Tamoxifen is the most used hormonal therapy for estrogen receptor positive breast cancer. CYP2D6 is the main enzyme in the metabolic pathway of tamoxifen to endoxifen. Variations in endoxifen plasma concentrations are associated with CYP2D6 polymorphisms. This study aimed to determine the association between the CYP2D6 polymorphisms and endoxifen plasma concentrations in a cohort of Zimbabwean breast cancer patients (n = 40). TaqMan genotyping and copy number assays were done to determine CYP2D6 genotypes. Tamoxifen and metabolites were quantitated using LC-MS/MS. The population had high frequencies of the CYP2D6 reduced function alleles, *17 (15%) and *29 (18%). The median endoxifen concentration was 4.78 ng/ml and 55% of the patients, mostly intermediate metabolizers were below the endoxifen therapeutic threshold 5.97 ng/ml. The CYP2D6 phenotypes and activity scores were significantly associated with endoxifen plasma concentrations (p = 0.0151) and with endoxifen to N-desmethyl tamoxifen ratios (p = 0.0006).

Aim: This study was conducted to develop a population pharmacokinetic (PK) model of methotrexate in Korean patients with hematologic malignancy, identify factors affecting methotrexate PK, and propose optimal dosage regimen for the Korean population. Methods: Data were retrospectively collected from 188 patients with acute leukemia or non-Hodgkin’s lymphoma who were admitted to Severance Hospital for the period from 2005 to 2015. Using demographic factors and laboratory results as potential covariates for PK parameters, model development was performed using NONMEM and optimal dosing regimens were developed using the final PK model. Results: A two-compartment model incorporating body weight via allometry best described the data, yielding typical parameter values of 25.99L for central volume of distribution (V_1), 18.76L for peripheral volume of distribution (V_2), 12.9L/h for clearance (CL) and 0.646L/h for inter-compartmental clearance. Covariate analyses showed that, at the weight of 50kg, CL decreased by 0.11 L/h for each one-year increase in age above 14 years old and decreased to 0.8-fold when serum creatinine level doubled, indicating the importance of age-specific dose individualization in methotrexate treatment. Volume of distribution at steady state derived from PK parameters (=V_1+V_2) was 0.90L/kg, which was similar to those in the Western or Chinese population. Optimal doses simulated from the final model successfully produced the PK measures close to the target chosen. Conclusion: The population PK model and optimal dosage regimens developed in this study can be used as a basis to achieve precision dosing in Korean patients with hematologic malignancy.

Purpose Chemodenervation with botulinum neurotoxin type A (BoNTA) is the preferred method for focal spasticity management among various treatment options. While BoNTA injection is considered safe, its widespread use and increasing evidence raise safety concerns. Case In this paper, we present a patient with central pontine myelinolysis, a rare disease, who developed Acute Respiratory Distress Syndrome (ARDS) on the third day after BoNTA application to the spastic gastrocnemius muscle group and required intubation in the intensive care unit due to this complication. Conclusion To our knowledge, this is the first case reported in the literature to develop an acute pulmonary complication after BoNTA injection into spastic lower extremity muscles.

Whole bowel irrigation is a method of gastric decontamination in the poisoned patient involving administration of large volumes of osmotically balanced polyethylene glycol-electrolyte solution to empty the gastrointestinal tract of ingested toxins before absorption, limiting systemic toxicity. While this approach may seem intuitive and it can lead to expulsion of tablets or packets in the rectal effluent, there is a lack of evidence correlating this with improved patient outcomes. Administration of whole bowel irrigation is also challenging to the inexperienced physician and associated with adverse effects, which may be serious. Recommendations for the consideration of whole bowel irrigation are limited to patients who have ingested modified release preparations, those of have ingested pharmaceuticals not adsorbed by activated charcoal, and for the removal of packages in body packers. Until more robust evidence is available from high-quality prospective studies demonstrating efficacy, the use of whole bowel irrigation should not be used routinely in poisoned patients.

Background: Several medicinal treatments for avoiding post-operative ileus (POI) after abdominal surgery have been evaluated in randomised controlled trials. This network meta-analysis aimed to explore the relative effectiveness of these different treatments on ileus outcome measures. Methods: A systematic literature review was performed to identify randomised controlled trials (RCTs) comparing treatments for post-operative ileus following abdominal surgery. A Bayesian network meta-analysis was performed. Direct and indirect comparisons of all regimens were simultaneously compared using random-effects network meta-analysis. Results: A total of 38 randomised controlled trials were included in this network meta-analysis reporting on 6371 patients. Our network meta-analysis shows that prokinetics significantly reduce the duration of first gas (Mean difference (MD) (hours) – 16; credible interval - 30, - 3.1; surface under the cumulative ranking curve (SUCRA) 0.418), duration of first bowel movements (Mean difference (MD) (hours) -25; credible interval - 39, - 11; SUCRA 0.25) and duration of post-operative hospitalisation (Mean difference (MD) (hours) – 1.9; credible interval – 3.8, - 0.040; SUCRA 0.34). Opioid antagonists are the only treatment that significantly improve the duration of food recovery (Mean difference (MD) (hours) - 19; credible interval - 26, - 14; SUCRA 0.163). Conclusion: Based on our meta-analysis, the two most consistent pharmacological treatments able to effectively reduce POI after abdominal surgery are prokinetics and opioid antagonists. The absence of clear superiority of one treatment over another highlights the limits of the pharmacological principles available.

The practice of documenting pharmacists’ interventions (PIs) has been endorsed by many hospital pharmacists’ societies and organizations worldwide. Current systems for recording PIs have been developed to generate data on better patient and healthcare outcomes, but harmonization and transferability are apparently minimal. The present work aims to provide a descriptive and comprehensive overview of the currently utilized PIs documentation and classification (D/C) tools contributing to increased evidence systematization. A systematic literature search was conducted in PUBMED, Scopus, Web of Science and CINAHL. Studies from 2008, after the release of the Basel Statements, were included if interventions were made by the hospital or clinical pharmacists in a global hospital setting. Publications quality assessment was accomplished using the Mixed Methods Appraisal Tool (MMAT). A total of 26 studies were included. Three studies did not refer to the D/C method, 10 used an in-house developed D/C method, seven used externally developed D/C tools and six studies described method validation or translation. Evidence confirmed that most of the D/C systems are designed in-house, but external development and validation of PI systems to be used in hospital practice is gradually increasing. Reports on validated PIs D/C tools that are being used in hospital clinical practice are limited, including countries with advanced hospital pharmacy practice. Unmet needs and gaps in practice were identified. Further research should be conducted to understand why using validated D/C methods is not a disseminated practice, knowing patients’ and organizational advantages.

AIMS The aim of this umbrella review was to identify tools and guidelines available to aid the deprescribing process of potentially inappropriate medications (PIM), evaluate their methods of development and validation, and describe at what level of evidence medications are included in the tools and guidelines. METHODS Searches were conducted on MEDLINE(Ovid), Embase.com, Cochrane CDSR, CINAHL (EBSCO), Web of Science Core Collection, and guideline databases from the date of inception to July 7, 2022. We described and compared the different characteristics and contents of tools and guidelines. RESULTS From 10,606 records screened, 23 systematic reviews and guidelines met the inclusion criteria. We then identified 90 tools (67 explicit, 12 mixed, 11 implicit), and 9 guidelines. The majority were developed for use in older adults (n = 74). Nineteen tools targeted older adults with limited life expectancy (LLE), and 7 targeted children <18 years. The majority (97%) of explicit/mixed tools were validated through Delphi techniques (n = 61). Two tools and eight guidelines provided information on the level of evidence for the included medications, of which less than a quarter were included based on high-quality evidence. CONCLUSION Existing tools are available for a diversity of populations. Discrepancies identified in categorizing medications as appropriate or not can be a result of low quality evidence. Particularly, tools for patients with LLE were developed based on very limited evidence, and research to generate this evidence is highly needed. Our medication lists, along with the level of evidence, could facilitate efforts to strengthen the evidence.

Aim: This study evaluated the effects of SHR0302 on the pharmacokinetics of cytochrome P450 (CYP) probe substrates. Methods: We performed a single-center, open-label, three-period drug-drug interaction (DDI) study in 24 healthy subjects (NCT05392127). Subjects received a single oral dose of 5 mg warfarin (CYP2C9), 20 mg omeprazole (CYP2C19), and 15 mg midazolam (CYP3A4) on day 1, 8, and 22, and received 0.5 mg repaglinide (CYP2C8) on day 7, 14, and 28. Multiple oral doses of 8 mg SHR0302 were administered once daily from day 8 to day 28. Results: The exposure of S-warfarin and repaglinide were comparable before and after SHR0302 administration. AUC of midazolam was not affected by SHR0302, whereas the administration of SHR0302 slightly decreased the Cmax of midazolam by 7.6% (single dose) and 15.7% (once daily for 14 days). The AUC0-t, AUC0-inf, and Cmax of omeprazole were slightly decreased after a single dose of SHR0302 by 19.2%, 21.8%, and 23.5%, respectively. In the presence of SHR0302 for 14 days, the AUC0-t, AUC0-inf, and Cmax of omeprazole were marginally reduced by 3.0%, 16.4%, and 8.3%, respectively. According to the induction mechanism of the CYP enzyme, for the investigation of the induction effect, the results of multiple administration of the perpetrator were more reliable than those of the single dose. Conclusion: The results demonstrated that co-administration of SHR0302 is unlikely to have a clinically meaningful effect on the exposure of drugs metabolized by CYP3A4, CYP2C8, CYP2C9, and CYP2C19 in healthy subjects.

C. Abstract AIM: Sevoflurane is an ether-based inhalational anesthetic that induces and maintains general anesthesia. Our study aimed to detect sevoflurane-induced nephrogenic diabetes insipidus using Data Mining Algorithms (DMAs) and molecular docking. The FAERS database was analyzed using OpenVigil 2.1 for disproportionality analysis. Methods: We analyzed FAERS data from 2004 to 2022 to determine the incidence of nephrogenic diabetes insipidus associated with sevoflurane. Reporting Odds Ratios (RORs) and Proportional Odds Ratios (PRRs) with 95% confidence intervals were calculated. We also used molecular docking with AutoDock Vina to examine sevoflurane’s binding affinity to relevant receptors. Results: A total of 554 nephrogenic diabetes insipidus cases were reported in FAERS, of which 2.5% (14 cases) were associated with sevoflurane. Positive signals were observed for sevoflurane with reporting odds ratios (ROR) of 76.012 (95% CI: 44.67-129.35) and proportional odds ratios (PRR) of 75.72 (Chi-sq: 934.688). Of the 14 cases, 50% required hospitalization, 14% resulted in death, and the remaining cases were categorized as other outcomes. Molecular docking analysis showed that sevoflurane exhibited high binding affinity towards AQP2 (4NEF) and AVRP2 (6U1N) with docking scores of -4.9 and -5.3, respectively. Conclusion: Sevoflurane use is significantly associated with the incidence of nephrogenic diabetes insipidus. Healthcare professionals should be cautious when using this medication and report any adverse events to regulatory agencies. Further research is needed to validate these findings and identify risk factors while performing statistical adjustments to prevent false-positives. Clinical monitoring is crucial to validate potential adverse effects of Sevoflurane.

Aim Dysfunction of nitric oxide (NO) – soluble guanylate cyclase (sGC) – cyclic guanosine monophosphate (cGMP) signalling is implicated in the pathophysiology of cognitive impairment and dementia. Zagociguat is a central nervous system-(CNS-) penetrant sGC stimulator designed to amplify NO-cGMP signalling in the CNS. This article reports on a phase 1b study evaluating the safety and pharmacodynamic effects of zagociguat. Methods In this randomized crossover study, 24 healthy participants ≥65 years of age were planned to receive 15 mg zagociguat or placebo once daily for two 15-day periods separated by a 27-day washout. Adverse events, vital signs, electrocardiograms, and laboratory tests to assess safety. Pharmacokinetics of zagociguat were evaluated in blood and CSF. Pharmacodynamic assessments included evaluation of cerebral blood flow, CNS tests, pharmaco-electroencephalography, passive leg movement, and biomarkers in blood, cerebrospinal fluid, and brain. Results Twenty-four participants were enrolled and 12 participants completed both treatment periods, while 12 participants completed only one treatment period. Zagociguat was well tolerated and penetrated the blood-brain barrier. Zagociguat induced modest decreases in blood pressure. No consistent effects of zagociguat on other pharmacodynamic parameters were detected. Conclusion Zagociguat was well tolerated and induced modest systemic blood pressure reductions consistent with other sGC stimulators. No clear pharmacodynamic effects of zagociguat were detected, perhaps due to optimal CNS function in healthy participants. Studies in participants with proven reduced cerebral blood flow or CNS function may be an avenue for further evaluation of the compound.

Aims: Older adults are vulnerable to medication-related harm mainly due to high use of medications and inappropriate prescribing. This study aimed to investigate the associations between inappropriate prescribing and number of medications identified at discharge from geriatric rehabilitation with subsequent post-discharge health outcomes. Method: REStORing health of acutely unwell adulTs (RESORT) is an observational, longitudinal cohort study of geriatric rehabilitation inpatients. Potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs) were measured at acute admission, and at admission and discharge from geriatric rehabilitation, using version 2 of the STOPP/START criteria. Results: 1890 patients (mean age 82.6 ± 8.1 years, 56.3 % females) were included. The use of at least 1 PIMs, or PPOs at geriatric rehabilitation discharge were not associated with 30-day and 90-day readmission and 3-month and 12-month mortality. Central nervous system (CNS)/psychotropics and fall risk PIMs were significantly associated with 30-day hospital readmission (adjusted odds ratio (AOR) 1.53; 95%CI 1.09─2.15), and cardiovascular PPOs with 12-month mortality (AOR 1.34; 95%CI 1.00─1.78). Increased number of discharge medications was significantly associated with 30-day (AOR 1.03; 95%CI 1.00─1.07) and 90-day (AOR 1.06; 95%CI 1.03─1.09) hospital readmissions. The use and number of PPOs (including vaccine omissions) were associated with reduced independence in instrumental activities of daily living scores at 90-days post geriatric rehabilitation discharge. Conclusion: The number of discharge medications, CNS/psychotropics and fall risk PIMs were significantly associated with readmission, and cardiovascular PPOs with mortality. Interventions are needed to improve appropriate prescribing in geriatric rehabilitation patients to prevent hospital readmission and mortality.

Pharmacometrics, the mathematical approaches to describe the transfer of drug through different biological compartments, are essential tools in clinical pharmacology research. The ethical necessity to study drugs accurately in the populations where they are to be used is increasingly recognized. To maximise the value of clinical data, study design and analysis must be appropriate. Historically, many datasets have been sent from African countries to better-resourced settings for analysis, but in recent years it has been demonstrated that capacity can be built and sustained within low and middle-income countries (LMIC)3. We report the establishment of the Uganda Chapter of Pharmacometrics Africa, to share learning with other countries seeking to build similar capabilities.

A document by Ranjeeta Sinvhal. Click on the document to view its contents.

Novel Gonadotrophin Releasing Hormone (GnRH) antagonist treatments have recently been developed in combination with hormonal add-back therapy, as an oral treatment option for women suffering from uterine fibroids. Registration trials assessing the GnRH antagonist combination preparations with relugolix, elagolix, and linzagolix have assessed treatment efficacy for fibroid related heavy menstrual blood loss in comparison to placebo. Marketing authorization has already been granted by several agencies including those in Europe, the United Kingdom, and the United States. Prior to marketing authorization, the European Medicines Agency recommends that Phase III registration trails should assess treatment efficacy in a representative study population, assess relevant outcomes with a comparison to gold-standard alternative treatment options and that long-term safety data will adequately be collected. In this review, we demonstrate limitations in the trial data generated to date, namely a lack of generalizability due to the restricted population studied, the absence of any comparison to alternative treatment methods, and findings limited to specific subgroups of patients because of the type of outcomes assessed. Symptoms related to uterine fibroids adversely affect many women’s quality of life and effective medical treatments are lacking. However, despite the urgent need for effective treatments, it is vitally important that novel drugs, like combination oral GnRH antagonists, undergo sufficiently rigorous evaluation of safety, effectiveness, and cost-effectiveness in a representative population compared with alternative treatment methods before introduction into mainstream clinical practice.

Health systems encourage switching from originators to biosimilars as biosimilars are more cost-effective. The speed and completeness of biosimilar adoption is a measure of efficiency. We describe the approach to biosimilar adoption at a single hospital and compare its efficiency against the English average. We additionally follow up patients who reverted to a previously used biologic, having switched to a biosimilar, to establish whether they benefitted from re-establishing prior treatment. The approach we describe resulted in a faster and more complete switch to biosimilars, which saved an additional £380,000 on drug costs in 2021/22. Of patients who reverted to their original biologic, 85% improved short-term where the concern was tolerability, and 90% where it was efficacy. Patients remained on treatment for a prolonged period after reverting. Our approach to biosimilar adoption outperformed the English average and permits patients to revert to their original biosimilar post-switch if appropriate.

Aim: Nirmatrelvir as a new 3CL protease inhibitor for treating COVID-19 drug of antiviral drug, the potential side effects have not yet been fully studied yet. The aim of this study was to identify potential risk of Nirmatrelvir by analyzing post-marketing safety data based on the largest publicly available worldwide pharmacovigilance database. Methods: We analyzed Nirmatrelvir adverse events to detect and characterize relevant safety signals based on the FDA Adverse Event Reporting System database in 2022. Case/non-case approach were used to estimate the reporting odds ratio (ROR) and information component (IC) with relevant confidence intervals (95% CI) for AEs with ≥4 counts. Results: Total of 26846 cases were included. Disease recurrence [ROR(95%CI)=413.2(395.6-431.59)], dysgeusia [ROR(95%CI)=110.84(106.04-115.85)], anosmia [ROR(95%CI)=15.21(12.76-18.11)], ageusia [ROR(95%CI)=9.80(8.50-11.3)] and urticaria [ROR(95%CI)=1.91(1.69-2.17)] were the main safety signals. In addition, abdominal pain upper and skin toxicity were two specific safety signals of Nirmatrelvir. In pregnant population, a significant increased ROR was found in life-threatening [ROR(95%CI)=5.12(1.38-19.00)]. Conclusion: We identified that disease recurrence, dysgeusia, abdominal pain upper and skin toxicity were the main and specific safety signals of Nirmatrelvir. Clinician and pharmacist should pay attention on these AEs. Notably, a potential risk of Nirmatrelvir in pregnant population should be alerted.

Aims: Mirvetuximab soravtansine is the first-in-class antibody-drug conjugate approved in November 2022 for the treatment of folate receptor-α positive ovarian cancer. The aim of this study was to develop a population pharmacokinetic (PK) model to describe the concentration-time profiles of mirvetuximab soravtansine, the payload (DM4) and a metabolite (S-methyl-DM4). Methods: Mirvetuximab soravtansine was administered intravenously from 0.15 to 7 mg/kg to 543 patients with predominantly platinum-resistant ovarian cancer in three clinical studies, and the plasma drug concentrations were analyzed using a nonlinear mixed-effects modelling approach to estimate the PK parameters, inter-individual variabilities, and residual errors. Stepwise covariate modelling was performed to identify covariates. Results: We developed a semi-mechanistic population PK model that included linear and nonlinear routes for the elimination of mirvetuximab soravtansine and a target compartment for the formation and disposition of the payload and metabolite in tumor cells. The model adequately described the concentration-time profiles for the three analytes. Patient body weight, serum albumin, and age were identified as the major covariates. Exposures in patients with renal or hepatic impairment were estimated. The effect of inhibition of cytochrome P450 (CYP) 3A4 on drug exposures was also evaluated. Conclusions: There is no need for dose adjustment due to covariate effects for mirvetuximab soravtansine administered at the recommended dose of 6 mg/kg based on adjusted ideal body weight. The model also showed that dose adjustment is not required for patients with mild or moderate renal impairment, mild hepatic impairment, or when concomitant weak and moderate CYP3A4 inhibitors are used.

Abstract Drug-drug interactions (DDIs) are common in cancer management and complicate the choice of anticoagulation in cancer-associated thrombosis. Cancer patients incur an increased risk of thrombotic events. Also, more bleeding events are observed in those who receive anticoagulation compared to those without cancer. In the treatment of cancer-associated thrombosis, non-vitamin K oral anticoagulants (NOACs) are at least as effective as low-molecular weight heparins, which became the standard of care after several trials demonstrated superiority over vitamin K antagonists. Non-inferiority has been shown for rivaroxaban, edoxaban and apixaban with a signal of fewer recurrent thrombotic events, albeit with an increase in bleeding events. Yet, potentially major drug-drug interactions have been identified as a reason to withhold NOACs and to rather choose an alternative. Furthermore, practical guidance on what constitutes a major interaction and/or how to deal with these interactions in clinical practice is limited. Hence, here we have provided a framework to allow clinicians to better deal with drug-drug interactions between NOACs and cancer therapies in the management of cancer-associated thrombosis. In this review we have discussed the current literature, how the pharmacokinetic profile links to the label information on DDI, and have provided a practical proposal, applied to a clinical case. Key words: drug-drug interactions, anticoagulation, non-vitamin K oral anticoagulants, cancer, cancer associated thrombosis