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.

Hyperbaric oxygen should not be used routinely for carbon monoxide poisoning: CONDavid N. Juurlink, MD, PhDDepartments of Medicine, Pediatrics, and Health Policy, Management and Evaluation, University of Toronto, the Ontario Poison Centre, and Sunnybrook Research InstituteWord count: 2036

Olanzapine pamoate is an intramuscular depot injection for the treatment of schizophrenia. Approximately 1.4% of patients develop a serious adverse event called Post Injection Delirium/Sedation Syndrome (PDSS); characterised by drowsiness, anticholinergic and extrapyramidal symptoms. The objective is to investigate olanzapine PDSS presentations including clinical features and treatment approach. This is a retrospective review of olanzapine PDSS patients from three toxicology units and the NSW Poisons Information between 2017 and 2022. Adult patients were included if they had intramuscular olanzapine then developed PDSS criteria. Clinical symptoms, treatment, timing and length of symptoms were extracted into a preformatted Excel database. There were 18 patients included in the series, with a median age of 49 years (IQR: 38-58) and male predominance (89%). Median onset time post injection was 30 minutes (IQR: 11-38). PDSS symptoms predominate with drowsiness, confusion and dysarthria. Median length of symptoms was 24 hours (IQR: 20-54). Most common treatment included supportive care without any pharmacological intervention (n=10), benzodiazepine (n=4) and benztropine (n=3). In one case, bromocriptine and physostigmine followed by oral rivastigmine were given to manage anti-dopaminergic and anti-cholinergic symptoms respectively. This proposed treatment combination could alleviate some of the symptoms. In conclusion, this case series supports the characterisation of PDSS symptomology predominantly being anti-cholinergic with similar onset (<1 hour) and duration (<72hours). A combination of bromocriptine and physostigmine followed by rivastigmine is proposed to manage PDSS if patients develop severe dopamine blockade or anti-cholinergic delirium.

Population pharmacokinetic (PK) and pharmacokinetic- pharmacodynamic (PK-PD) models were used to quantify the exposure-response (E-R) relationship between nalbuphine exposure and 2 widely used rating scales for itch: the Numerical Rating Scale for the subject’s ‘average’ itch experience (NRS-AV) and the Worst Itch (WI-NRS), with 24-hour recall. Simulations based on the model E-R relationship were used to support dose selection for future clinical investigations and were evaluated with a target of reducing the 7-day average of the 24-hour WI-NRS by at least 30% from baseline in the majority of the analysis population. Data from two clinical trials (NCT02373215: 9 healthy subjects; NCT02174419: 62 subjects with PN), in patients with Prurigo Nodularis (PN) with moderate to severe itch who received treatment with either of 2 doses of Nalbuphine ER versus placebo, were used for the analysis. A two-compartment PK model with serial zero and first-order oral absorption was used to describe drug exposure. A sigmoidal maximum effect (Emax) model with a placebo effect was used to model the itch response endpoints (NRS-AV, WI-NRS). The PK/PD model adequately predicted the exposure-related reduction in both NRS-AV and WI-NRS over time with approximately 63% and 27% of Emax, respectively. Exposures associated with 80% of Emax were achieved in about 78% of the patients at 162 mg BID compared to 35% at 81 mg BID. Simulated dose-response indicated that 108 and 162 mg BID doses result in the highest proportion of patients achieving at least a 30% reduction in NRS-AV and WI-NRS, respectively.

Aim To clarify the incidence and risk factors of infusion-related reactions (IRRs) to trastuzumab in breast cancer patients and verify the preventive effects of glucocorticoids. Methods The electronic medical record data at the time of trastuzumab administration were retrospectively reviewed. The following exclusion criteria were applied to 229 breast cancer patients who received trastuzumab at Osaka Medical and Pharmaceutical University Hospital during the 4-year study period: missing information on human epidermal growth factor receptor type 2 (HER2) status (n=1); missing information on eosinophils (n=11); or use of treatments other than trastuzumab (n=41). Results The 176 patients included in the study received 2,320 infusions. Fifty-eight patients (33.0%) experienced IRRs, and IRRs occurred in 80 (3.4%) of the 2,320 infusions. Owing to the hierarchical structure of the data, the independence of the observed values was evaluated using the intraclass correlation coefficient. Multivariate multilevel logistic regression analysis showed that premedication with dexamethasone was effective in lowering IRR risk with trastuzumab (mg; per unit; odds ratio, OR=0.62; 95% confidence interval, 95% CI, 0.44‒0.86; p=0.005). Preoperative status (OR=34.7; 95% CI, 5.0–242.0; p<0.001) and high doses of trastuzumab (mg/kg; per unit; OR=59.6; 95% CI, 19.7–180.0; p<0.001) were independent risk factors for IRRs. Conclusion The results of this study suggest that premedication with dexamethasone has a protective effect against IRRs caused by trastuzumab in breast cancer treatment. Future studies are needed to determine the optimal dosing of dexamethasone to prevent IRRs and the impact of dexamethasone on the efficacy of trastuzumab treatment.

Abstract Objective To compare the Liverpool Causality Assessment Tool versus Naranjo Scale for screening suspected adverse drug reaction (ADR) cases. Methods We retrospectively reviewed patient charts with a history of suspected ADR, scored using both instruments and determined how each correlates with laboratory and other investigations. 924 charts from the Clinical Pharmacology Clinic at the London Health Sciences Centre were reviewed and 529 charts contained objective findings to support or against the diagnosis of ADR. The participant age ranged from 1 month old to 93 years. We determined the sensitivity and specificity of Liverpool and Naranjo tools for predicting ADRs with scores ranging from “Possible” to “Definite” were considered positive and “Unlikely/Doubtful” as negative for ADR. These results were confirmed by laboratory or clinical (re-challenge) testing in 529 cases. Results Liverpool causality tool had sensitivity (SN) of 97.2% ± 2.4% and specificity (SP) of 2.3% ± 1.57%. The positive (PPV) and negative predictive values (NPV) were 34.1% and 61.5%, respectively. The Naranjo scale had SN of 81.2% ± 5.69% and SP of 13.2% ± 3.56%. PPV and NPV were 32.7% and 57.5%, respectively. Conclusions The Liverpool Causality Assessment Tool is a more sensitive tool than the Naranjo Scale in the assessment of possible ADRs but both tools have poor specificity. The Liverpool Tool can be a useful screening tool in settings where other tests may not be readily available. However the low PPV and NPV of both instruments suggests pursue further testing is needed to confirm or deny an ADR.

Aim: To identify older patients’ risk factors for drug-related readmissions and assess the preventability of older patients’ drug-related revisits. Methods: Post-hoc analysis of a randomised clinical trial with patients aged ≥ 65 years at eight wards within four hospitals in Sweden. The primary outcome used to identify risk factors was drug-related readmission within 12 months post-discharge. A Cox proportional hazards model was made with sociodemographic and clinical baseline characteristics. Four hundred trial participants were randomly selected and their revisits (admissions and emergency department visits) were assessed to identify potentially preventable drug-related revisits, related diseases and causes. Results: Among 2,637 patients (median age (interquartile range) 81 (74–87) years), 582 (22%) experienced a drug-related readmission within 12 months. Sixteen risk factors (hazard ratio > 1, p < 0.05) related to age, previous hospital visits, medication use, multimorbidity and cardiovascular, liver, lung and peptic ulcer disease were identified. The 400 patients experienced a total of 522 hospital revisits, of which 85 (16%) were potentially preventable drug-related revisits. The two most prevalent diseases and causes related to preventable revisits were heart failure (n=24, 28%) and chronic obstructive pulmonary disease (n=13, 15%), and inadequate treatment (n=23, 27%) and insufficient or no follow-up (n=22, 26%). Conclusion: Risk factors for drug-related readmissions in older hospitalised patients were age, previous hospital visits, medication use and multiple diseases. Potentially preventable drug-related hospital revisits are common and might be prevented through adequate medication use and follow-up in older patients with cardiovascular or lung disease.

Background There is evidence gastrointestinal (GI) motility may play a role in the development of GI cancers. Weak opioids (codeine and dihydrocodeine) decrease GI motility, but their effect on GI cancer risk has not been assessed. Aim To assess the association between weak opioids and cancers of the GI tract. Methods A series of nested case-control studies was conducted using Scottish general practice records from the Primary Care Clinical Informatics Unit Research database. Oesophageal (n=2,432), gastric (n=1,443), and colorectal cancer (n=8,750) cases, diagnosed between 1999 and 2011, were identified and matched with up to five controls. Weak opioid use was identified from prescribing records. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression, adjusting for relevant comorbidities and medication use. Results There was no association between weak opioids and colorectal cancer (adjusted OR=0.96, CI 0.90, 1.02, p=0.15). There was an increased risk of oesophageal (adjusted OR=1.16, CI 1.04, 1.29, p=0.01) and gastric cancer (adjusted OR=1.26, CI 1.10, 1.45, p=0.001). The associations for oesophageal cancer, but not gastric cancer, were attenuated when weak opioid users were compared with users of another analgesic (adjusted OR=1.03 CI 0.86, 1.22, p=0.76 and adjusted OR=1.29 CI 1.02, 1.64, p=0.04 respectively). Conclusion In this large population-based study, there was no consistent evidence of an association between weak opioids and oesophageal or colorectal cancer risk, but a small increased risk of gastric cancer. Further investigation is required to determine whether this association is causal or reflects residual confounding or confounding by indication.

The recent introduction of the European Medical Device Regulation poses stricter legislation for manufacturers developing medical devices in the EU. Many devices have been placed into a higher risk category, thus requiring more data before market approval, and a much larger focus has also been placed on safety. For implantable and Class III devices, the highest risk class, clinical evidence is a necessity. However, the requirements of clinical study design and developmental outcomes are only described in general terms due to the diversity of devices. A structured approach to determining the requirements for the clinical development of high-risk medical devices is introduced, utilising the question-based development framework, which is already used for pharmaceutical drug development. An example of a novel implantable device for haemodialysis demonstrates how to set up a relevant target product profile defining the device requirements and criteria. This can then be used to define specific questions to be answered during clinical development, based upon 5 general questions as specified by the question-based framework. The result is a clear and evaluable overview of requirements and methodologies to verify and track these requirements in the clinical development phase. Development organisations will be guided to the optimal route, also to abandon projects destined for failure in an early stage to minimise development risks. Moreover, the framework facilitates communication with funding agencies, regulators and clinicians, while highlighting remaining “known unknowns” that are to be answered in the post-market phase after sufficient benefit has been established relative to the risks.

A common approach to assess the efficacy of piperacillin is to firstly measure the total concentration, and to afterwards apply a theoretical unbound fraction of 70% to obtain the unbound concentration. However, hypoalbuminemia is a common phenomenon in critically ill patients, resulting in variations in unbound fraction. Therefore, we aimed to simulate the impact of piperacillin unbound fraction fluctuations on the predictive performance of a population pharmacokinetic model and on dosing recommendations of piperacillin. Unbound factors of 70, 75, 80 and 85% were applied to total concentrations of piperacillin administered by continuous infusion from an external dataset. A validated model was used for assessment of predictive performance and to estimate patient clearance. Dosing simulations were performed to evaluate target attainment. Variation in unbound fraction caused minimal impact on piperacillin clearance and target attainment but revealed to influence model evaluation.

We report a case of TEN probably related to Pristinamycin

Aim: Advanced age is an important risk factor for adverse events during procedural sedation. Remimazolam is safe and effective in adults’ gastroscopy sedation. The ideal dose and availability for elderly patients are not well known. We aim to investigate its 95% effective dose (ED95) for elderly patients undergoing gastroscopy, and to assess its safety and efficacy, with propofol as the comparison. Methods: The trial consists of two parts, patients who are over 65 and scheduled for elective outpatient painless gastroscopy were enrolled. In the first part, Dixon’s up-and-down methodology was used to determine the ED95 of remimazolam and propofol for inhibiting body movement during gastroscopic insertion, in combination with 0.2μg/kg remifentanil. In the second part, patients in each group received 0.2μg/kg remifentanil and the ED95 dose of the study drug for sedation induction, adding supplemental doses to maintain sedation depth when necessary. The primary outcome was the incidence of adverse events. The secondary outcome was the recovery time. Results: The ED95 of remimazolam and propofol induction dose were 0.204mg/kg [95% CI (0.175–0.390) mg/kg] and 1.994 mg/kg [95% CI (1. 739–5.955) mg/kg] respectively in gastroscopy. Adverse events were reported in 40.6% of patients in the remimazolam group and 83.1% in the propofol group (p<0.001), whereas the remimazolam group showed a higher incidence of hiccup(p=0.017). A shorter time to awakening (p<0.05) in the remimazolam group was observed. Conclusion: For elderly patients undergoing gastroscopy, the ED95 dose of remimazolam is a safer alternative than propofol when inducing the same sedation depth.

Aims Protein kinase inhibitors (PKI) have revolutionized the prognosis of several types of cancer, justifying the acceleration of their clinical evaluation before they obtain marketing authorization. Pharmacovigilance signals of heart failure (HF) following exposure to PKIs have been detected in recent years. Our objective was to identify the PKIs most frequently associated with the development of HF. Methods Using the French National Healthcare Database, all patients newly exposed to a PKI between January 2011 and June 2014 were followed up for 18 months. Specific hospitalisation diagnosis and long-term disease codes related to HF were used to identify HF patients. HF Incidence Rate Ratios (IRR) were measured and adjusted Hazard Ratios (aHR) were estimated using a Cox model. Results Thirteen PKIs were studied. Among the 49,714 new PKI users during the study period, the mean IRR of HF was 3.38 per 100 person-years, with a median time to onset of 155 days. We found a significant increase in the incidence of HF for 6 drugs: pazopanib (aHR= 2.42, 95% CI: 1.67-3.52), dasatinib (aHR= 2.22, 95% CI: 1.42-3.44), ruxolitinib (aHR= 2.11, 95% CI: 1.69-2.64), crizotinib (aHR= 1.71, 95% CI: 1.07-2.72), everolimus (aHR= 1.45, 95% CI: 1.26-1.67) and vemurafenib (aHR= 1.37, 95% CI: 1.01-1.86). Conclusions Our study provides knowledge on HF following exposure to a PKI. Additional studies could confirm these results for dasatinib, everolimus, pazopanib and ruxolitinib, and particularly for the two drugs with results slightly above the significance threshold, crizotinib and vemurafenib in our sensitivity analyses.

Title:Tranexamic acid-associated fatal status epilepticus in a paediatric patientAuthor:Dr Santosh Patel MD, FRCA, PG Dip (Med Edu)Consultant AnaesthetistDepartment of anaesthesiaTawam hospitalAl AinUnited Arab EmiratesCorrespondence address: as above.Email: [email protected]: No source of funding to declareConflicts of interest: Nothing to declareDear Editor,I have read with interest a case report and literature review published in the British journal of pharmacology on tranexamic acid (TXA) associated SE in a 4-year child who underwent tonsillectomy.1 I would like to congratulate the authors for reporting the case despite the fatal outcome. Considering that the use of TXA is expanding to minimise blood loss in a wide range of surgeries, an evidence-based therapeutic approach for its associated seizures is of paramount importance.The authors described in their report (also mentioned in Table 2) and concluded that general anaesthetics, propofol and halogenated inhaled anaesthetics are considered the first line of management of TXA-associated seizures due to their direct activity at glycine receptors. In support of their statement, they have quoted three references (references 35,45,46 in their report). However, in their articles, the authors did not recommend the use of general anaesthetics (propofol and halogenated inhalational anaesthetics) as the first line of treatment for TXA-related seizures. It is valuable to point out to the readers that their conclusion is not valid and needs clarification and correction.TXA-associated hyperexcitability of neural networks is because it is a competitive antagonist of glycine and GABAA receptors.2 Following IV TXA administration, not all seizures progress to status epilepticus. Although TXA-related seizures commonly manifest as generalised tonic-clonic activity, focal seizures have been reported; which are not an indication for the use of general anaesthetics. Refractory status epileptics (RSE) and super RSE are uncommon following IV TXA although this is a common feature following intrathecal TXA.3Propofol’s anticonvulsant, hypnotic, sedative and anaesthetic effects are mediated via multiple complex molecular mechanisms, including modulation of GABAA and glycine receptors. GABAA receptor modulation by propofol has distinct dose-dependent effects likely involving multiple sites of action; clinical concentrations of propofol potentiate GABA-activated currents, increase open channel frequency, and reduce the rate of desensitization, while intermediate concentrations directly activate GABAA channels, and even higher concentrations inhibit receptor function.4Propofol can cause neuroexcitatory effects, including tonic-clonic seizures, particularly during the start or weaning from propofol infusion.5 Among the various mechanisms that have been proposed for these neuroexcitatory symptoms are antagonism of glycine and dopamine receptors, hyposensitization of GABAergic pathways and dysregulated inhibition of NMDA glutamate receptors.6Its use is associated with side effects, including hypotension (and the associated use of vasopressors) and respiratory depression. With prolonged infusion, propofol infusion syndrome (PIS) may occur, which may contribute to morbidity and mortality of RSE. Children are more susceptible to developing this complication. Propofol infusion therapy is not recommended as the first line of treatment for TXA-associated seizures, and its use is reserved for severe cases in children.Inhalational anaesthetics are beneficial for the control of seizure activity via inhibition of NMDA excitotoxicity and potentiation of inhibitory functions of GABAA and glycine receptors. However, it is essential to highlight that there are several limitations to the use of inhalational anaesthetic agents. First, the only clinical evidence of their use is from the minimal number of case reports. Second, TXA-related seizures often manifest in the postoperative period in the recovery room or in ICU, where delivery and scavenging of inhalational agents via ventilator may not be feasible. Third effective end-tidal concentration and optimal therapeutic duration are not known. Finally, in higher concentrations, they cause cardiac depression and cerebral vasodilation. Therefore, their use is limited as salvage therapy for the management of TXA-associated RSE and super RSE.In summary, the authors’ conclusion is incorrect, and clinicians should follow currently available evidence-based professional guidelines to manage TXA-associated status epilepticus.8,9References:1. Aboul-Fotouh S, Habib MZ, Magdy SM, Hassan BEE. Tranexamic acid-associated fatal status epilepticus in a paediatric non-cardiac surgery: A case report and literature review. Bri J Clin Pharmacol 2022;1-6. doi:10.1111/bcp.152962. Lecker I, Wang D, Whissell P, et al. Tranexamic acid-associated seizures: causes and treatment. Ann of Neurol 2015;79(1):18-26. doi:10.1002/ana.245583. Patel S, Robertson B, McConachie I. (2019). Catastrophic drug errors involving tranexamic acid administered during spinal anaesthesia.Anaesthesia ,74(7),904-14 https://doi.org/10.1111/anae.146624. Platholi J, Hemmings H. (2022). Effects of general anesthetica on synaptic transmission and spasticity. Currt Neuropharmacol2022;20(1):27-54. doi: 10.2174/1570159X19666210803105232.5. Walder B, Tramèr MR, Seeck M. (2002). Seizure-like phenomena and propofol: a systematic review. Neurology 2002; 58(9):1327-32. 10.1212/wnl.58.9.13276. Pantelakis L, Alvarez V, Gex G, Godio M. Severe neuroexcitatory reaction: A rare and underrecognized life-threatening complication of propofol-induced anesthesia. The Neurohospitalist2021;11(1):49-53. doi: 10.1177/1941874420929536.7. Godec S, Gradisek MJ, Mirkovic T etal. Ventriculolumbar perfusion and inhalational anesthesia with sevoflurane in an accidental intrathecal injection of tranexamic acid: unreported treatment options. Reg Anesthe Pain Med 2022;47(1):65-68 10.1136/rapm-2021-1024988. Nelson SE, Varelas PN. Status epilepticus, refractory status epilepticus, and super-refractory status epilepticus. Continuum (Minneap Minn). 2018;24(6):1683-1707.9. Vossler DG, Bainbridge JL, Boggs JG etal.. Treatment of refractory convulsive status epilepticus: a comprehensive review by the American Epilepsy Society Treatments Committee. Epilepsy Curr.2020;20(5):245-64.

Interferon-beta, the most widely prescribed medication for multiple sclerosis, is generally considered safe. Nevertheless, rarely serious and/or life-threatening side effects have been reported such as thrombotic microangiopathy. A few mechanisms have been proposed to explain how interferon causes thrombotic microangiopathy, but insufficient immunological studies have been unable to pin this phenomenon down to a single pathophysiologic pathway. We report thrombotic microangiopathy due to acquired complement factor I deficiency in a male receiving interferon-beta treatment for multiple sclerosis. After three years of starting the therapy, the 28-year-old patient presented with malignant hypertension causing seizures, rapidly progressive renal failure requiring hemodialysis, and hemolytic anemia. Corticosteroid and plasma exchange sessions permitted hemolysis control. Nonetheless, the patient remained hemodialysis-dependent. Exploration of the complement system found a complement factor I deficiency whose activity normalized at the control carried out after two years. We concluded that IFNβ treatment may cause complement factor I deficit, which can lead to thrombotic microangiopathy and severe renal failure.

This case report describes of a pharmacokinetic drug–drug interaction between crizotinib, a tyrosine kinase inhibitor, and sofosbuvir/velpatasvir, a direct-acting antiviral drug, leading to cardiac toxicity. A 75-year-old man, with no cardiovascular history but a diagnosis of metastatic non-small cell lung cancer with MET exon-14 deletion and hepatitis C virus infection genotype 1A, received both crizotinib and sofosbuvir/velpatasvir. Crizotinib was well tolerated, but 1 week after sofosbuvir/velpatasvir initiation, the patient experienced bilateral lower-limb edema and class III NYHA dyspnea. We assumed that increased exposure to crizotinib could account for this cardiac toxicity. Drug causality was probable according to the Naranjo scale. We hypothesized a reciprocal interaction between crizotinib and velpatasvir, mediated by both cytochrome 3A4 (CYP3A4) and P-glycoprotein (P-gp). Clinicians should be aware of the risk of drug–drug interactions between direct-acting antiviral agents that inhibit CYP3A4 (glecaprevir) and/or P-gp (voxilaprevir) and anticancer tyrosine kinase inhibitors that are mostly CYP3A4 and/or P-gp substrates (gefitinib, afatinib, erlotinib, crizotinib, ceritinib, lorlatinib, brigatinib, capmatinib etc.).