Clinical Pharmacology

The misleading use of the term pragmatic in pre-licensing medicine trials

Promising effects of moderate-dose corticosteroid therapy in the blanking period for prevention of atrial fibrillation (AF) recurrences in patients undergoing AF ablation

Effects of guggulsterones-containing thermogenic complex on elvitegravir plasma concentrations: a case report

Medication and medical diagnosis as risk factors for falls in older hospitalized patients Abstract Objective To examine the impact of medication and medical conditions on the fall risk in older hospitalized patients. Design Matched case-control study. Setting Large regional hospital in a mid-sized German city. Subjects Four hundred eighty-one inpatients aged ≥ 65 years who fell during hospitalization ("cases") and a control group of 481 controls, matched for age, gender, and hospital department. Methods Diagnosis, medication, vital parameters, and injuries were compared between cases and controls. Univariate and multivariable odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated. Main results Several drugs were significantly associated with falls in multivariate analyses: long-acting benzodiazepines (adjusted OR = 3.49; 95%-CI = 1.16–10.52), serotonin-noradrenalin reuptake inhibitors (SNRI) (2.57; 1.23–5.12), Z-drugs (2.29; 1.38–3.59), low-potency neuroleptics (1.87; 1.08–3.23), ACE inhibitors/sartans (1.42; 1.07–1.89). Digoxin (0.32; 0.11–0.99) and aldosterone receptor antagonists (0.54; 0.33–0.88) were negatively associated with falls. No significant association in multivariate analyses was found for short- and intermediate-acting benzodiazepines, mirtazapine, and opioids. Hyponatremia (1.52; 1.15–2.03) and leukocytosis (1.39; 1.05–1.87) in blood examination on admission showed significant association with falls. As secondary diagnoses, Parkinson syndrome (2.38; 1.27–4.46) and delirium (3.74; 2.26–6.21) were strongly associated with falls. The use of more than one psychoactive drug was a separate risk factor for falls (p < 0.0001). Conclusion Several drugs including SNRI, neuroleptics, and Z-drugs showed a significant association with inpatient falls. The frequently prescribed tetracyclic antidepressant mirtazapine did not appear to increase the risk of falls. Psychoactive polypharmacy should be avoided.

Half-dose ticagrelor versus high-dose clopidogrel in reducing platelet reactivity in acute coronary syndrome patients with high on-clopidogrel platelet reactivity (divide study) Abstract Purpose High on-treatment platelet reactivity (HTPR) after clopidogrel administration in patients with acute coronary syndrome (ACS) has been associated with an increased risk of adverse events. Our previous studies reported that half-dose ticagrelor provides a similar inhibitory effect on adenosine diphosphate (ADP)–induced platelet aggregation as standard-dose ticagrelor, but half-dose of ticagrelor has not been studied in Chinese ACS patients with HTPR. This study aimed to compare the antiplatelet action of half-dose ticagrelor with high-dose clopidogrel in ACS patients with HTPR. Methods In this single-center randomized controlled trial, 80 (of 418 screened, 19.13%) ACS patients with HTPR while on clopidogrel were randomized to either half-dose ticagrelor (90 mg LD, then 45 mg twice daily) or high-dose clopidogrel (150 mg once daily). Platelet function was assessed by thromboelastography (TEG) and light transmission aggregometry (LTA), and adverse events were monitored throughout the study for 30 days. Results The ADP-induced platelet inhibition rate (IR) as measured by TEG was significantly higher for half-dose ticagrelor compared with high-dose clopidogrel (70.40% [61.10%–91.70%] vs. 44.25% [34.67%–79.07%], p = 0.001). The repeated HTPR rate was dramatically higher for high-dose clopidogrel compared with half-dose ticagrelor (6 of 32, 18.75% vs. 1 of 35, 2.85%; p = 0.04). No patients in either treatment group exhibited a major bleeding event or other adverse events. Conclusions In ACS patients with HTPR, half-dose ticagrelor is more effective than high-dose clopidogrel in reducing platelet reactivity (NCT03062462).

Pharmacokinetics of venlafaxine in treatment responders and non-responders: a retrospective analysis of a large naturalistic database Abstract Purpose To assess in a large naturalistic sample, whether clinical response to a treatment with venlafaxine is associated with different patterns of plasma concentrations of active moiety, AM (sum of venlafaxine (VEN) and its active metabolite O-desmethylvenlafaxine (ODVEN)). Methods Applying a regression model, plasma concentrations and plasma concentrations corrected-by-dosage (C/D) for AM were included as independent variable with Clinical Global Impressions-Improvement (CGI-I) scale ratings as dependent variable. Moreover, AM, VEN, and ODVEN were compared between treatment responders and non-responders, defining response as much or very much improved on the CGI-I scale based on the non-parametric Mann-Whitney U (M-W-U) test with a significance level of 0.05. Results No correlations were found between AM and C/D AM plasma concentrations and CGI-I ratings (regression coefficient 0.0, CI 0.000, 0.001, p = 0.492 for AM and 0.047, CI − 0.065, 0.159, p = 0.408 for C/D AM). Venlafaxine daily dosage did not differ between responders and non-responders (217.7 ± 76.9 vs. 222.0 ± 72.7 mg/day, p = 0.45 for M-W-U). Responders displayed lower ODVEN (p = 0.033) and AM (p = 0.031) plasma concentrations than non-responders (p = 0.033 and 0.031, respectively for M-W-U). No other differences were detected. Using a cut-off level of 400 ng/mL for AM concentrations, a higher percentage of responders was reported in the group of patients with AM < 400 ng/mL (13.04%) compared to patients with AM > 400 ng/mL (8%) (p = 0.038). Conclusions Higher ODVEN and AM concentrations in non-responders than in responders indicate that treatment escalation above upper thresholds of therapeutic reference ranges of venlafaxine is not promising. Hence, the therapeutic reference range for venlafaxine can help in improving outcomes in a measurement-based care model that takes advantage of therapeutic drug monitoring.

The effect of ketoconazole on praziquantel pharmacokinetics and the role of CYP3A4 in the formation of X-OH-praziquantel and not 4-OH-praziquantel Abstract Aim The study sought to determine the effect of ketoconazole (KTZ) on the pharmacokinetics of praziquantel (PZQ) and on the formation of its major hydroxylated metabolites, cis- and trans-4-OH-PZQ, and X-OH-PZQ in healthy subjects. Methods Two treatments were evaluated by single-dose PK studies; the reference treatment was a 20 mg/kg dose of praziquantel given alone. The test treatment was a 20 mg/kg dose of praziquantel given in combination with 200 mg of ketoconazole. The study had a balanced and randomised cross-over design. Serial blood samples were collected between 0 and 12 h after each drug administration. PZQ, and cis- and trans-4-OH-PZQ and X-OH-PZQ concentrations in plasma were determined by LC-MS. A non-compartmental approach was used for pharmacokinetic analysis. Data were analysed using ANOVA and assessment of the 90% confidence interval of the geometric means of the log-transformed PK parameters obtained for each treatment. Results The pharmacokinetics of PZQ following the two treatments, PZQ alone and PZQ + KTZ, were not equivalent based on the assessment of the 90% CI of the geometric mean ratios of the AUC and Cmax (α = 0.05). The geometric mean ratios of the AUC and Cmax were found to be 176.8% and 227% respectively. The 90% CI of the AUC and Cmax were found to be 129.8%–239.8% and 151.4%–341.4% respectively. The AUC of PZQ was increased by 75% with KTZ co-administration (3516 vs 6172 ng h/ml) (p < 0.01). Meanwhile, the mean AUC of trans-4-OH-PZQ increased by 67% (61,749 ng h/ml vs 103,105 ng h/ml) (p < 0.01). X-OH-PZQ levels were reduced by about 57% (semi-quantified as 7311 ng h/ml vs 3109 ng h/ml by using trans-4-OH as standards) (p < 0.01) with KTZ co-administration. Conclusions The relative bioavailability of praziquantel was increased by concomitant KTZ administration. KTZ preferentially inhibited the formation of X-OH-PZQ rather than 4-OH-PZQ, confirming in vitro data which implicates CYP3A4 in the formation of X-OH-PZQ rather than 4-OH-PZQ. The 4-hydroxylation of PZQ was shown to be the major metabolic pathway of PZQ, as evidenced by larger quantities of 4-OH-PZQ produced, thus explaining the modest albeit significant effect of ketoconazole on PZQ pharmacokinetics.

Adverse drug reaction causality assessment tools for drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: room for improvement Abstract Purpose Establishment of causality between drug exposure and adverse drug reactions (ADR) is challenging even for serious ADRs such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Several causality assessment tools (CAT) exist, but the reliability and validity of such tools is variable. The objective of this study was to compare the reliability and validity of existing ADR CATs on SJS/TEN cases. Methods Seven investigators completed three CAT (ALDEN, Naranjo, Liverpool) for 10 SJS/TEN cases. Each CAT categorized the causality of 30 potential drugs as definite/very probable, probable, possible, or doubtful/unlikely. An additional reviewer provided expert opinion by designating the implicated drug(s) for each case. A Kappa score was generated to compare CAT responses both by method (reliability of all 7 reviewers, by CATs) and by reviewer (reliability of the 3 CAT, by reviewer). A c statistic was calculated to assess validity. Results Inter-rater reliability by CAT was poor to fair: ALDEN 0.22, Naranjo 0.11, and Liverpool 0.12. Reliability was highest when causality classification was definite/very probable (0.16–0.41). Similarly, intra-rater reliability by reviewer was poor. When comparing the validity of the overall CAT to expert reviewer, area under the curve was highest for ALDEN (c statistic 0.65) as compared to Liverpool (0.55) or Naranjo (0.54). Conclusion Available CAT have poor reliability and validity for drug-induced SJS/TEN. Due to the importance of determining ADR causality for research, industry, and regulatory purposes, development of an enhanced tool that can incorporate data from immunological testing and pharmacogenetic results may strengthen CAT usefulness and applicability for drug-induced SJS/TEN.

Safety aspects of antiepileptic drugs—a population-based study of adverse effects relative to changes in utilisation Abstract Purpose Antiepileptic drugs (AEDs) are increasingly used, and knowledge about adverse effects is scarce based on clinical studies. The purpose of the present study was to characterise adverse effects reports of AEDs in Norway relative to changes in utilisation in various indications from population-based data to elucidate important safety aspects of use of AEDs. Methods Aggregated data of adverse effects reported for AEDs in Norway from the EudraVigilance-database (2004–2013) in addition to indication-specific use of AEDs during 2004–2015 from the Norwegian Prescription Database were used. Results The use of AEDs increased twofold the last decade due to use in psychiatry and neuropathic pain: lamotrigine, pregabalin, gabapentin, valproate, and carbamazepine. There were 1593 adverse effects reported (403 Individual Case Safety Reports, 2/3 women), 0–95 years (mean 46). Most adverse effects were reported for pregabalin (593), carbamazepine (265), lamotrigine (206), gabapentin (144), and valproate (119), where pregabalin had by far the highest reports in relation to the number of users. The most frequently reported adverse drug effects included rash, dizziness, cross-sensitivity reactions, and pyrexia. Overall, nervous system disorders constitute the largest organ class with the majority of the reports. Reporting of fatal outcomes is mandatory, and sudden unexplained death in epilepsy (SUDEP) was reported in 34 occasions. Conclusions This study demonstrates that most adverse effects reported concerned AEDs increasingly used in non-epilepsy indications: neuropathic pain (pregabalin, gabapentin, carbamazepine) and psychiatry (lamotrigine, valproate, carbamazepine). Pregabalin had the highest prevalence of adverse effects reported in relation to number of users. This elucidates an important part of pharmacovigilance for improved safety and considerations in clinical practice.

The effect of L-carnitine on inflammatory mediators: a systematic review and meta-analysis of randomized clinical trials Abstract Aim and background Reducing inflammation by nutritional supplements may help to reduce the risk of many chronic diseases. Our aim in this meta-analysis was to determine the effect of L-carnitine on inflammatory mediators including C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). Methods Our systematic search to find relevant randomized clinical trials (RCTs) was performed up to October 2018 using ISI Web of Science, Google Scholar, PubMed/Medline, and SCOPUS. In this meta-analysis, the weighted mean differences (WMD) with standard errors (SE) were used to pool the data. WMD was calculated by subtracting change-from-baseline mean values in the control group from change-from-baseline mean values in the intervention group in each study. To identify heterogeneity among studies, the I2 statistic was employed. The protocol was registered with PROSPERO (No. CRD42019116695). Results Thirteen articles were included in our systematic review and meta-analysis. The results of the meta-analysis indicated that L-carnitine supplementation was significantly associated with lower levels of CRP in comparison to controls (WMD = −1.23 mg/L; 95% CI: −1.73, −0.72 mg/dL; P < 0.0001). Also, a slight but statistically significant decrease was observed in IL-6 and TNF-α levels (WMD = −0.85 pg/dL; 95% CI: −1.38, −0.32 pg/dL; P = 0.002 and WMD = −0.37 pg/dL; 95% CI: −0.68, −0.06 pg/dL; P = 0.018, respectively). Conclusion Our results indicate that L-carnitine reduced inflammatory mediators, especially in studies with a duration of more than 12 weeks. Further studies with different doses and intervention durations and separately in men and women are necessary.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com