Aim Dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) remains the standard of care. CYP2C19 genetic polymorphisms results in variable Clopidogrel bioactivation. Increased function (CYP2C19*17) allele carriers (rapid metabolizers (RM) or ultrarapid metabolizers (UM)), are Clopidogrel hyper-responders and hence more susceptible to Clopidogrel related bleeding. Since current guidelines recommend against routine genotyping following PCI, data on the clinical utility of CYP2C19*17 genotype guided strategy are sparce. Our study provides real-world data on the 12-month follow-up of CYP2C19 genotyping in patients post-PCI. Methods This is a cohort study within an Irish population receiving 12 months of DAPT following PCI for ACS or CCS. It identifies the prevalence of CYP2C19 polymorphisms within an Irish population and describe the ischaemic and bleeding outcomes after 12 months of Clopidogrel DAPT. Results 129 patients were included with the following CYP2C19 polymorphism prevalence: 30.2% hyper-responders (26.4% RM (1*/17*), 3.9% UM (17*/17*)) and 28.7% poor-responders (22.5% IM (1*/2*), 3.9% IM (2*/17*), 2.3% PM (2*/2*)). Total bleeding incidence at 12-months increased from poor-responders (0.0%) to normal-responders (15.0%), to hyper-responders (25.0%). Compared to poor-responders, hyper-responders were significantly more likely to experience a bleeding event (25.0% vs 0.0%, P = 0.044). Conclusions The prevalence of CYP2C19 polymorphisms in Ireland is 58.9% (30.2% CYP2C19*17, 28.7% CYP2C19*2) with approximately 1 in 3 chance of being a Clopidogrel hyper-responder. The trend of increasing bleeding with increasing CYP2C19 activity, suggests a genotype guided strategy may have clinical utility identifying high-bleeding-risk with Clopidogrel in CYP2C19*17 carriers but further studies are required.

A document by Emma Magavern. Click on the document to view its contents.

A 53-year-old woman with a history of acute myeloid leukemia received a second allogenic hematopoietic stem cell transplant (HSCT) and was prescribed, among other medications, acyclovir and letermovir (480 mg daily oral dose) for prophylaxis of respectively herpes simplex and cytomegalovirus infection. The patient was admitted in the intensive care unit (ICU) for dyspnea and oliguria. Laboratory investigations revealed acute kidney injury, but also a severe and progressive lactic acidosis. Liver function tests were within normal range. The combination of lactic acidosis, hypoglycaemia and acylcarnitine profile in plasma suspected a mitochondrial toxicity. Letermovir therapy was interrupted and determination of plasma letermovir pharmacokinetics revealed a prolonged terminal half-life (40.7 h) that was not significantly influenced by continuous venovenous hemofiltration. Exploration for genetic polymorphisms revealed that the patient was SLCO1B1*5/*15 (c.521T>C homozygous carrier and c.388A>G heterozygous carrier) with a predicted non-functional OATP1B1 protein. The relationship between letermovir accumulation and development of lactic acidosis requires further observations.

Atomoxetine is mainly metabolized by CYP2D6 while CYP2C19 plays a secondary role. It is known that patients carrying genotypes encoding decreased/absent CYP2D6 metabolism obtain higher atomoxetine concentrations and are at increased risk of adverse effects. Here, we aimed to investigate the added effects of reduced-function CYP2C19 genotype on atomoxetine concentrations in real-world settings. Serum atomoxetine concentrations and CYP2D6/2C19 genotypes were included from a therapeutic drug monitoring service. Patients were first subgrouped according to CYP2D6 encoding normal, reduced or absent CYP2D6 metabolism, referred to as normal (NM), intermediate (IM) or poor metabolizers (PM). Then, the effect of reduced-function CYP2C19 genotypes was investigated. Genotyping of the CYP2D6 nonfuctional or reduced variant alleles comprised CYP2D6*3-*5, *9-*10 and *41. For CYP2C19, the CYP2C19*2 was analysed to define metabolizer phenotype. Dose-adjusted serum atomoxetine concentration was the exposure measure. Using a patient cohort (n=315), it was found that CYP2D6 IM and PM patients had 1.9-fold (95%CI: 1.4-2.7) and 9.6-fold (5.9-16) higher exposure of atomoxetine compared with CYP2D6 NMs. CYP2C19*2 carriers had 1.5-fold (1.1-2.2) higher atomoxetine exposure than non-carriers regardless of CYP2D6 genotype. CYP2D6 genotype has a great impact on atomoxetine exposure, where our real-world data suggest atomoxetine dose requirements to be around half and one-tenth in CYP2D6 IM and PM vs. NM patients, respectively. When adding CYP2C19 genotype as a factor of relevance for personalized atomoxetine dosing, CYP2C19*2 carriers should further reduce the dose by a third. These findings suggest that pre-emptive CYP2D6/CYP2C19 genotyping should be performed to individualize atomoxetine dosing and prevent adverse effects.

Aims: Nusinersen is administered intrathecally for treating spinal muscular atrophy (SMA). Procedural sedation is common with intrathecal treatment in children. This retrospective study presents our experience with procedural sedation during the intrathecal treatment of pediatric patients with SMA I, II, and III. Methods: Data were collected the from the anesthesia charts and electronic medical records of 14 pediatric patients with SMA types I, II, and III who underwent procedural sedation for repeated intrathecal treatments for SMA. Intravenous induction was performed, and patients were oxygenated with a face mask or nasal cannula while spontaneous breathing continued. Results: Fourteen patients were included in the study: one SMA I, eight SMA II, and five SMA III. They underwent 88 intrathecal nusinersen injections totally. In the one SMA I patient, of eight months, the procedure was performed under local anesthesia. In all other patients, the treatments were performed under procedural sedation. Different combinations of midazolam, ketamine, propofol, fentanyl, and remifentanil were used. The mean doses of the agents used were 0.03 mg/kg, 0.97 mg/kg, 2.71 mg/kg, 0.84 mcg/kg and 0.5 mcg/kg respectively. There were no intraoperative or postoperative complications. Conclusion: We found the procedural sedation to be sufficient, effective, and safe in SMA II and III pediatric patients who underwent nusinersen treatment intrathecally, provided anesthetic agents are titrated.and administered carefully.

Abstract Dopamine agonists are a key tool in the therapeutic arsenal of endocrinologists worldwide. They exert their effects by binding to dopamine 2 (D2) receptors expressed by pituitary tumor cells, to modulate hormonal secretion and tumor size. They are the established first-line treatment for prolactinomas which express high levels of D2 receptors. Growing data supports their use as an adjuvant treatment option for other pituitary tumors including growth hormone, adrenocorticotrophic hormones, thyroid hormone secreting adenomas and non-functional pituitary tumors, all of which have been shown to express D2 receptors as well, albeit to varying extents. For those pituitary tumors inadequately treated by dopamine agonist alone, combined agonism of D2 and somatostatin receptors, represent a new frontier in clinical development. Here we review the development and role of dopamine agonist for the treatment of prolactinomas, the literature supporting their adjuvant use for the treatment of all other pituitary tumors, and recent progress in the development of the next generation of chimeric compounds that target D2 and other receptor subtypes highly expressed on pituitary tumor cells.

Aim: Thyroidectomy is frequently associated with substantial postoperative pain. Esketamine, an N-methyl-D-aspartate receptor antagonist, has been demonstrated to be effective in multiple analgesia. We hypothesized that intraoperative administration of esketamine may reduce perioperative opioid consumption and postoperative pain in patients undergoing thyroidectomy. Methods: Sixty patients undergoing thyroidectomy were randomly assigned to two groups. Patients in the saline group received a pre-incisional intravenous bolus of 0.9% NaCl followed by an intraoperative infusion of 0.9% NaCl; patients in the esketamine group received a pre-incisional intravenous bolus of esketamine (0.5 mg kg-1) followed by an intraoperative infusion of esketamine (0.24 mg kg-1 h-1). The primary outcome was perioperative sufentanil consumption. The postoperative pain, sleep quality, and adverse events during the first postoperative 24 h were also evaluated. Results: Patients in the esketamine group consumed significantly less sufentanil than those in the saline group (24.6 ± 3.1 μg vs. 33.7 ± 5.1 μg, mean difference, 9.1; 95% confidence interval, 6.9–11.3, P <0.001). Postoperative pain scores were significantly lower in the esketamine group than those in the saline group during the first 24 h postoperatively (P <0.05). Patients receiving esketamine experienced higher sleep quality than those in the saline group during surgical night (P = 0.043). There were no significant differences in adverse events between the two groups. Conclusion: Intraoperative administration of esketamine reduces perioperative sufentanil consumption and postoperative pain without increasing adverse events in patients undergoing thyroidectomy. The development of combined anesthesia regimens, including esketamine, may foster strategies for pain management during thyroidectomy.

The effects of polymorphisms of ABCB1 and ABCG2 on the dose-adjusted plasma trough concentrations and cerebrospinal fluid (CSF)-to-plasma ratios of ponatinib were evaluated. Blood (C4) and CSF (CSF4) concentrations at 4 h after administration were determined. The median (95% confidence interval (CI)) CSF4-to-C4 ratio of ponatinib in subjects homozygous for ABCB1 variants 1236T/T, 2677T/T+T/A, or 3435T/T were significantly higher than that in a group of subjects with other genotypes (P = 0.026, 0.012, and 0.015, respectively). The median (95% CI) CSF4-to-C4 ratio of ponatinib in four patients with the combination of ABCB1 variants 1236T/T-2677T/T+T/A-3435T/T was 2.62 (1.42 – 3.42)%; this ratio was significantly higher than that in subjects with other genotypes [1.08 (0.89 – 1.47)%; P = 0.006]. The brain distribution of ponatinib was affected by ABCB1 polymorphisms and therefore seems to be modulated by P-glycoprotein at the blood-brain and blood-CSF barriers.

Objective: This clinical study was conducted to evaluate the impact of ritlecitinib on the pharmacokinetics (PK) of caffeine, a cytochrome P450 1A2 (CYP1A2) substrate. Methods: In this single-center, single-arm, open-label, fixed-sequence study, healthy participants received a single 100-mg dose of caffeine on two separate occasions: on Day 1 of Period 1 as monotherapy and on Day 8 of Period 2 after oral administration of ritlecitinib 200 mg once daily (QD) for 8 days. Serial blood samples were collected and analyzed using a validated LC/MS assay. PK parameters were estimated by using a non-compartmental method. Safety was monitored by physical examination, vital signs, electrocardiograms, and laboratory assessments. Results: Twelve participants were enrolled and completed the study. Co-administration of caffeine 100 mg in the presence of steady-state levels of ritlecitinib (200 mg QD) increased caffeine exposure compared with caffeine given alone. Area under the curve (AUCinf) and maximum concentration (Cmax) of caffeine increased by approximately 165% and 10%, respectively, when co-administered with ritlecitinib. The ratios of the adjusted geometric means (90% CI) for caffeine AUCinf and Cmax were 265.14% (234.12%-300.26%) and 109.74% (103.90%-15.91%), respectively, when caffeine was co-administered with steady-state ritlecitinib (test) compared with its administration alone (reference). Multiple doses of ritlecitinib when co-administered with a single dose of caffeine were generally safe and well tolerated in healthy participants. Conclusion: Ritlecitinib is a moderate inhibitor of CYP1A2 and can increase systemic exposures of CYP1A2 substrates.

Setting-up a high quality and efficient pharmacovigilance (PV) system in multi-country clinical trials can be more challenging for academic sponsors than for industrials. Generating high-quality safety data, compliant with legal and regulatory standards such as European or World Health Organization (WHO), places special requirements on the PV system. The scenario becomes more complicated when dealing with multi-country European clinical trials where heterogeneity on safety process can be encountered. Some Sponsors face these challenges are even more difficult for pediatric trials. A possible solution to ensure that the safety of all participants is equally guaranteed and the PV system fulfills all regulations could be to set up a centralized PV system. This paper introduces the key points to consider when implementing and organizing such system in multi-national European clinical trials. It is based on the Inserm-ANRS MIE pharmacovigilance department’s experience and aims to harmonize and anticipate the needs, in particular by implementing safety procedures and a network of local safety officers. This system is very useful to respond to the challenges of a European clinical trial, notably when considering the complexity of local safety requirements of each country, signal management and the specificities of paediatric regulation.

Background: Infections are common complications after stroke and associated with unfavorable outcomes. We evaluated the efficacy and safety of prophylactic antibiotics for post-acute stroke infection. Methods: We searched PubMed, Embase, the Cochrane Library, SinoMed, China National Knowledge Infrastructure, and WanFangData from inception to February 15th, 2022. We calculated the pooled risk ratio (RR) and mean differences (MDs) with 95% confidence interval (CI), evaluated the risk of bias and conducted sensitivity analysis with RevMan version 5.4.1 and Stata version 14.0 software. The overall quality of evidence was evaluated using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Results: Twelve studies (4809 participants) were included in this meta-analysis. There was no significant difference in the mortality rate [RR 1.03 (95% Cl: 0.91-1.16)], pneumonia [RR 0.94 (95% CI: 0.79-1.11)], and the incidence of adverse events between the prophylactic antibiotics and control groups. Prophylactic antibiotics significantly reduced the incidence of infections [RR 0.72 (95% Cl: 0.58-0.89)], and urinary tract infections [RR 0.39 (95% Cl: 0.3-0.49)] in patients with acute stroke. We performed a subgroup analysis and found a decreasing trend in pneumonia in patients with early prophylactic use of antibiotics within 24 hours after admission [RR 0.81 (95%CI: 0.62-1.07)] as compared with those using prophylactic use of antibiotics within 48 hours after admission [RR 0.94 (95%CI: 0.79-1.11)]. Conclusions: Prophylactic antibiotics did not significantly reduce the mortality rate and pneumonia in patients with acute stroke but reduced the incidence of infections and urinary tract infections.

Reactivation of the scar resulting from intracutaneous injection of Bacillus Calmette-Guérin (BCG) is a common specific reaction in Kawasaki’s Disease. It has also sporadically been associated with viral infections, Multisystem Inflammatory Syndrome in Children, influenza vaccination and mRNA COVID-19 vaccination. Since the start of the COVID-19 vaccination campaign in January 2021, the Netherlands Pharmacovigilance Centre Lareb has received 22 case reports of BCG reactivation after vaccination with a COVID-19 vaccine. In 20 case reports it concerned mRNA COVID-19 vaccines Moderna (14) and Pfizer (6). In 2 case reports the viral vector COVID-19 vaccine AstraZeneca was administered. Erythema and pain were the most frequently reported symptoms and the size of the inflammation was between 1.5 to 5 cm. BCG reactivation occurred with a median time to onset of 2 days after the second or booster COVID-19 vaccination, whereas the median time to onset was 7 days after the first COVID-19 vaccination. None of the BCG reactivations were treated. The exact mechanism of the occurrence of this specific reaction remains unknown, however involvement of heat shock protein 65 is suggested. BCG reactivation is a non-serious, self-limiting reaction that can occur after vaccination with both mRNA and viral vector COVID-19 vaccines.

AIMS Doxorubicin-induced cardiotoxicity (DIC) is a significant cause of mortality in cancer care. This study was conducted to establish the frequency of DIC in Zimbabwean breast cancer patients on doxorubicin and to test the DIC predictive power of genetic biomarkers. METHODS A cohort of 50 Zimbabwean breast cancer patients treated with doxorubicin were followed up for 12 months with serial echocardiography and genotyped for UGTA1A6*4, SLC28A3 and RARG. 11% of the patients experienced DIC. RESULTS The frequency of SLC28A3 (rs7853758), UGT1A6*4 (rs17863783) and RARG (rs2229774) was 60.7%, 17.9% and 14.3% respectively. No association between DIC and the three variants was observed. CONCLUSIONS This is the first study on the prevalence of DIC and associated genetic biomarker predictive evaluation in Zimbabwean breast cancer patients. The genetic frequencies observed in our study was different to that reported in other populations. A larger sample size with a longer follow up time will be necessary in future studies.

Background: TMS-007, an SMTP family member, modulates plasminogen conformation and enhances plasminogen-fibrin binding, leading to promotion of endogenous fibrinolysis. Its anti-inflammatory action mediated by soluble epoxide hydrolase inhibition contributes to the efficacy. Evidence suggests that TMS-007 can effectively treat experimental thrombotic and embolic strokes with a wide time window while reducing hemorrhagic transformation. Aims: To evaluate the safety, pharmacokinetics, and pharmacodynamics of TMS-007 in healthy volunteers. Methods: A randomized, placebo-controlled, double blind, dose-escalation study, administered as a single intravenous infusion of TMS-007 in cohorts of healthy male Japanese subjects. There were 6 cohorts planned, but 5 were completed. In each cohort (n = 8), individuals were randomized to receive one of 5 doses of TMS-007 (3, 15, 60, 180, or 360 mg; n = 6) or placebo (n = 2). Results: TMS-007 was generally well-tolerated, and no serious adverse events attributed to the drug. A linear dose-dependency was observed for plasma TMS-007 levels. No symptoms of bleeding were observed in brain MRI analysis, and no bleeding-related responses in laboratory testing were found. The plasma levels of the coagulation factor fibrinogen and the anti-fibrinolysis factor 2-antiplasmin levels were unchanged after the TMS-007 dosing. A slight increase in the plasma level of plasmin-α2-antiplasmin complex, an index of plasmin formation, was observed in some subjects who received 360 mg of TMS-007 (≈ 6 mg kg−1). Conclusions: TMS-007 is generally well-tolerated and exhibits favorable pharmacokinetic profiles that warrant further clinical development.

A document by Thomas Svare Ehlers. Click on the document to view its contents.

The European Medicines Agency (EMA) started operating under its new legal mandate on 1 April 2022. The mandate brings new responsibilities to the Agency in three different areas: • Reinforcement of the role and activities of the EMA pandemic Task Force(which is now known as the Emergency Task Force (ETF)). • A stronger role of EMA in the monitoring of shortages of critical medicines, medical devices and in-vitro diagnostics, both in anticipation of and during a crisis. • A more coordinated mechanism of European Union (EU) experts advice on medical devices classified as high-risk (class IIa and III or class D (1)) and in-vitro diagnostic medical devices. Here we consider the impact of the COVID-19 pandemic on the operations of EMA and the European medicines regulatory network, and how EMA’s new mandate will strengthen the Agency’s and the Network’s ability to face crises. EMA’s extended mandate brings clear benefits in terms of response to public health emergencies at EU level, which ranges from improvements in crisis management to avoiding medicine shortages and improving access to diagnostics and medical devices that are safe and conform to their expected function.

Aims: This study aims to evaluate the drug-drug interaction（DDI） between hetrombopag and cyclosporine in healthy Chinese subjects. Methods: Twenty-six eligible subjects enrolled in this single-center, single-sequence, open-label, DDI study with three treatment periods, receiving 5 mg hetrombopag once on day 1, 100 mg cyclosporine twice daily from day 11 to day 15, and 5 mg hetrombopag + 100 mg cyclosporine on day 16. Serial blood samples were collected for pharmacokinetic evaluation. Adverse events were monitored throughout the study. Results: The plasma hetrombopag geometric mean ratios (GMRs) (90% CI) of Cmax, AUC0-t and AUC0-∞ of co-administration of hetrombopag with cyclosporine vs hetrombopag alone are 95.97% (70.08%, 131.43%), 105.75% (75.04%, 149.04%) and 104.19% (74.71%, 145.32%), respectively, indicating multiple doses of cyclosporine had minimal effects on hetrombopag exposure. The GMRs (90% CI) of Cmax and AUCss,tau for blood cyclosporine of co-administration vs cyclosporine alone were 100.49% (91.89%, 109.89%) and 100.81% (107.88%, 103.82%), respectively, suggesting a single dose of hetormbopag had no impact on the exposure of cyclosporine. Co-administration of hetormbopag with cyclosporine was generally well tolerated. Conclusion: No clinically significant DDI was observed when co-administration of hetrombopag with cyclosporine. No additional dose adjustment is warranted for this combination.

Aim: Cisplatin causes acute kidney injury (AKI) in approximately one-third of patients. Serum creatinine and urinary output are poor markers of cisplatin-induced (AKI). Metabolomics was utilized to identify predictive or early diagnostic biomarkers of cisplatin-induced AKI. Methods: Thirty-one adult head and neck cancer patients receiving cisplatin (dose ≥ 70 mg m2 -1) were recruited for metabolomics analysis. Urine and serum samples were collected prior to cisplatin (pre), 24-48 hours after cisplatin (24-48h), and 5-14 days (post) after cisplatin. Based on serum creatinine concentrations measured at the post timepoint, 11/31 patients were classified with clinical AKI. Untargeted metabolomics was performed using liquid chromatography-mass spectrometry. Results: Metabolic discrimination was observed between “AKI” patients and “no AKI” patients at all timepoints. Urinary glycine, hippuric acid sulfate, 3-hydroxydecanedioc acid, and suberate were significantly different between AKI patients and no AKI patients prior to cisplatin infusion. Urinary glycine and hippuric acid sulfate were lower (-2.22-fold and -8.85-fold), whereas 3-hydroxydecanedioc acid and suberate were higher (3.62-fold and 1.91-fold) in AKI patients relative to no AKI patients. Several urine and serum metabolites were found to be altered 24-48 hours following cisplatin infusion, particularly metabolites involved with mitochondrial energetics. Conclusion: We propose glycine, hippuric acid sulfate, 3-hydroxydecanedioc acid, and suberate as predictive biomarkers of predisposition to cisplatin-induced AKI. Metabolites indicative of mitochondrial dysfunction may serve as early markers of subclinical AKI.