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.

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.

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

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.

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.).

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.

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.

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 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.

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.

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.

Aim: Although there is a high risk of gastrointestinal (GI) bleeding in the elderly, few studies have quantified the impact of risk factors on GI complications in elderly nonsteroidal anti-inflammatory drug (NSAID) users. This study aimed to develop and validate a risk prediction score to identify high-risk elderly patients using NSAID for severe GI complications. Methods: We used the following two Korean claims datasets: customized data with an enrollment period 2016–2017 for model development, and the sample data in 2019 for external validation. We conducted a nested case-control study for model development and validation. NSAID users were identified as the elderly (≥ 65 years) who received NSAIDs for more than 30 days. Patients who experienced serious GI complications, defined as hospitalizations or emergency department visits, were diagnosed with GI bleeding or perforation. We derived a model using logistic regression and cross-validation. Results: In the external validation cohort, we identified 372 cases from 254,551 patients. We identified 8,176 cases and 81,760 controls with a 1:10 matched follow-up period in the derivation cohort. In the external validation cohort, we identified 372 cases from 254,551 patients. The risk predictors were high-dose NSAIDs, NSAID type, complicated GI ulcer history, male sex, concomitant gastroprotective agents, relevant co-medications, severe renal disease, and cirrhosis. Area under the receiver operating characteristic curves was 0.77 (95% confidence interval, 0.75–0.80) in the external validation dataset. Conclusion: The prediction model may be a useful tool for reducing the risk of serious GI complications by identifying high-risk elderly patients.

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.

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.

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 field of pharmacometrics has been responsible for countless advancements within the drug development space. In recent years, we have witnessed the implementation of both new and revived analytical methods to increase clinical trial success and even supplement the need for clinical trials all together. Throughout this article we will explore the path of pharmacometrics from its inception to present day. At this point in time, the target of drug development has been the average patient, and population approaches have primarily been utilized to support just that. The challenge we are now facing involves the translation from treating the typical patient to treating the real-world patient. For this reason, it is our opinion that future development efforts should account more for the individual. With advanced pharmacometric methods and growing technological infrastructure, precision medicine can become a development priority rather than a clinician's burden.

Bleomycin is an antibiotic with cytotoxic properties, commonly used in combination regimens for the treatment of Hodgkin lymphoma. The inconsistency in dosage nomenclature of bleomycin seems to be universal in many countries, which increases the risk of medication error. However, as far as we know no cases have reported. Here we present a case report of a medication error caused by bleomycin overdose. A 25-year-old patient with Stage II Hodgkin Lymphoma received a 150 USP bleomycin, which dosage was ten times higher than usually used, as part of the doxorubicin, bleomycin, vindesine, dacarbazine protocol (ABVD) at the third cycles of chemotherapy. After the medication error was found, the patient was immediately treated with intravenous rehydration and furosemide to promote clearance of drugs. To prevent lung injury, the methylprednisone and acetylcysteine was given. The patient developed a slight nausea and a mild rash, which gradually improved after the treatment. After the evaluation with PET-CT, the patient received four cycles of AVD chemotherapy. During the treatment and one-year follow-up period, no other obvious abnormalities were observed. The toxicities, clinical managements and selection of further chemotherapy after bleomycin overdose deserved serious attention in this case. More importantly, the management measures after this error can be used for reference in other hospitals.