An open-label randomized study of the relative absorption of gastro-resistant risedronate taken fasted or with food versus immediate-release risedronate.

Patients with osteoporosis often take oral bisphosphonates with food, rendering these medications ineffective. This study compared the relative absorption of four formulations of gastro-resistant (GR; formulations 1-4) risedronate 35 mg versus immediate-release (IR) risedronate 35 mg taken fasted. Secondarily, it compared the relative absorption of GR formulations administered fed and fasted, and determined the site of disintegration. Healthy participants (N = 160) were randomized to one of nine treatment groups: IR risedronate taken fasted (group A) or formulations 1-4 taken fasted or fed (groups B-I). Fasted groups fasted for 8 h pre-dose and 4 h post-dose. Fed groups fasted for 7.5 h, then took risedronate with breakfast. Urine was collected until 72 h post-dose and analyzed using liquid chromatography. From each group, up to seven participants underwent scintigraphic monitoring to assess tablet disintegration. The percentage of total dose recovered in urine (A'e ) was ~0.5% for group A. The A'e of formulations 1-4 taken fasted was 0.220% (90% confidence interval 0.124-0.389), 0.298% (0.122-0.730), 0.154% (0.090-0.264), and 0.108% (0.051-0.231), respectively. With food, the A'e of formulation 1 decreased least versus fasted (-27%) compared with the A'e of formulations 2, 3, and 4 (-73%, -80%, and -65%, respectively). Formulations 1-3 disintegrated in the small intestine, formulation 4 closer to the large intestine. All GR formulations were well tolerated and in line with the known safety profile for IR risedronate. Formulation 2 had the highest absorption when taken fasted, whereas the absorption of formulation 1 was least affected by food.

A Post-Authorization Safety Study of Quetiapine as Antidepressant Treatment in Sweden: Nested Case-Control Analyses of Select Outcomes.

INTRODUCTION: This post-authorization safety study (PASS) was a commitment to the European Medicines Agency. OBJECTIVE: This PASS investigated quetiapine as antidepressant treatment in Swedish registers with regard to the risk for all-cause mortality, self-harm and suicide, acute myocardial infarction, stroke, diabetes mellitus, extrapyramidal disorders, and somnolence. METHODS: Users of quetiapine and antidepressants (2011‒2014) who had changed treatment in the past year were included. Conditional logistic regression models were used to calculate odds ratios (ORs) and their 95% confidence intervals (CIs) for each outcome in nested case-control studies for quetiapine as combination therapy and monotherapy, monotherapy with antidepressants, and no medication, versus the use of combinations of antidepressants (reference group). RESULTS: Overall, 7421 quetiapine users and 281,303 antidepressant users were included. For quetiapine in combination, risks were increased for all-cause mortality [adjusted OR (aOR) 1.31, 95% CI 1.12-1.54] compared with combinations of antidepressants; however, when stratified by age, only patients ≥ 65 years of age had an increased mortality, and, in a post hoc analysis excluding patients with Parkinson's disease, no mortality increase remained. Furthermore, the risk for self-harm and suicide was increased (aOR 1.53, 95% CI 1.31-1.79), but when stratified by age, the risk increase was found only among patients aged 18-64 years. Risks were also increased for stroke among patients ≥ 65 years of age (aOR 1.47, 95% CI 1.01-2.12), for extrapyramidal disorder (aOR 6.15, 95% CI 3.57-10.58), and for somnolence (aOR 2.41, 95% CI 1.42-4.11). CONCLUSION: Risks for all-cause mortality, self-harm and suicide, and stroke in older patients may be higher among patients treated with quetiapine and antidepressant combination therapy.

Pharmacokinetics of the Oral Selective CXCR2 Antagonist AZD5069: A Summary of Eight Phase I Studies in Healthy Volunteers.

OBJECTIVE: The aim of this study was to summarise the pharmacokinetic findings from eight phase I studies in healthy volunteers given oral AZD5069, a selective small-molecule CXCR2 antagonist. METHODS: 240 healthy volunteers across eight phase I studies received single (0.1-200 mg) or multiple once- or twice-daily (10-120 mg) oral AZD5069 as solution, suspension, capsules or tablets. Pharmacokinetics were evaluated using non-compartmental analysis methods. RESULTS: AZD5069 was rapidly absorbed (time to maximum concentration ~ 2 h) under fasting conditions. A high-fat, high-calorie meal delayed and reduced the peak plasma AZD5069 concentration (Cmax) by 50%, but total exposure (AUC) was unchanged (fed:fasting geometric mean ratio 90% confidence interval within 0.80-1.25). The plasma concentration of AZD5069 declined with an initial half-life of 4 h and terminal half-life of 11 h. Steady-state plasma concentrations were achieved within 2-3 days and accumulation was ~ 1.1-fold with twice-daily dosing. Systemic exposure was approximately proportional to dose. Intra- and inter-subject variability in AUC was 3-11 and 29-64%, respectively. Less than 5% of the AZD5069 dose was excreted as parent drug in the urine. Elderly subjects had 39% higher AZD5069 AUC and 21% higher Cmax than younger adults. Japanese subjects had similar or slightly higher exposure to AZD5069 than Caucasian subjects. Co-administration with ketoconazole resulted in 2.1-fold higher AUC and 1.6-fold higher Cmax. All formulations had similar bioavailability. CONCLUSIONS: AZD5069 demonstrated predictive linear pharmacokinetics with low intra- and moderate inter-subject variability and no major influences from ethnicity, age, food or formulation. Half-life data indicated suitability for twice-daily dosing. CLINICALTRIALS. GOV IDENTIFIERS: NCT00953888, NCT01051505, NCT01083238, NCT01100047, NCT01332903, NCT01480739, NCT01735240, NCT01989520.

The impact of loading approach and biological activity on NOM removal by ion exchange resins.

The present study investigated the impact of different loading approaches and microbial activity on the Natural Organic Matter (NOM) removal efficiency and capacity of ion exchange resins. Gaining further knowledge on the impact of loading approaches is of relevance because laboratory-scale multiple loading tests (MLTs) have been introduced as a simpler and faster alternative to column tests for predicting the performance of IEX, but only anecdotal evidence exists to support their ability to forecast contaminant removal and runtime until breakthrough of IEX systems. The overall trends observed for the removal and the time to breakthrough of organic material estimated using MLTs differed from those estimated using column tests. The results nonetheless suggest that MLTs could best be used as an effective tool to screen different ion exchange resins in terms of their ability to remove various contaminants of interest from different raw waters. The microbial activity was also observed to impact the removal and time to breakthrough. In the absence of regeneration, a microbial community rapidly established itself in ion exchange columns and contributed to the removal of organic material. Biological ion exchange (BIEX) removed more organic material and enabled operation beyond the point when the resin capacity would have otherwise been exhausted using conventional (i.e. in the absence of a microbial community) ion exchange. Furthermore, significantly greater removal of organic matter could be achieved with BIEX than biological activated carbon (BAC) (i.e. 56 ±â€¯7% vs. 15 ±â€¯5%, respectively) when operated at similar loading rates. The results suggest that for some raw waters, BIEX could replace BAC as the technology of choice for the removal of organic material.

Results from a drug utilization study of extended release quetiapine fumarate prescribed by psychiatrists as treatment for major depressive disorder in selected countries in the European Union.

This multicenter, observational drug utilization (DU) study (NCT01594996) investigated the profile of patients and specialist providers who prescribed extended release quetiapine fumarate (quetiapine XR) for treatment of major depressive disorder (MDD) across five European countries (Germany, Italy, Romania, Spain, and Sweden). A DU data abstraction form captured information on the characteristics of physicians, patients, and drugs utilized in the medical management of depressive episodes in MDD, where the therapeutic regimen included quetiapine XR. Data were reported descriptively. This analysis included 811 patients. Psychiatric histories indicated a burden of severe MDD in these patients. Patient demographics were similar across countries; however, those in Sweden had a younger mean age. Physicians' ratings of the therapeutic effect of prior treatment with antidepressants suggested the need for an add-on treatment for most patients. Overall, 15.7% of patients initiated quetiapine XR treatment as monotherapy. Presence of psychotic symptoms during depressive episodes predicted treatment with higher than recommended doses of quetiapine XR (odds ratio=3.11; 95% confidence interval: 1.6-6.0). This analysis demonstrated similarities in DU across the countries analyzed, largely in accordance with the recommended dose of quetiapine XR as an adjunctive therapy to antidepressants in MDD (50-300 mg/day).

Effectiveness of a risk-minimization activity involving physician education on metabolic monitoring of patients receiving quetiapine: results from two postauthorization safety studies.

Following Good Pharmacovigilance Practices Module XVI, two complementary studies were performed that included process and outcome measurements of the effectiveness of physician education on metabolic monitoring of patients receiving quetiapine. A multinational survey of 800 European Union physicians was utilized to assess the receipt of educational materials and also to assess the degree of monitoring as reported by physicians. Recall of receipt of educational materials ranged from 16.0 to 69.0% across the participating countries; however, physicians reported that 64.5% of patients were being monitored, with the majority reporting performance of three or more of four key metabolic-monitoring activities. Higher rates of monitoring were reported by those who reported receiving materials. Assessment of outcomes in a separate retrospective analysis of electronic medical record data showed lower levels of monitoring performed by specialist physicians. The monitoring activities observed were assessed as acceptable on the basis of the established performance of UK physicians, who are incentivized to deliver preventive screening.

A randomised, placebo-controlled study of the CXCR2 antagonist AZD5069 in bronchiectasis.

This randomised double-blind placebo-controlled parallel-group multicentre phase IIa study evaluated the effect of the CXCR2 antagonist AZD5069 on sputum neutrophil counts in adults with bronchiectasis.Patients were randomised 1:1 to receive AZD5069 80 mg or placebo orally twice daily for 28 days. Assessments included blood cell counts, inflammatory markers in blood, morning spontaneous sputum, lung function, safety and tolerability and patients completed daily BronkoTest diary cards. The primary outcome measure was the change in absolute sputum neutrophil count.Of 52 randomised patients, 45 completed treatment, 20 (76.9%) out of 26 receiving AZD5069 and 25 (96.2%) out of 26 receiving placebo. AZD5069 reduced the absolute neutrophil cell count in morning sputum by 69% versus placebo (p=0.004); percentage sputum neutrophil count was reduced by 36% (p=0.008). The number of infections/exacerbations was similar with AZD5069 and placebo (nine versus eight), but these led to more study discontinuations with AZD5069 (four versus zero). Sputum interleukin (IL)-6 and growth-regulated oncogene (GRO)-α and serum GRO-α, IL-1ß and IL-8 levels increased with AZD5069 versus placebo (all p<0.001), while serum high-sensitivity C-reactive protein levels did not change. AZD5069 was well tolerated.AZD5069 markedly reduced absolute sputum neutrophil counts in bronchiectasis patients, although this was not associated with improvements in clinical outcomes in this exploratory study.

Effects of an oral MMP-9 and -12 inhibitor, AZD1236, on biomarkers in moderate/severe COPD: a randomised controlled trial.

BACKGROUND: There is a pressing need for new forms of treatment for COPD. Based on the known pathophysiology of COPD, inhibition of matrix metalloproteinases is a theoretically promising approach. This Phase IIa study evaluated the effects of AZD1236, a selective MMP-9 and MMP-12 inhibitor, on the biomarkers of inflammation and emphysematous lung tissue degradation in patients with moderate-to-severe COPD. METHODS: This was a multinational, randomized, double-blind, placebo-controlled signal-searching study conducted in men and women aged ≥40 years with stable moderate-to-severe COPD. After a 2-6-week period to eliminate any remaining effects of previous medication, 55 patients received oral AZD1236 75 mg or matching placebo twice daily for 6 weeks. Differential cell count and TNF-α levels in induced sputum and 24-h urinary desmosine excretion were the main study variables, but a range of exploratory biomarkers was also assessed in induced sputum, blood and urine. Secondary variables included lung function and patient-recorded Clinical COPD Questionnaire (CCQ) responses and diary records of symptoms, adverse events, use of rescue medication and AZD1236 plasma concentrations. RESULTS: The majority of variables showed little change compared to placebo although there was a possible, but not statistically significant reduction in urinary desmosine excretion and reductions in the number and percentage of lymphocytes in sputum and blood with AZD1236. No effect was seen on clinical parameters after 6 weeks of treatment. The proportion of patients experiencing adverse events was similar in both treatment groups. CONCLUSIONS: AZD1236 dosed orally at 75 mg twice daily was generally well tolerated over 6 weeks in patients with moderate-to-severe COPD. No clinical efficacy of AZD1236 was demonstrated in this short-term signal-searching study, although possible evidence of an impact on desmosine may suggest the potential value of selective inhibitors of MMPs in the treatment of COPD in longer term trials.

Safety and tolerability of an oral MMP-9 and -12 inhibitor, AZD1236, in patients with moderate-to-severe COPD: a randomised controlled 6-week trial.

BACKGROUND: Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). This phase IIa study investigated the safety and tolerability of oral AZD1236, an MMP-9 and MMP-12 inhibitor, in patients with COPD. Efficacy analyses were included on an exploratory basis. METHODS: This was a multinational, randomised, double-blind, parallel-group study conducted in 74 men and women aged ≥40 years with stable moderate-to-severe COPD. After a 2-week run-in period, patients received oral AZD1236 75 mg, or matching placebo, twice daily for 6 weeks (on top of background medication with short-acting bronchodilators and/or inhaled corticosteroids, if applicable). In addition to safety and tolerability endpoints (AEs, vital signs and laboratory assessments) efficacy was assessed as a secondary objective (spirometry, 6MWT, BODE index and biomarkers in blood and urine. Clinical COPD Questionnaire (CCQ), peak expiratory flow (PEF) and daily diary cards of symptom severity were completed by the patients. RESULTS: The incidence of adverse events (AEs) was similar in AZD1236 and placebo recipients; 28 in 13 patients (37%) and 21 in 17 patients (44%), respectively; the difference in actual number reported accounted for primarily by mild AEs in the AZD1236 group. The most commonly experienced AEs in both groups were COPD exacerbations, headache and viral infections. One patient in the AZD1236 group experienced a serious AE of interstitial nephritis (comprising of acute renal failure, rash, fever and blood eosinophilia) considered to be related to treatment. After 6 weeks, AZD1236 had demonstrated no significant effect on lung function, 6MWT, BODE index or biomarkers compared with placebo. No meaningful differences were observed in patient-reported CCQ score, PEF, COPD symptoms or use of rescue medication. CONCLUSIONS: For most of these COPD patients, with the particular exception of one who experienced a serious AE, AZD1236 at 75 mg twice daily was generally well tolerated and had an acceptable safety profile. Therapeutic efficacy could not be demonstrated, possibly due to the stable disease and background medications of the patients enrolled in this small, short-term study.

Assessment of levetiracetam bioavailability from targeted sites in the human intestine using remotely activated capsules and gamma scintigraphy: Open-label, single-dose, randomized, four-way crossover study in healthy male volunteers.

BACKGROUND: Levetiracetam is a broad-spectrum antiepileptic drug that binds to synaptic vesicle protein SV2A. Levetiracetam is indicated in the adjunctive treatment of partial-onset seizures, myoclonic seizures, and generalized tonic-clonic seizures. It is also approved in Europe as monotherapy for newly diagnosed partial-onset seizures. A Phase I clinical pharmacology trial was conducted during preregistration clinical development to better understand the regional gastrointestinal (GI) absorption of levetiracetam. OBJECTIVE: This study evaluated the relative bioavailability of levetiracetam in various regions of the GI tract using a noninvasive, remote-controlled capsule device providing targeted drug delivery, relative to that after oral administration, and explored the drug's absorption characteristics in healthy volunteers. METHODS: Pharmacokinetic data were obtained from healthy men aged 18 to 65 years in an open-label, single-dose, randomized, 4-way crossover study. Treatments included levetiracetam 250 mg administered as an immediate-release tablet and capsule delivery of 250 mg drug substance (levetiracetam powder without excipients) to the proximal small bowel, distal small bowel, and ascending colon. The location of the capsule in the GI tract was monitored using γ-scintigraphic imaging. Blood samples for plasma levetiracetam concentration were collected before dosing; at 10, 20, 30, and 45 minutes; and at 1, 1.5, 2, 3, 6, 9, 12, 16, 20, and 24 hours after tablet intake or after capsule activation. Pharmacokinetic parameters C(max), T(max), AUC0₋(last), AUC0₋(∞) and t(½) were calculated using noncompartmental methods. Tolerability was determined using clinical assessment, monitoring of vital signs, laboratory analysis, and interviews with the volunteers regarding adverse events. RESULTS: Nine healthy men, 7 whites and 2 Asians, were enrolled (mean [SD] age, 31 [14] years; weight, 77 [5] kg; height, 176 [6] cm). Six volunteers completed all 4 treatments. Seven adverse events (headache [3], lethargy [2], tachycardia [1], and contusion [1]) were reported in 5 volunteers, but only 2 (headache and lethargy) were judged by the investigator to be possibly drug related. The geometric mean (%CV) AUC(0-last) values of levetiracetam delivered in the proximal small bowel, distal small bowel, ascending colon, and stomach (oral tablet) were 58.2 (9.3%), 59.6 (8.9%), 51.5 (12.0%), and 59.0 (7.4%) µg · h/mL, respectively. Values for bioavailability in the proximal small bowel, distal small bowel, and ascending colon relative to the tablet were 98.5% (95% CI, 89.7%-108.2%), 100.8% (95% CI, 91.4%-111.1%), and 87.1% (95% CI, 77.9%-97.5%). CONCLUSION: After delivery in the proximal small bowel, distal small bowel, or ascending colon, the systemic bioavailability of levetiracetam (AUC), but not C(max) and T(max), appeared comparable to that after oral administration and thus appeared site independent in this small group of healthy fasting men.

The assessment of human regional drug absorption of free acid and sodium salt forms of acipimox, in healthy volunteers, to direct modified release formulation strategy.

Acipimox is an analog of nicotinic acid and is indicated for the treatment of dyslipidemia. It is also believed to improve glucose control by enhancing insulin sensitivity. The purpose of this study was to direct modified release (MR) formulation strategy by comparing the bioavailability of two forms of acipimox (free acid and sodium salt) from the distal small bowel (DSB) and colon with an immediate release formulation. Two parallel groups of healthy volunteers completed an open label, non-randomized, three-way crossover study. The rate and extent of acipimox absorption was highest following administration of the immediate release capsules, and was not influenced by the form of the drug administered. Following administration to the DSB, the relative bioavailability was approximately 52% and 30% for the salt form and free acid form, respectively. Following administration to the colon, the extent of absorption was further reduced. The data indicate that bioavailability from the DSB was limited by the solubility of the drug coupled with an absorption window, whilst absorption from the colon was limited by permeability. The study provided detailed information to support and guide the formulation strategy for a MR form of acipimox, which may improve the treatment of adult patients with type II diabetes and dyslipidemia.

In vivo disintegration profiles of encapsulated and nonencapsulated sumatriptan: gamma scintigraphy in healthy volunteers.

The goal of this exploratory pilot study was to use gamma scintigraphy to evaluate, under physiological conditions, disintegration profiles of encapsulated and nonencapsulated formulations of 100 mg sumatriptan. Using a crossover design, healthy volunteers (n = 10) ingested 100-mg doses of sumatriptan tablets radiolabeled with 111Indium, as well as encapsulated sumatriptan tablets that were prepared similarly, then placed within a gelatin capsule and backfilled with an excipient blend radiolabeled with 99mTechnetium. A gamma camera recorded scintigraphic images until 5 hours postdose. Initial disintegration of the gelatin capsule was observed at a mean (range) of 5 minutes (1-11 minutes); disintegration was complete within 14 minutes (5-24 minutes). For nonencapsulated versus encapsulated tablets, the mean (+/- standard deviation) time to initial disintegration (6 +/- 5 minutes vs 8 +/- 5 minutes) and time to complete disintegration (18 +/- 14 minutes vs 16 +/- 7 minutes) were comparable. Results of this study demonstrate that encapsulated and nonencapsulated sumatriptan have equivalent in vivo dissolution rates.

Pharmacoscintigraphic assessment of the regional drug absorption of the dual angiotensin-converting enzyme/neutral endopeptidase inhibitor, M100240, in healthy volunteers.

M100240 is the thioester of MDL 100,173, a dual angiotensin-converting enzyme (ACE)/neutral endopeptidase (NEP) inhibitor currently in phase II development. The purpose of this study was to evaluate the relative bioavaibility of M100240 in various regions of the gastrointestinal tract using the Enterion capsule, a noninvasive radiocontrolled device providing targeted drug delivery, to explore the absorption characteristics of M100240 in healthy volunteers. In addition, the absolute bioavailability of an immediate-release formulation of M100240 was assessed. Pharmacokinetic data were obtained from 13 healthy subjects in an open-label, single-dose, randomized, five-period crossover study. Treatments included 25 mg M100240 administered via short intravenous infusion, oral immediate-release tablet administration, and oral Enterion capsule delivery of drug substance to the proximal small bowel, distal small bowel, and ascending colon. Each treatment was separated by a 14-day drug-free washout period. The localization of the Enterion capsule in the gastrointestinal tract was monitored using scintigraphic imaging. M100240 and MDL 100,173 plasma concentrations were quantified using a validated LC/MS/MS method, and pharmacokinetic parameters were calculated using noncompartmental methods. The estimates of relative bioavailability in the proximal small bowel, distal small bowel, and ascending colon relative to the oral immediate-release tablet are approximately 94%, 97%, and 41%, respectively. M100240 is primarily absorbed throughout the proximal and distal small bowel with modest absorption in the ascending colon. The absolute bioavailability estimate of the M100240 immediate-release formulation is 49%. These data characterize the fundamental in vivo performance attributes of M100240, thereby providing an approach for optimizing prototype modified-release formulations for this compound.