Bioavailability studies with Digoxin-Sandoz® and Lanoxin®

Summary Various brands of digoxin tablets, and even different batches of one brand, may differ greatly in bioavailability. Digoxin-Sandoz^® tablets have been compared with Lanoxin^® manufactured between 1969 and 1972 and after May 1972. Comparisons were also made between and within batches of Digoxin-Sandoz tablets. Three separate cross-over studies were conducted involving a total of 20 volunteers. Digoxin-Sandoz tablets were shown to have a constant bioavailability and to produce plasma concentrations very similar to new Lanoxin. Storage for 2 years of one batch of Digoxin-Sandoz did not alter the bioavailability. Particle size was shown to influence bioavailability. Care should be exercised when plasma data alone are interpreted as an index of bioavailability. Measures of bioavailability based on plasma data obtained up to 6 h after administration differed from those based on cumulative urinary excretion data (in this study by a factor of about 2), which can lead to the belief that a difference in bioavailability is much greater than is actually the case. Data from cumulative urinary excretion, collected over a sufficiently long period of time, are likely to be the most reliable method for determining the bioavailability of a substance such as digoxin.     

Comparative effectiveness of interferons in relapsing–remitting multiple sclerosis: a meta-analysis of real-world studies

Background: Differences between interferons have been evaluated for over 20 years. While randomized controlled trial (RCT) data is mainly used for assessments and strong data for causal inferences, it does not necessarily reflect everyday practice. Real-world data may provide additional information.

Purpose: To assess the results, quality, and representativeness of observational studies directly comparing interferons (IFNs) in RRMS.

Methods: Medline and Embase were searched for observational studies comparing IFN-beta-1a 30?mcg IM (Avonex¹), IFN-beta-1a 44?mcg SC (Rebif²) and/or IFN-beta-1b 250?mcg SC (Betaseron³). Outcomes included annualized relapse rate (ARR), proportions relapse free, confirmed progression free, treatment persistence, and neutralizing antibodies rates (NABs) measured up to 5 years of treatment. Data was combined using random effects meta-analyses. Categorical values were analyzed using chi-squared and Mann–Whitney tests.

Results: Thirty-six studies examining 32,026 patients (72.5% females, age?=?39.2?±?3.7 years, disease duration?=?5.6?±?2.0 years) were identified. Thirty-three studies investigated IFN-beta-1a IM (N?=?11,925), 30 IFN-beta-1a SC (N?=?10,684) and 34 IFN-beta-1b SC (N?=?9417). Baseline ARRs were similar (1.37?±?0.35, 1.51?±?0.27 and 1.55?±?0.23, respectively; P?=?.101) as were EDSS scores (2.24?±?0.39, 2.33?±?0.30, 2.55?±?0.38; P?=?.070) and >75% were naïve to IFNs. On treatment, ARRs were comparable (IFN-beta-1a IM 0.52?±?0.27, IFN-beta-1a SC 0.51?±?0.24, IFN-beta-1b SC 0.55?±?0.23; P?=?.595). Proportions of relapse-free patients were similar between drugs (P?>?.05 for all data points), except that IFN-beta-1a SC was superior to IFN-beta-1b SC in years 3–5 (all P?≤?.001). After 1 year, EDSS scores were comparable; after 2 years, IFN-beta-1a IM and IFN-beta-1a SC incurred less disease progression than IFN-beta-1b SC (P?P?P?Conclusions: In this comprehensive meta-analysis of real-world studies in RRMS, IFN-beta-1a IM, IFN-beta-1a SC and IFN-beta-1b SC had similar clinical profiles. When selecting an IFN, practitioners should consider observational data in their decision making process.     

Cypher® versus Taxus®: the stent war

Cypher^® (sirolimus-eluting stent) and Taxus^® (paclitaxel-eluting stent) have been approved for use in percutaneous coronary intervention. Both of the stents have shown superiority over bare metal stents in reducing major adverse cardiac events, restenosis rates and target vessel revascularisation. Results of clinical trials with head-to-head comparison of Taxus and Cypher stents in patients with obstructive coronary artery diseases have recently been reported. This review compares the performance of Cypher and Taxus stents as noted in observational studies and clinical trials in various types of coronary artery lesions.     

Adverse events of statin–fenofibric acid versus statin monotherapy: a meta-analysis of randomized controlled trials

Abstract

Background:

Patients with mixed dyslipidemia can benefit from the combination of fenofibric acid (FA) with statins, but concerns about adverse events make physicians reluctant to prescribe the combination therapy.     

Prolonged infusion versus intermittent boluses of β-lactam antibiotics for treatment of acute infections: a meta-analysis

The clinical advantages of prolonged (extended/continuous) infusion remain controversial. Previous studies and reviews have failed to show consistent clinical benefits of extending the infusion time. This meta-analysis sought to determine whether prolonged β-lactam infusions were associated with a reduction in mortality and improvement in clinical success. A search of PubMed, EMBASE and The Cochrane Library for randomised controlled trials (RCTs) and observational studies comparing prolonged infusion with intermittent bolus administration of the same antibiotic in hospitalised adult patients was conducted. Primary outcomes evaluated were mortality and clinical success. A total of 29 studies with 2206 patients (18 RCTs and 11 observational studies) were included in the meta-analysis. Compared with intermittent boluses, use of prolonged infusion appeared to be associated with a significant reduction in mortality [pooled relative risk (RR) = 0.66, 95% confidence interval (CI) 0.53–0.83] and improvement in clinical success (RR = 1.12, 95% CI 1.03–1.21). Statistically significant benefit was supported by non-randomised studies (mortality, RR = 0.57, 95% CI 0.43–0.76; clinical success, RR = 1.34, 95% CI 1.02–1.76) but not by RCTs (mortality, RR = 0.83, 95% CI 0.57–1.21; clinical success, RR = 1.05, 95% CI 0.99–1.12). The positive results from observational studies, especially in the face of increasing antibiotic resistance, serve to justify the imperative need to conduct a large-scale, well-designed, multicentre RCT involving critically ill patients infected with high minimum inhibitory concentration pathogens to clearly substantiate this benefit.     

Paraquat and Parkinson’s disease: a systematic review and meta-analysis of observational studies

This investigation aimed to conduct a systematic review of the literature and meta-analysis to determine whether exposure to the herbicide paraquat was associated with the development of Parkinson’s disease (PD). Observational studies that enrolled adults exposed to paraquat with PD as the outcome of interest were searched in the PubMed, Embase, LILACS, TOXNET, and Web of Science databases up to May 2019. Two authors independently selected relevant studies, extracted data, and assessed methodological quality. The evidence certainty was assessed by the GRADE approach, which served as basis for a tentative causality assessment, supplemented by the Bradford Hill criteria when necessary. Results from nine case–control studies indicated that PD occurrence was 25% higher in participants exposed to paraquat. The only cohort investigation included demonstrated a non-significant OR of 1.08. Results from subgroup analyses also indicated higher PD frequency in participants that were exposed to paraquat for longer periods or individuals co-exposed with paraquat and any other dithiocarbamate. Data indicate apositive association between exposure to paraquat and PD occurrence, but the weight-of-evidence does not enable one to assume an indisputable cause–effect relationship between these two conditions. Better designed studies are needed to increase confidence in results.

Systematic Review Registration: PROSPERO CRD42017069994.     

Letter to the editor for a published article titled “The effect of online versus hospital warfarin management on patient outcomes: a systematic review and meta-analysis”

International Journal of Clinical Pharmacy -     

Fluoroquinolone-based versus β-lactam-based regimens for complicated intra-abdominal infections: a meta-analysis of randomised controlled trials

Complicated intra-abdominal infections (cIAIs) are common and confer significant morbidity, mortality and costs. In this era of evolving antimicrobial resistance, selection of appropriate empirical antimicrobials is paramount. This systematic review and meta-analysis of randomised controlled trials compared the effectiveness and safety of fluoroquinolone (FQ)-based versus β-lactam (BL)-based regimens for the treatment of patients with cIAIs. Primary outcomes were treatment success in the clinically evaluable (CE) population and all-cause mortality in the intention-to-treat (ITT) population. Subgroup analyses were performed based on specific antimicrobials, infection source and isolated pathogens. Seven trials (4125 patients) were included. FQ-based regimens included moxifloxacin (four studies) or ciprofloxacin/metronidazole (three studies); BL-based regimens were ceftriaxone/metronidazole (three studies), carbapenems (two studies) or piperacillin/tazobactam (two studies). There was no difference in effectiveness in the CE (2883 patients; RR = 1.00, 95% CI 0.95–1.04) or ITT populations (3055 patients; RR = 0.97, 95% CI 0.94–1.01). Mortality (3614 patients; RR = 1.04, 95% CI 0.75–1.43) and treatment-related adverse events (2801 patients; RR = 0.97, 95% CI 0.70–1.33) were also similar. On subset analysis, moxifloxacin was slightly less effective than BLs in the CE (1934 patients; RR = 0.96, 95% CI 0.93–0.99) and ITT populations (1743 patients; RR = 0.94, 95% CI 0.91–0.98). Although FQ- and BL-based regimens appear equally effective and safe for the treatment of cIAIs, limited data suggest slightly inferior results with moxifloxacin. Selection of empirical coverage should be based on local bacterial epidemiology and patterns of resistance as well as antimicrobial stewardship protocols.     

Efficacy and safety of adalimumab for the Crohn’s disease: a systematic review and meta-analysis of published randomized placebo-controlled trials

Purpose

The aim of this study was to evaluate the efficacy and safety of adalimumab (ADA) for Crohn’s disease.

Methods

Electronic databases, including PubMed, Embase, the Cochrane Library, and the Science Citation Index, were searched to retrieve relevant trials. We estimated pooled estimates of the odds ratio (OR) and relevant 95 % confidence interval (CI) using fixed effects model or random effects model as appropriate.

Results

Six randomized placebo-controlled studies met the selection criteria. Short-term clinical response/remission and long-term remission were better in the ADA groups than in the control groups (P?<?0.05), both in anti-TNF-naive patients and in subjects who lost their response and/or became intolerant to infliximab (IFX). And ADA was also effective for patients who were previously treated with IFX, and its efficacy in infliximab-exposed patients was probably less than in infliximab-naive patients. In patients with active Crohn’s disease (CD), ADA therapy was more effective than placebo for obtaining complete fistula closure. In comparison with placebo, ADA does not increase the risk of serious adverse events.

Conclusions

ADA appears to be effective in achieving short-term clinical response/remission, long-term remission, and complete fistula healing in CD, including patients not manageable with IFX, and appears to have a favorable safety profile. A longer duration of follow-up and a larger number of patients are required to better assess the safety profile of ADA in CD.     

Development of a Novel Simplified PBPK Absorption Model to Explain the Higher Relative Bioavailability of the OROS® Formulation of Oxybutynin

A new minimal Segmented Transit and Absorption model (mSAT) model has been recently proposed and combined with intrinsic intestinal effective permeability (P _eff,int ) to predict the regional gastrointestinal (GI) absorption (f _abs ) of several drugs. Herein, this model was extended and applied for the prediction of oral bioavailability and pharmacokinetics of oxybutynin and its enantiomers to provide a mechanistic explanation of the higher relative bioavailability observed for oxybutynin’s modified-release OROS® formulation compared to its immediate-release (IR) counterpart. The expansion of the model involved the incorporation of mechanistic equations for the prediction of release, transit, dissolution, permeation and first-pass metabolism. The predicted pharmacokinetics of oxybutynin enantiomers after oral administration for both the IR and OROS® formulations were in close agreement with the observed data. The predicted absolute bioavailability for the IR formulation was within 5% of the observed value, and the model adequately predicted the higher relative bioavailability observed for the OROS® formulation vs. the IR counterpart. From the model predictions, it can be noticed that the higher bioavailability observed for the OROS® formulation was mainly attributable to differences in the intestinal availability (F _G ) rather than due to a higher colonic f _abs , thus confirming previous hypotheses. The predicted f _abs was almost 70% lower for the OROS® formulation compared to the IR formulation, whereas the F _G was almost eightfold higher than in the IR formulation. These results provide further support to the hypothesis of an increased F _G as the main factor responsible for the higher bioavailability of oxybutynin’s OROS® formulation vs. the IR.     

Insomnia medication: Do published studies reflect the complete picture of efficacy and safety?

Selective publication can have a deleterious effect on evidence based medicine, health policy decision making and treatment guidelines. Using the European Public Assessment Reports (EPARs) as reference, this study examined selective publication and selective reporting of efficacy and safety of insomnia medication.EPARs of with three insomnia medications were used to identify all clinical trials that were performed between 1998 and 2007 for the purpose of registration in the EU. The matching publication for each trial was searched through a systematic literature search. Accuracy of information in the publications was examined by comparison to the information in the EPARs.Only 55% of the trials with insomnia medications identified in EPARs were published. Positive trials were approximately two times more likely to be published. The lag time from study completion to publication was shorter for the positive compared to the negative trials. Sample size did not correlate with publication of negative trials. The meta-analysis of the effect size of insomnia medication was 1.6 times larger in the published data compared to the complete data. While the primary end points of the trials were reported reliably in the publications, remarkable inconsistencies were detected in the reporting of the secondary end points, methods, results and, especially safety. In conclusion, selective publication and reporting lead to an overestimation of efficacy and underestimation of safety of insomnia products. Authors of treatment guidelines should be aware of this bias. EPARs/FDA reviews provide a more unbiased view of the benefit-risk balance of insomnia and other medications and hence these documents should be consulted by e.g. authors of meta-analyses and of treatment guidelines.     

UK addiction research 1994–2001: A profile of studies published in Addiction Abstracts

Introduction: In 2002 the National Treatment Agency for Substance Misuse commissioned a consultation exercise to help identify future research priorities. An overview of UK research published in the journal Addiction Abstracts contributed to this.

Method: Using a Microsoft Access database, two reviewers systematically profiled all 840 UK abstracts published between 1994 and 2001. The database included 72 fields for each abstract and a coding framework of predefined options.

Results: Fifty-seven percent (n?=?482) of the 840 abstracts reported studies involving licit substances, of which 65% discussed alcohol and 30% covered tobacco/nicotine. Sixty-three percent (n?=?530) covered illicit substances, a high proportion of which described non-specific drug use such as ‘general drug use’ (32%) or ‘injecting’ (16%), rather than individual substances. Heroin was the most common substance specified (8%). Few of the 840 abstracts focused upon subjects with predefined demographic characteristics: 8% detailed single gender studies; 2% reported an ethnic focus. Subgroup surveys were the most frequent research method adopted (32%); 15% described literature reviews, and 7% were ‘laboratory experimental’. Two percent of studies were identified as randomized controlled trials.

Conclusion: Our research presents a useful profile of published UK research and provides a focus for reflection and debate on future priorities.     

Eudragit®: a technology evaluation

Introduction: Eudragit is the brand name for a diverse range of polymethacrylate-based copolymers. It includes anionic, cationic, and neutral copolymers based on methacrylic acid and methacrylic/acrylic esters or their derivatives.

Areas covered: In this review, the physicochemical characteristics and applications of different grades of Eudragit in colon-specific/enteric-coated/sustained release drug delivery and taste masking have been addressed.

Expert opinion: Eudragits are amorphous polymers having glass transition temperatures between 9 to > 150^oC. Eudragits are non-biodegradable, nonabsorbable, and nontoxic. Anionic Eudragit L dissolves at pH > 6 and is used for enteric coating, while Eudragit S, soluble at pH > 7 is used for colon targeting. Studies in human volunteers have confirmed that pH drops from 7.0 at terminal ileum to 6.0 at ascending colon, and Eudragit S based systems sometimes fail to release the drug. To overcome the shortcoming, combination of Eudragit S and Eudragit L which ensures drug release at pH < 7 has been advocated. Eudragit RL and RS, having quaternary ammonium groups, are water insoluble, but swellable/permeable polymers which are suitable for the sustained release film coating applications. Cationic Eudragit E, insoluble at pH ≥ 5, can prevent drug release in saliva and finds application in taste masking.     

Toward a more systematic assessment of smoking: development of a smoking module for PROMIS®

Introduction

The aim of the PROMIS® Smoking Initiative is to develop, evaluate, and standardize item banks to assess cigarette smoking behavior and biopsychosocial constructs associated with smoking for both daily and non-daily smokers.

Methods

We used qualitative methods to develop the item pool (following the PROMIS® approach: e.g., literature search, “binning and winnowing” of items, and focus groups and cognitive interviews to finalize wording and format), and quantitative methods (e.g., factor analysis) to develop the item banks.

Results

We considered a total of 1622 extant items, and 44 new items for inclusion in the smoking item banks. A final set of 277 items representing 11 conceptual domains was selected for field testing in a national sample of smokers. Using data from 3021 daily smokers in the field test, an iterative series of exploratory factor analyses and project team discussions resulted in six item banks: Positive Consequences of Smoking (40 items), Smoking Dependence/Craving (55 items), Health Consequences of Smoking (26 items), Psychosocial Consequences of Smoking (37 items), Coping Aspects of Smoking (30 items), and Social Factors of Smoking (23 items).

Conclusions

Inclusion of a smoking domain in the PROMIS® framework will standardize measurement of key smoking constructs using state-of-the-art psychometric methods, and make them widely accessible to health care providers, smoking researchers and the large community of researchers using PROMIS® who might not otherwise include an assessment of smoking in their design. Next steps include reducing the number of items in each domain, conducting confirmatory analyses, and duplicating the process for non-daily smokers.     

A review of published studies of patients’ illness perceptions and medication adherence: Lessons learned and future directions

BackgroundPatients who seek medical care and who are prescribed medication may choose to either accept or not accept the prescriber’s recommendations to use the prescribed medication. The Common Sense Model (CSM) is one behavioral model that can help researchers and practitioners to identify patients’ illness perceptions that drive their decisions.ObjectiveThis article reviews published research that evaluated the impact of illness representations (as defined in CSM) with medication adherence.MethodsA narrative review of published research in illness representation and medication adherence was conducted. Articles were searched using MEDLINE, PreMEDLINE, evidence-based medicine reviews, and the International Pharmaceutical Abstracts databases and using the search terms medication adherence, compliance, illness perception, self-regulation theory, and common-sense model.ResultsEleven published studies were identified that compared illness representation (or illness perception) and medication adherence. Each illness representation factor, with the exception of illness coherence, directly or indirectly impacted medication adherence. Illness identity, where symptoms are used to label a health condition, can impact medication adherence, even with asymptomatic conditions such as hypertension. Patient age, disease condition, and culture may impact patient response to illness perceptions. Recommendations for future research are to (1) use longitudinal studies to evaluate the cause-effect relationships between illness perceptions and medication adherence, (2) study patients’ early experiences with their illness, (3) recruit patients who are nonadherent, (4) use clinical outcome measures in addition to the self-report medication adherence measures, and (5) include patient age and culture in the model.ConclusionsAlthough the CSM is a well-known patient behavior model, its use to explain medication adherence has been limited to cross-sectional studies across various health conditions. Further research is needed to elucidate the relationships between illness perceptions and patient medication adherence, which can help practitioners to better engage and communicate with patients.     

Beyond classical meta-analysis: can inadequately reported studies be included?

Classical meta-analysis requires the same data from each clinical trial, thus data-reporting must be of a high-quality. Imputation methods are used to include studies that provide incomplete information on variability and the fixed and random effects of a drug. Regression models can be used to include studies other than randomized placebo-controlled studies. In the example outlined here, the use of non-randomized single-arm studies and studies against comparator treatments has little influence on the estimation of the treatment effect in comparison with placebo, an effect that is based on the randomized placebo-controlled studies. The inclusion of other studies serves to increase the precision of the effect of the treatment compared with baseline. Although multiple imputation techniques enable a larger number of studies to be included, which will typically increase the precision of the estimated effect, a careful sensitivity analysis is also required.     

Inter-study variability of preclinical in vivo safety studies and translational exposure–QTc relationships – a PKPD meta-analysis

Background and Purpose

Preclinical cardiovascular safety studies (CVS) have been compared between facilities with respect to their sensitivity to detect drug-induced QTc prolongation (ΔQTc). Little is known about the consistency of quantitative ΔQTc predictions that are relevant for translation to humans.

Experimental Approach

We derived typical ΔQTc predictions at therapeutic exposure (ΔQTc_THER) with 95% confidence intervals (95%CI) for 3 K_v11.1 (hERG) channel blockers (moxifloxacin, dofetilide and sotalol) from a total of 14 CVS with variable designs in the conscious dog. Population pharmacokinetic-pharmacodynamic (PKPD) analysis of each study was followed by a meta-analysis (pooling 2–6 studies including 10–32 dogs per compound) to derive meta-predictions of typical ΔQTc_THER. Meta-predictions were used as a reference to evaluate the consistency of study predictions and to relate results to those found in the clinical literature.

Key Results

The 95%CIs of study-predicted ΔQTc_THER comprised in 13 out of 14 cases the meta-prediction. Overall inter-study variability (mean deviation from meta-prediction at upper level of therapeutic exposure) was 30% (range: 1–69%). Meta-ΔQTc_THER predictions for moxifloxacin, dofetilide and sotalol overlapped with reported clinical QTc prolongation when expressed as %-prolongation from baseline.

Conclusions and Implications

Consistent exposure-ΔQTc predictions were obtained from single preclinical dog studies of highly variable designs by systematic PKPD analysis, which is suitable for translational purposes. The good preclinical–clinical pharmacodynamic correlations obtained suggest that such an analysis should be more routinely applied to increase the informative and predictive value of results obtained from animal experiments.Tables of Links