-2b despite their lower exposure to the drug compared with patients treated with peginterferon alfa-2a. (c) 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chronic hepatitis C virus (HCV) infection is usually asymptomatic in children, but significant liver disease may occur. We evaluated the efficacy, safety, and pharmacokinetics of interferon alfa‐2b and ribavirin in children with chronic HCV. We determined the optimal ribavirin dose in an initial cohort of a phase 1 study and then subsequently used it, in combination with interferon alfa‐2b, in a second cohort of this study and a phase 3 trial. The primary efficacy endpoint in all studies was sustained virological response, defined by undetectable serum HCV RNA 24 weeks after completion of therapy. All efficacy and safety analyses were performed on the intent‐to‐treat population. Children receiving interferon alfa‐2b plus ribavirin 15 mg/kg/d in the phase 1 study had the maximum reduction in serum HCV RNA at treatment weeks 4 and 12 with an acceptable safety profile. This ribavirin dose was selected as optimal and used in all subsequent studies. In all, 46% (54/118) of optimally treated children achieved sustained virological response. Sustained virological response was significantly higher in children with HCV genotype 2/3 (84%) than in those with HCV genotype 1 (36%). Adverse events led to dose modification in 37 (31%) and discontinuation in 8 (7%). Multiple‐dose interferon alfa‐2b and ribavirin peak and trough concentrations and area‐under‐the‐curve were similar between children and adults. In conclusion, interferon alfa‐2b in combination with ribavirin is effective and safe in children with chronic hepatitis C virus. (HEPATOLOGY 2005;42:1010–1018.)

These data suggest that divided daily dose administration (every 12 or 6 hours) significantly increases posaconazole exposure under fasted conditions.

Posaconazole is a potent, extended-spectrum triazole antifungal agent currently in clinical development for the treatment of invasive fungal infections. This study was conducted to compare the bioavailability and resulting serum concentrations of posaconazole 800mg following administration of three different dose regimens to fasting adults.

Several epidemiological studies have suggested that longer-term use of NSAIDs may reduce the risk of developing Alzheimer's disease (AD). Although there were encouraging results from some earlier studies, more recent longer-term, larger, placebo-controlled clinical trials utilising drugs with an anti-inflammatory action have produced disappointing outcomes. Re-analysis of the epidemiological data has shown that the protective effect is limited to a subgroup of NSAIDs, including flurbiprofen, which have Aβ-42 lowering properties and which were not used in the previous longer-term placebo-controlled trials. Flurizan (MPC-7869 (R)-flurbiprofen) is a single enantiomer of flurbiprofen, which has been shown to lower brain levels of Aβ-42 in a mouse model of AD (Tg2576), with some evidence of an effect on learning and memory. There is little risk of gastric toxicity because of a lack of anti-COX activity, and the compound has been shown to be safe and well tolerated in healthy older volunteers (55-80yrs) at doses of up to 1600mg per day when administered for 21 days in a phase I study. It is therefore an exciting potential disease modifying treatment for AD. This presentation will provide efficacy and safety data from a clinical trial of Flurizan, which to our knowledge will be the first multi-centre, placebo-controlled, double-blind clinical study of a selective Aβ-42 lowering agent in patients with mild to moderate Alzheimer's disease. This is a one-year trial evaluating both 400mg BID and 800mg BID of (R)-flurbiprofen per day, in 210 patients (50% female) with mild to moderate AD (MMSE 15-26). It employed the ADAS-cog, ADCS-ADL, CDR-sb, CIBIC plus, NPI and MMSE as outcome measures. At baseline the mean age of the subjects was 75 years with an average MMSE score 21 and an average standard ADAS-cog score 23. Of the patients enrolled in the trial, 94 per cent were also taking stable doses of cholinesterase inhibitors. Concomitant treatment with memantine was not allowed. The study completes in March 2005, and the cognitive, functional, global and behavioural outcomes will be presented, together with the safety data.

Background & Aims: Pegylated interferon alfa-2b (PEG-IFN-alfa(2b)) has been shown to provide superior efficacy to IFN-alfa(2b) in patients with chronic hepatitis C (predominantly genotype :1) infection as measured by viral clearance. This study was conducted to determine the optimal dosing regimen of PEG-IFN-alfa(2b) required to obtain a maximum decrease of hepatitis C viral RNA. Methods: This was a 24-week, open-label, multicenter, parallel-group, randomized, active-controlled trial in the United Kingdom, France, and Israel. Individuals (n = 61) with chronic hepatitis C infection, genotype 1, received IFN-alfa(2b) 3 mlU 3 times weekly for 24 weeks, or PEG-IFN-alfa(2b) 1.5 or 3.0 mu g/kg/wk, as total weekly full or split doses, for :12 weeks. At week 12, serum RNA titer was measured, and all PEG-IFN-alfa(2b) patients continued with 1.5 mu g/kg/wk for a further:12 weeks. Results: Mean serum hepatitis C RNA levels decreased in all groups at weeks :12 and 24. PEG-IFN-alfa(2b) :1.5 mu g/ kg/wk was superior to IFN-alfa(2b) in decreasing mean serum hepatitis C RNA (P <.05 at week 12). The efficacy of split-dose PEG-IFN-alfa(2b) 1.5 or 3.0 mu g/ kg/wk regimens was not significantly different from full-dose PEG-IFN-alfa(2b) 1.5 mu g/kg/wk. However, there was a significant decrease in neutrophil count in groups receiving PEG-IFN-alfa(2b) 3.0 mu g/kg/wk or lower, multiple-dose per week regimens. Conclusions: PEG-IFN-alfa(2b) 1.5 mu g/kg once weekly is the optimal dosing frequency for patients with chronic hepatitis C with predominantly genotype 1 infection. More frequent dosing or increasing the dose to 3.0 mu g/kg/wk did not result in improved antiviral effects, but did decrease neutrophil counts.

Posaconazole is a triazole antifungal in development for the treatment of invasive fungal infections. The authors evaluated the pharmacokinetics and safety of posaconazole in healthy subjects and in those with mild (CL CR = 50–80 mL/min), moderate (CL CR = 20–49 mL/min), and severe chronic renal disease (CL CR <20 mL/min; receiving outpatient hemodialysis) (n = 6/group). Subjects received one 400‐mg dose of posaconazole oral suspension with a standardized high‐fat breakfast. For hemodialysis‐dependent subjects, this dose was given on a nonhemodialysis day, and a second 400‐mg dose was given 6 hours before hemodialysis. Blood samples were collected before dose and up to 120 hours postdose. For hemodialysis‐dependent subjects following the second dose, additional samples (predialyzed and postdialyzed) were collected before, during, and after dialysis. There was no correlation between posaconazole pharmacokinetics and mild to moderate renal disease; the slopes of the linear regressions for creatinine clearance versus posaconazole AUC, C max , CL/F, and t 1/2 values were not significantly different from zero ( P > .130). Mean CL/F values before and during hemodialysis were comparable. Furthermore, the difference in the predialyzed and postdialyzed posaconazole concentrations was only ∼3%, supporting that posaconazole was not removed by hemodialysis. Protein binding was similar in all groups (∼98%) and was unaffected by hemodialysis. Posaconazole was generally well tolerated. One patient had elevated liver function test results that were not present at baseline and were thought to be possibly related to posaconazole. Results of this single‐dose study indicate that dosage adjustments for patients with varying degrees of renal disease are not required.

Posaconazole is an antifungal with a wide-spectrum of activity against common and emerging fungal pathogens. In this randomised, open-label, two-way crossover study, the potential for drug interactions with posaconazole via the cytochrome P450 (CYP450) enzyme pathway was evaluated. Thirteen subjects received posaconazole tablets (2×100mg) once daily for 10 days or no treatment; following a 14-day washout period, subjects were crossed over to the alternate treatment. The inhibition spectra of posaconazole were examined using a cocktail of the following probe substrates: caffeine (CYP1A2), tolbutamide (CYP2C8/9), dextromethorphan (CYP2D6 and total CYP3A4), chlorzoxazone (CYP2E1), and midazolam (hepatic CYP3A4). Except for midazolam, which was intravenously infused on Day 10, the cocktail probes were administered simultaneously on Day 9 during both treatment periods. Blood and urine samples were collected at specified times to quantitate probe substrates and/or metabolites. Based on insignificant differences in mean probe ratios, posaconazole did not inhibit CYP1A2, 2C8/9, 2D6, or 2E1. However, the midazolam AUC(tf) was higher in the posaconazole than no-treatment group (93.4ngh/ml versus 51.4ngh/ml, P<0.01), indicating inhibition of hepatic CYP3A4. Drug interactions mediated by various CYP450 are common with the currently available triazole antifungals, however these results suggest that posaconazole may have an improved and more narrow drug interaction profile (CYP3A4 only) compared with other triazoles.

Aims This randomized, crossover, single-dose study evaluated the relative oral bioavailability of posaconazole suspension and coprecipitate tablet formulations. Additionally, the study determined whether systemic exposure to posaconazole was affected by prandial status or by the fat content of a meal.Methods This was a randomized, open-label, four-way crossover, single-dose study in 20 healthy men. Posaconazole pharmacokinetics were evaluated over 72 h following a single oral dose of posaconazole suspension (200 mg/5 ml) administered with a high-fat meal, a nonfat breakfast, or after a 10 h fast, or posaconazole tablets (2 x 100 mg) administered with a high-fat meal.Results The posaconazole suspension showed a significant increase in bioavailability compared with the tablet (increase in AUC(0,72 h)=137% (90% confidence interval (CI) 119%, 156% and C-max=123% (90% CI 104%, 146%). The mean increases in AUC(0,72 h) and C-max values were about 400% when administered with a high-fat meal compared with administration of the suspension in the fasting state (AUC(0,72 h) 90% CI 343%, 448%; C-max 90% CI 352%, 493%). Administration of the suspension with a nonfat meal enhanced exposure, resulting in an increase in AUC(0,72 h) of 264% (90% CI 231%, 302%) and in C-max of 296% (90% CI 250%, 350%) relative to the fasted state.Conclusions The suspension formulation of posaconazole was associated with enhanced systemic exposure and increased relative bioavailability compared with the tablet. Food substantially enhanced the rate and extent of posaconazole absorption in healthy subjects.

ABSTRACTPosaconazole is a potent broad-spectrum azole antifungal agent in clinical development for the treatment of invasive fungal infections. This study evaluated the potential for a pH-dependent pharmacokinetic interaction between posaconazole and an antacid (Mylanta), under fasting and nonfasting conditions. Twelve men completed this randomized, four-period crossover, single-dose study. Subjects received 200 mg of posaconazole following a 10-h fast, with 20 ml of Mylanta and a 10-h fast, with 20 ml of Mylanta and a high-fat breakfast, and with a high-fat breakfast alone. Antacid coadministration had no statistically significant effects on posaconazole bioavailability under fasting or nonfasting conditions. In the fasting state, antacid slightly increased the relative oral bioavailability of posaconazole by 15% (P= 0.296); in the nonfasting state, antacid decreased the relative bioavailability of posaconazole by 12% (P= 0.352). Food increased the relative oral bioavailability of posaconazole by 400% (P= 0.001). In conclusion, the effect of antacid on posaconazole exposure in the fasting or nonfasting state was small and is not considered clinically significant.

Clinical Pharmacology & Therapeutics (2003) 73, P45–P45; doi:

Posaconazole (SCH 56592) is a novel broad spectrum triazole antifungal agent that is currently in phase III clinical trials for the treatment of systemic fungal infections. This study was initiated to determine if orally administered posaconazole to humans would result in the formation of active metabolite(s). Plasma samples from a multiple-rising dose study in healthy volunteers were analyzed by validated HPLC and microbiological methods. The HPLC analysis involved extraction with a mixture of organic solvent (methylene chloride-hexane) followed by separation on a C18 column and quantification by UV absorbance at 262 nm. The microbiological assay was performed utilizing an agar diffusion method using Candida pseudorropicalis ATCC 46764 as the test organism. Potency was determined by comparing the growth inhibition zones produced by the test sample to those produced by standard concentrations prepared in plasma. Individual and mean plasma concentration-time profiles were similar for both HPLC and microbiological assays. The area under the plasma concentration-time curves of the microbiological and HPLC results were similar with a mean (RSD) ratio of 105.5% 15.3%), indicating that there was no relevant biologically active metabolite of posaconazole in human plasma.