Erik Eliasson

Background and purpose: The clinical significance of individual CYP2D6 activity for the outcome of tamoxifen treatment in early breast cancer is unclear. Our previous investigation in patients diagnosed over the period 1998–2000 indicated an association between reduced CYP2D6 activity and poor outcome in premenopausal women. The aim of this study was to investigate the association between CYP2D6 genotype and clinical outcome in a larger tamoxifen treated cohort. Patients/material and methods: Swedish breast cancer patients who initiated adjuvant tamoxifen treatment over the period 2006–2014 constituted the full study cohort. Clinical information was collected from medical records. Data on endocrine treatment, use of CYP2D6 inhibitors was retrieved from the Swedish Prescribed Drug Register. CYP2D6 was genotyped and translated into predicted metabolic activity. The association between CYP2D6 activity and clinical outcome was analyzed using Cox regression, controlling for potential confounding variables. Subgroup analyses were performed based on menopausal status, tamoxifen treatment for at least 1 year and as single endocrine treatment, HER2-status and tamoxifen monotherapy. Results: A total of 1,103 patients were included. A total of 761 patients received tamoxifen as monotherapy. A total of 42% were premenopausal. Median follow-up was 11.4 years. No significant association was found between CYP2D6 activity and recurrence (adjusted hazard ratio [aHR] 1.18, 95% CI 0.92; 1.52) or breast cancer mortality (aHR 1.41, 95%CI 0.93; 2.13) in the full cohort, or in the subgroup with tamoxifen monotherapy (aHR 1.39, CI 0.99; 1.96 and 1.88, CI 0.98; 3.60 respectively). Interpretation: No association was noted between reduced CYP2D6 activity and poorer outcome in this early breast cancer cohort, with patients generally at lower risk of recurrence, reflecting the role of adjuvant tamoxifen in current clinical practice.

Without drug treatment, invasive fungal infections are associated with very high mortality. The use of antifungal agents needs to be personalised with regards to infective agent, dose regimen, drug-drug interactions, and tolerability or drug safety issues. Therapeutic drug monitoring (TDM) may help to optimise drug therapy in the individual case, but the clinical indications for TDM differ between different antifungal agents. Here, we aim to summarise the current, clinical view on antifungal TDM in relationship to the clinical pharmacology of each drug.

Background: Ultrafiltration (UF) is a conventional method for isolating the protein-unbound plasma fractions of therapeutic drugs. However, the ideal UF conditions for specific compounds remain largely unexplored. By comparing UF-derived unbound concentrations with the corresponding results obtained using a reference method, the authors sought to identify appropriate UF conditions for cefotaxime, cloxacillin, flucloxacillin, and piperacillin. Methods: In vitro microdialysis (MD) with a no-net-flux approach was used as a reference method for plasma protein separation, for which UF performance was assessed. Four levels of relative centrifugal force (2500–11,290 g ) and 2 levels of temperature (37 vs. 22°C) during 10 minutes of UF centrifugation were evaluated. Ultrafiltrates and reference microdialysates were analyzed using liquid chromatography-tandem mass spectrometry to obtain unbound concentrations. After identifying the appropriate UF conditions in the spiked plasma samples, exploratory analyses of clinical samples (n = 10 per analyte) were performed. Results: Of the evaluated UF alternatives, the best overall agreement with the MD-derived reference concentrations was obtained with 11,290 g UF performed at 22°C. For cloxacillin specifically, 37°C UF yielded better agreement than 22°C UF at 11,290 g. Clinical sample analyses indicated minimal differences between 22°C and 37°C at 11,290 g UF for cefotaxime and piperacillin. However, consistently lower levels of unbound cloxacillin (median: −23%, IQR: −19% to −24%) and flucloxacillin (median: −27%, IQR: −21 to −34%) were observed after UF at 22°C versus 37°C. Conclusions: For the evaluated UF device, 10 minutes of 11,290 g UF at 22°C is appropriate for flucloxacillin, cefotaxime, and piperacillin, and can arguably be justified for cloxacillin as well for laboratory practice purposes. Maintenance of 37°C during high-centrifugal UF may lead to overestimation, particularly for unbound flucloxacillin.

Purpose: Change in mammographic density has been suggested to be a proxy of tamoxifen response. We investigated the effect of additional adjuvant systemic therapy and CYP2D6 activity on MD change in a cohort of tamoxifen-treated pre- and postmenopausal breast cancer patients. Methods: Swedish breast cancer patients (n = 699) operated 2006–2014, genotyped for CYP2D6, having at least three months postoperative tamoxifen treatment, a baseline, and at least one follow-up digital mammogram were included in the study. Other systemic adjuvant treatment included chemotherapy, goserelin, and aromatase inhibitors. Change in MD, dense area, was assessed using the automated STRATUS method. Patients were stratified on baseline characteristics, treatments, and CYP2D6 activity (poor, intermediate, extensive, and ultrarapid). Relative density change was calculated at year 1, 2, and 5 during follow-up in relation to treatments and CYP2D6 activity. Results: Mean relative DA decreased under the follow-up period, with a more pronounced MD reduction in premenopausal patients. No significant effect of chemotherapy, aromatase inhibitors, goserelin, or CYP2D6 activity on DA change was found. DA did not revert to baseline levels after tamoxifen discontinuation. Conclusion: Our results indicate that other systemic adjuvant therapy does not further reduce MD in tamoxifen-treated breast cancer patients. We could not confirm the previously suggested association between CYP2D6 activity and MD reduction in a clinical setting with multimodality adjuvant treatment. No rebound effect on MD decline after tamoxifen discontinuation was evident.

Purpose: To study the association between interacting drugs and bleeding or thromboembolism in atrial fibrillation outpatients treated with non-vitamin K antagonist oral anticoagulants (NOACs). Methods: Population-based cohort study of outpatients treated with NOACs in Sweden from 2008 to 2017. Patients with atrial fibrillation and newly initiated NOAC treatment were identified in the Prescribed Drug Register. Comorbidities and outcome data were retrieved from the Patient Register and the Cause of Death Register. Cox-regression analyses were performed to evaluate the primary endpoints any severe bleed and ischemic stroke/transient ischemic attack/stroke unspecified during the first six months of treatment. Secondary endpoints were gastrointestinal bleeding, intracranial bleeding, ischemic stroke, and venous thromboembolism. Results: Increased risk of any severe bleed was found when NOAC treatment, and drugs with pharmacodynamic effect on bleeding were combined, compared to NOAC only. An increased risk with these combinations was evident for apixaban (hazard ratio (HR) 1.47; 95% CI 1.33–1.63), rivaroxaban (HR 1.7; 95% CI 1.49–1.92), and dabigatran (HR 1.26; 95% CI 1.05–1.52). For apixaban, there was an increased risk of any severe bleed when combined with CYP3A4 and/or P-glycoprotein (P-gp) inhibitors (HR 1.23; 95% CI 1.01–1.5). The use of inducers of CYP3A4 and/or P-gp was low in this cohort, and effects on ischemic stroke/TIA/stroke unspecified could not be established. Conclusion: Increased risk of bleeding was seen for pharmacodynamic and pharmacokinetic interactions with NOACs. Prescribers need to be vigilant of the effect of interacting drugs on the risk profile of patients treated with NOACs.

In a recent Swedish register study, a limited number of specific drugs explained a large part of clinically relevant, potential drug-drug interactions (DDI), as defined and detected by the DDI database SFINX. Regarding interactions that should be avoided according to the definition in the database (class D), 15 drug combinations accounted for as much as 80 % of the prevalence in the Swedish population. Ten specific drugs were involved in 94 % of all detected class D interactions. About half of the clinically relevant interactions detected during the four-month study period were associated with an increased risk of adverse drug reactions, whereas the other half has a potential to cause therapeutic failure. An increased awareness among prescribers of these interacting drugs could contribute to safer and more effective drug use.

Patients with severe sepsis/septic shock have a high mortality. Beta-lactam antibiotics are normally first line treatment. This antimicrobial class has been associated with time-dependent efficacy. It is therefore plausible that administration as prolonged infusion will increase the therapeutic effect, as compared to short term bolus injections, which is the most common practice today. We have reviewed 14 randomized controlled studies to investigate whether prolonged infusion provides lower mortality and/or increased clinical cure. In summary, convincing advantages with prolonged infusion could not be found, however randomized studies are heterogeneous, and it cannot be excluded that some subgroups of critically ill patients could benefit from such treatment.

The cytochrome P450 (CYP) 2C8*3 allele is associated with reduced metabolic activity of paclitaxel. This study was aimed to investigate the inhibitory effect of losartan on paclitaxel metabolism in human liver microsomes (HLMs) and to determine the impact of theCYP2C8*3 polymorphism.HLMs that contained theCYP2C8*1 homozygote (HL60) orCYP2C8*3 heterozygote (HL54) genotype were used for the inhibition study. Losartan, at a concentration of 50 μmol/L, significantly inhibited paclitaxel metabolism by 29% and 57% in theHL60 (p < 0.001) andHL54 (p < 0.01), respectively. When usingHL60, losartan and theCYP3A4‐selective inhibitors, erythromycin and ketoconazole, caused a greater inhibition of the paclitaxel metabolism than quercetin, aCYP2C8‐selective inhibitor. This demonstrated that the paclitaxel metabolism was mainly catalysed byCYP3A4 inHL60. There were no significant differences found for the inhibitory effects caused by the four inhibitors of the paclitaxel metabolism inHL54, indicating that bothCYP2C8 andCYP3A4 play important roles in paclitaxel metabolism inHL54. These findings suggest that 50 μmol/L of losartan inhibits bothCYP2C8 andCYP3A4 inHLMs. In summary, losartan inhibited paclitaxel metabolism, with concentrations over 50 μmol/L in HLMs. The CYP2C8*3 allele carriers are likely susceptible to the interactions of losartan and CYP3A4 inhibitors to paclitaxel metabolism.