Pharmacogenomics of celiprolol – evidence for a role of P‐glycoprotein and organic anion transporting polypeptide 1A2 in celiprolol pharmacokinetics

The aim of this study was to search for associations of genetic variants with celiprolol pharmacokinetics in a large set of pharmacokinetic genes, and, more specifically, in a set of previously identified candidate genes ABCB1, SLCO1A2, and SLCO2B1. To this end, we determined celiprolol single‐dose (200 mg) pharmacokinetics and sequenced 379 pharmacokinetic genes in 195 healthy volunteers. Analysis with 46,064 common sequence variants in the 379 genes did not identify any novel genes associated with celiprolol exposure. The candidate gene analysis showed that the ABCB1 c.3435T>C and c.2677T/G>A, and the SLCO1A2 c.516A>C variants were associated with reduced celiprolol area under the plasma concentration‐time curve (AUC_0–∞). An alternative analysis with ABCB1 haplotypes showed that, in addition to SLCO1A2 c.516A>C, three ABCB1 haplotypes were associated with reduced celiprolol AUC_0–∞. A genotype scoring system was developed based on these variants and applied to stratify the participants to low and high celiprolol exposure genotype groups. The mean AUC_0–∞ of celiprolol in the low exposure genotype group was 55% of the mean AUC_0–∞ in the high exposure group (p = 1.08 × 10⁻¹¹). In addition, the results showed gene‐gene interactions in the effects of SLCO1A2 and ABCB1 variants on celiprolol AUC_0–∞ (p < 5 × 10⁻⁶) suggesting an interplay between organic anion transporting polypeptide 1A2 and P‐glycoprotein in celiprolol absorption. Taken together, these data indicate that P‐glycoprotein and organic anion transporting polypeptide 1A2 play a role in celiprolol pharmacokinetics. Furthermore, patients with ABCB1 and SLCO1A2 genotypes associated with low celiprolol exposure may have an increased risk of poor blood‐pressure lowering response to celiprolol.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

High interindividual variability exists in the pharmacokinetics of celiprolol. There are no comprehensive studies evaluating how variability in pharmacokinetic genes associates with celiprolol exposure.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study searched for associations of genetic variants with celiprolol pharmacokinetics in a large set of pharmacokinetic genes, and, more specifically, in a set of previously identified candidate genes ABCB1, SLCO1A2, and SLCO2B1.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study showed that genetic variants in ABCB1 and SLCO1A2 are associated with celiprolol pharmacokinetics. Based on the results, a genotype scoring system was developed and applied to stratify the participants to low and high celiprolol exposure genotype groups.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This knowledge might aid in identifying individuals with increased risk of insufficient celiprolol exposure and therapeutic failure. Furthermore, the data suggest an interplay between OATP1A2 and P‐gp in the small intestine, which may be relevant also for other drugs that are substrates of both of these transporters.     

Serum levels of beta 2-microglobulin in various types of hemodialysis

beta 2-microglobulin (beta 2 m) is the major constituent of amyloid fibrils in dialysis-related amyloidosis (DRA), which is considered to be one of the most severe adverse effect of long-term dialysis. In this study we evaluated the efficiency of beta 2 m removal during different dialysis procedures. A total of 45 patients undergoing hemodialysis were divided in five groups: cuprophane dialysis (n = 10), high-flux polysulphone dialysis (n = 10), postdilutional hemodiafiltration (n = 10), conventional postdilutional hemofiltration (n = 10) and predilutional on-line hemofiltration (n = 5). Serum level of beta 2 m was determined before and after different procedures using ELISA. In the group of patients on cuprophane dialysis was registered an elevation of beta 2 m and of 16.8 +/- 11.4% on the average. Serum level of beta 2 m was decreased following all other procedures on the average of 40.7 +/- 16.4% after high-flux polysulphone dialysis, 42.0 +/- 13.7% after conventional hemofiltration, 64.7 +/- 9% after hemodiafiltration and 67.9 +/- 10.1% after predilutional hemofiltration. The best removal of serum beta 2 m was realized by predilutional hemofiltration. Also, we have noticed that patients treated with high-flux synthetic membranes in the longer time-period have lower predyalisis value of beta 2 m compared to patients treated with cuprophane membrane. Further long-term studies will be necessary to conclude whether these procedures could be successful prophylactic and/or therapeutic regimen for dialysis-related amyloidosis.     

Spectrophotometric and HPLC determination of fleroxacin in tablets

The paper describes and compares spectrophotometric and HPLC determination of fleroxacin in commercial tablets. The optimum conditions for spectrophotometric assay were found to be at pH < 3.5 (0.1 M HCl) at a wave length of 286 nm. HPLC analysis was carried out on a Beckman ODS 5 microns column in a pH 3 phosphoric acid solution (detector wave length 254 nm).     

Assessing variability and uncertainty in orthopedic randomized controlled trials

Background and purpose — Low statistical power remains endemic in clinical medicine including orthopedics and manifests as high uncertainty and wide confidence intervals (CI). We evaluated the reporting and correspondence between power calculation and observed data on key parameters of variability and uncertainty in orthopedic randomized controlled trials (RCTs).Material and methods — RCTs with 1:1 allocation published in 8 major orthopedic journals between 2016 and 2017 with one continuous primary outcome were included in the review. The components of power calculation and observed standard deviation (SD), mean difference (MD), and confidence interval (CI) of MD between groups were assessed for primary outcome.Results — 160 RCTs were included, of which 93 (58%) and 138 (86%) studies reported the estimated SD and MD in the power calculation, respectively. The median ratio of the estimated SD and SDs observed in the data was 1.0 (IQR –0.76 to 1.32) for 69 (43%) studies. Only 31 of 138 studies reported the CI of MD in primary outcome. In 42% of the negative studies, the estimated MD was included in the CI of the observed MD.Interpretation — The key parameters of data variability, both in power analyses and in final study results, were poorly reported. Low power in orthopedics may result from too high an estimated effect size due to an overoptimistic estimate of MD between study groups. In almost half of the studies, overlap of the CI of the observed MD and estimated MD suggested that the reported results of these studies were inconclusive.

Adequate statistical power is the cornerstone of reproducible and high-quality clinical research. High statistical power is needed to increase the likelihood that a study will detect an effect when there is an effect to be detected. According to the CONSORT statement (Schulz et al. 2010), power calculations are based on the estimated mean difference (MD_est) between compared groups, the estimated standard deviation (SD_est) or variability of the outcome at a particular point in time, and the chosen level of error, namely, type 1 and 2 errors. A complement of type 2 error is statistical power.Despite the increasing use of power calculations, low power among RCTs to find small and medium effect sizes still remains endemic in clinical medicine, including orthopedics (Button et al. 2013, Abdullah et al. 2015, Sabharwal et al. 2015, Szucs and Ioannidis 2017, Reito et al. 2020). In studies using a priori power analysis, low power may arise from overestimated mean difference (MD), from underestimated standard deviation (SD), or from both (Vickers 2003, Cook et al. 2018). In many orthopedic RCTs, a patient-level minimal clinically important difference (MCID) is currently the basis of the group-level MD_est used in power calculations. Usually, the MD_est used in power calculations represents the clinically relevant difference valued by the investigators (Ostelo et al. 2008, de Vet and Terwee 2010, Angst et al. 2017, Jayadevappa et al. 2017, Dabija and Jain 2019). In this study we use the terms “MD_est” and “MCID” interchangeably.Small sample sizes will yield high uncertainty of the outcome variable, which may, in turn, manifest as wide confidence intervals (CIs) (Anderson 2019). The mainstay in the interpretation of negative trials is to declare no statistically significant difference or “no difference” between the study groups if the CI of MD (CI_MD) between groups includes equivalence in means, i.e., zero difference. A more appropriate interpretation would be to interpret the CI_MD to see which values for group difference are excluded by the data based on the chosen confidence level (Gelman and Greenland 2019).In this systematic review, we investigated (1) the reporting of the key parameters of variability and uncertainty; (2) the correspondence of the SD_est of the primary outcome used in the power analysis to that actually observed in the study population; (3) the overlap of the MD_est between groups to the CI_MD in the primary outcome between study groups, and (4) the difference in sample size and estimated effect size in studies with and without overlap in MD_est and CI_MD in orthopedic RCTs published in 8 journals in the years 2016 and 2017.     

Assessment of inter- and intra-observer reliability in the determination of radiographic version and inclination of the cup in metal-on-metal hip resurfacing

Purpose  

Determination of the cup orientation after metal-on-metal hip resurfacing may provide important information in the postoperative follow-up. We present a mathematical method based on a previously described approach to assess the version and inclination of the cup in the metal-on-metal bearing without a separate software computation from plain radiographs. The aim of the study was to assess the intra- and inter-observer reliability of this method.     

Outcome of Birmingham hip resurfacing at ten years: role of routine whole blood metal ion measurements in screening for pseudotumours

Purpose

Emerging concern has arisen because of recent papers reporting a high prevalence of pseudotumours (PTs), even in patients with surface arthroplasties with a good clinical track record. The aim of our study was to establish the ten year survivorship of Birmingham hip resurfacing (BHR), to investigate whole blood (WB) metal ion levels and prevalence of adverse reactions to metal debris (ARMeD) and to determine the association of blood metal ion levels and symptoms with ARMeD in patients operated on with BHR at our institution.

Methods

Between May 2001 and May 2004, 261 consecutive BHRs were implanted in 219 patients. All living, nonrevised patients underwent a systematic screening programme consisting of clinical examination, WB cobalt and chromium measurements and targeted cross-sectional imaging.

Results

The ten year survival for the entire cohort was 91 % (89–93 %), with any revision as the endpoint. Prevalence of ARMeD was 6.9 % in male and 8.8 % in female patients. Symptomatic patients with elevated metal ion levels evinced highest prevalence (63 %) of PTs compared with asymptomatic patients with elevated metal ion levels (42 %) and symptomatic patients with nonelevated metal ions (11 %).

Conclusions

Contradicting the current international guidelines, our results suggest that it seems beneficial to combine routine metal ion measurement with clinical assessment, even in patients with well-functioning BHRs. Further follow-up will reveal whether new PTs will develop in these patients and BHR survivorship in the longer term.     

Peripheral inflammatory markers and clinical correlations in patients with frontotemporal lobar degeneration with and without the C9orf72 repeat expansion

Journal of Neurology - In this study, our aim was to evaluate potential peripheral inflammatory changes in frontotemporal lobar degeneration (FTLD) patients carrying or not the C9orf72 repeat...