Adverse effects of biologics: a network meta-analysis and Cochrane overview.

BACKGROUND: Biologics are used for the treatment of rheumatoid arthritis and many other conditions. While the efficacy of biologics has been established, there is uncertainty regarding the adverse effects of this treatment. Since serious risks such as tuberculosis (TB) reactivation, serious infections, and lymphomas may be common to the biologics but occur in small numbers across the various indications, we planned to combine the results from biologics used in many conditions to obtain the much needed risk estimates. OBJECTIVES: To compare the adverse effects of tumor necrosis factor blocker (etanercept, adalimumab, infliximab, golimumab, certolizumab), interleukin (IL)-1 antagonist (anakinra), IL-6 antagonist (tocilizumab), anti-CD28 (abatacept), and anti-B cell (rituximab) therapy in patients with any disease condition except human immunodeficiency disease (HIV/AIDS). METHODS: Randomized controlled trials (RCTs), controlled clinical trials (CCTs) and open-label extension (OLE) studies that studied one of the nine biologics for use in any indication (with the exception of HIV/AIDS) and that reported our pre-specified adverse outcomes were considered for inclusion. We searched The Cochrane Library, MEDLINE, and EMBASE (to January 2010). Identifying search results and data extraction were performed independently and in duplicate. For the network meta-analysis, we performed mixed-effects logistic regression using an arm-based, random-effects model within an empirical Bayes framework. MAIN RESULTS: We included 163 RCTs with 50,010 participants and 46 extension studies with 11,954 participants. The median duration of RCTs was six months and 13 months for OLEs. Data were limited for tuberculosis (TB) reactivation, lymphoma, and congestive heart failure. Adjusted for dose, biologics as a group were associated with a statistically significant higher rate of total adverse events (odds ratio (OR) 1.19, 95% CI 1.09 to 1.30; number needed to treat to harm (NNTH) = 30, 95% CI 21 to 60) and withdrawals due to adverse events (OR 1.32, 95% CI 1.06 to 1.64; NNTH = 37, 95% CI 19 to 190) and an increased risk of TB reactivation (OR 4.68, 95% CI 1.18 to 18.60; NNTH = 681, 95% CI 143 to 14706) compared to control.The rate of serious adverse events, serious infections, lymphoma, and congestive heart failure were not statistically significantly different between biologics and control treatment. Certolizumab pegol was associated with significantly higher risk of serious infections compared to control treatment (OR 3.51, 95% CI 1.59 to 7.79; NNTH = 17, 95% CI 7 to 68). Infliximab was associated with significantly higher risk of withdrawals due to adverse events compared to control (OR 2.04, 95% CI 1.43 to 2.91; NNTH = 12, 95% CI 8 to 28). Indirect comparisons revealed that abatacept and anakinra were associated with a significantly lower risk of serious adverse events compared to most other biologics.  Although the overall numbers are relatively small, certolizumab pegol was associated with significantly higher odds of serious infections compared to etanercept, adalimumab, abatacept, anakinra, golimumab, infliximab, and rituximab; abatacept was significantly less likely than infliximab and tocilizumab to be associated with serious infections.  Abatacept, adalimumab, etanercept and golimumab were significantly less likely than infliximab to result in withdrawals due to adverse events. AUTHORS' CONCLUSIONS: Overall, in the short term biologics were associated with significantly higher rates of total adverse events, withdrawals due to adverse events and TB reactivation. Some biologics had a statistically higher association with certain adverse outcomes compared to control, but there was no consistency across the outcomes so caution is needed in interpreting these results.There is an urgent need for more research regarding the long-term safety of biologics and the comparative safety of different biologics. National and international registries and other types of large databases are relevant sources for providing complementary evidence regarding the short- and longer-term safety of biologics. 

Metformin for lung cancer prevention and improved survival: a novel approach.

Diabetes mellitus has been associated with increased risk for the development of many types of cancer. Metformin, an oral medication and first-line treatment for type 2 diabetes mellitus, has been suggested to reduce cancer risk and mortality in various types of cancer. This study focuses on assessing metformin association with lung cancer as reported in the literature. Recent studies and reviews investigating metformin effects on lung cancer incidence and patient survival are critically and systematically discussed.

Development of a sufficient design for estimation of fluconazole pharmacokinetics in people with HIV infection.

AIMS: To assess an optimal design that is sufficient to gain precise estimates of the pharmacokinetic (PK) parameters for fluconazole in people with HIV infection. METHODS: Two studies were identified, the first in healthy volunteers and the second in HIV patients. The investigators (J.F.R. and S.B.D.) were blinded to the second study results. The healthy volunteer study was modelled and a design was found to estimate the PK parameters. The design was evaluated by comparison of the standard errors of the parameters and the predictive performance of the optimal design. The predictive performance was assessed by comparing model predictions against observed concentrations for two models. The first model, termed 'sufficient design', was developed from data extracted from the HIV study that corresponded to the optimal design. The second model, termed 'HIV outcome model', by modelling all the data from the HIV study. RESULTS: An optimal design HIV study was developed which had considerably fewer blood samples and dosing arms compared with the actual HIV study. The optimized design performed as well as the actual HIV study in terms of parameter precision. The performance of the design, described as the precision (mg l(-1))(2) (95% confidence interval) of the predicted concentrations to the actual concentrations for the 'sufficient design' and 'HIV outcome model' models were: 0.63 (0.40, 0.87) and 0.56 (0.32, 0.79), respectively. CONCLUSION: This study demonstrates how data from healthy volunteers can be utilized via optimal design methodology to design a successful study in the target population.

Population pharmacokinetics and pharmacodynamics of cefpirome in critically ill patients against Gram-negative bacteria.

OBJECTIVES: To develop a population pharmacokinetics model for cefpirome in ICU patients, to assess pharmacokinetic-pharmacodynamic profiles vs. MIC distribution of likely ICU pathogens, and to assess their expected cumulative fraction of response (CFR). DESIGN AND SETTING: Prospective observational study in a multidisciplinary ICU. MEASUREMENTS AND RESULTS: Twelve patients received 2g cefpirome intravenously over 12h. Thirteen blood samples were taken on two occasions. Demographic and creatinine clearance data were collected. Based on the final covariate model obtained using NONMEM, Monte Carlo simulations were undertaken to simulate free-drug concentrations for two administration methods: intermittent bolus administration (IBA) and continuous infusion (CI) with a loading dose of 0.5 g. Concentration-time profiles were evaluated by the probability of achieving free-drug concentrations above the MIC for more than 65% of dosing interval. Using MIC distributions from the EUCAST programme the CFR for each method was evaluated. A three-compartment model with zero-order input best described the concentration-time data. The CFR for Escherichia coli and Klebsiella spp. was greater than 97% in all IBA and CI doses but for Pseudomonas aeruginosa, and Acinetobacter spp. achieved target concentrations of 56% and 46%, respectively. High-dose CI cefpirome (6g/day) for P. aeruginosa and Acinetobacter spp. was required to achieve CFR of 89%. CONCLUSION: Measured creatinine clearance appears to be a good marker of cefpirome clearance and potentially could be used to individualise cefpirome therapy. When given as IBA or CI for E. coli and Klebsiella spp., cefpirome should be successful. Cefpirome fails to achieve the bactericidal target even when administered at high-doses such as 6g/day for P. aeruginosa and Acinetobacter spp. Prospective clinical studies are needed to conclusively validate these findings.

Diagnostic accuracy of cystatin C compared to serum creatinine for the estimation of renal dysfunction in adults and children--a meta-analysis.

OBJECTIVES: To perform a systematic review comparing the diagnostic accuracy of CysC with SCr. METHODS: MEDLINE and EMBASE (January 1984-February 2006) were searched. Studies included i) evaluated CysC against a recognised 'gold standard' method for determining GFR using a receiver operating characteristics (ROC) curve analysis and ii) included data that could be extracted into a 2x2 table. RESULTS: The search identified 27 population groups in 24 studies (n=2007) that compared the diagnostic accuracy of CysC with SCr. The diagnostic odds ratios (DORs) (95% CI) of predicting renal dysfunction derived from a Moses-Littenberg linear regression model were 3.99 (3.41-4.57) for CysC and 2.79 (2.12-3.46) for SCr. CONCLUSION: The diagnostic accuracy for impaired renal function favours CysC. However, the confidence intervals for the pooled DORs for the biomarkers overlap. The ability of CysC (cut-off values between 0.9 and 1.4 mg/L) to rule in renal impairment (as measured by inulin-determined GFR of 60-79 mL/min/1.73 m2) in persons in whom this is suspected is large and conclusive.

General practitioner management of shoulder pain in comparison with rheumatologist expectation of care and best evidence: an Australian national survey.

OBJECTIVES: To determine whether current care for common shoulder problems in Australian general practice is in keeping with rheumatologist expectations and the best available evidence. METHODS: We performed a mailed survey of a random sample of 3500 Australian GPs and an online survey of all 270 rheumatologists in Australia in June 2009. Each survey included four vignettes (first presentation of shoulder pain due to rotator cuff tendinopathy, acute rotator cuff tear in a 45 year-old labourer and early and later presentation of adhesive capsulitis). For each vignette, GPs were asked to indicate their management, rheumatologists were asked to indicate appropriate primary care, and we determined best available evidence from relevant Cochrane and other systematic reviews and published guidelines. RESULTS: Data were available for at least one vignette for 614/3500 (17.5%) GPs and 64 (23.8%) rheumatologists. For first presentation of rotator cuff tendinopathy, 69% and 82% of GPs and 50% and 56% rheumatologists would order a shoulder X-ray and ultrasound respectively (between group comparisons P = 0.004 and P<0001). Only 66% GPs and 60% rheumatologists would refer to an orthopaedic surgeon for the acute rotator cuff tear. For adhesive capsulitis, significantly more rheumatologists recommended treatments of known benefit (e.g. glucocorticoid injection (56% versus 14%, P<0.0001), short course of oral glucocorticoids (36% versus 6%, p<0.0001) and arthrographic distension of the glenohumeral joint (41% versus 19%, P<0.0001). CONCLUSIONS: There is a mismatch between the stated management of common shoulder problems encountered in primary care by GPs, rheumatologist expectations of GP care and the available evidence.

Pharmacokinetic-pharmacodynamic rationale for cefepime dosing regimens in intensive care units.

OBJECTIVES: (i) To develop a population pharmacokinetics (PK) model for cefepime in patients in intensive care units (ICUs). (ii) To assess the pharmacokinetic-pharmacodynamic profile of various cefepime dosing regimens and to assess their expected probability of target attainment (=PTA expectation value) against common ICU pathogens such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii. METHODS: Thirteen ICU patients received cefepime 2 g 12 hourly intravenous (3 min). Twelve blood samples were taken on two occasions: (i) immediately after initial dose; and (ii) between days 3 and 6 after starting therapy. Population PK models were developed using NONMEM. Based on the final covariate model, Monte Carlo simulations were undertaken (n=1000) to simulate free-drug concentrations of cefepime for two administration methods: (i) intermittent bolus administration (IBA); and (ii) continuous infusion (CI). Concentration-time profiles were evaluated by the probability of achieving free-drug concentration above the MIC for >65% of the dosing interval. Finally, using local MIC distributions of E. coli, K. pneumoniae, P. aeruginosa and A. baumannii the PTA expectation values for each dosing administration method were evaluated. RESULTS: A three-compartment model with zero-order input best described the concentration-time data. The PTA expectation values for E. coli and K. pneumoniae were >90% in all CI doses but only when administered as 1 g every 6 h and higher daily doses for IBA. For the current treatment protocol, 2 g every 12 h, P. aeruginosa and A. baumannii achieved target concentrations of only 54% and 28%, respectively. For P. aeruginosa, a CI of at least 4 g/day was required to achieve a PTA expectation value>90% while for A. baumannii a 6 g/day CI only achieved a PTA expectation value of 75%. CONCLUSIONS: When given as IBA or CI for E. coli and K. pneumoniae, cefepime should be successful in achieving the bactericidal target. For P. aeruginosa higher doses of cefepime (>4 g/day) are required to achieve the required PTA expectation value. Cefepime fails to achieve the bactericidal target even when administered at high doses, e.g. 6 g/day, for A. baumannii.