Changes In Pharmacokinetics Research Articles

Comparison of Pharmacokinetic Profiles of 14 Major Bioactive Components in Normal and Arthritic Model Rats after Oral Administration of Angelicae pubescentis Radix by UPLC-MS/MS.

An ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was established to simultaneously determine 14 compounds of Angelicae pubescentis Radix (APR) in normal and arthritis rat plasma in which chloramphenicol and daidzein were used as the internal standards. After protein precipitation with acetonitrile, separation was carried out on a Thermo Hypersil GOLD C18 column using gradient elution with 0.1% formic acid aqueous and acetonitrile consisting as the mobile phase at a flowing rate of 0.3 mL/min. A Thermo TSQ QUANTIS triple quadrupole mass spectrometer was used to detect 14 compounds in positive/negative ion exchange mode and this study was the first to investigate the pharmacokinetic changes of the active compounds in rats under the pathological state of arthritis. The method was verified and the results showed that the intra- and interday precision, accuracy, matrix effect, and extraction recovery were all acceptable, and the analytes were stable under different storage conditions. In addition, the pharmacokinetic behaviors of the 14 compounds were significantly different in model rats compared with normal rats. This indicated that the pharmacokinetic behavior of drugs will vary with the pathological state of the body, which suggested that individualized and reasonable drug administration plans should be formulated for different pathological states in clinical practice. This study provided a scientific basis and data support for better understanding the pharmacodynamic substance basis and clinical application of APR against arthritis.

Integrate thermostabilized fusion protein apocytochrome b 562 RIL and N-glycosylation mutations: A novel approach to heterologous expression of human UDP-glucuronosyltransferase (UGT) 2B7.

Human UDP-glucuronosyltransferase (UGT) 2B7 is a crucial phase II metabolic enzyme that transfers glucuronic acid from UDP-glucuronic acid (UDPGA) to endobiotic and xenobiotic substrates. Biophysical and biochemical investigations of UGT2B7 are hampered by the challenge of the integral membrane protein purification. This study focused on the expression and purification of recombinant UGT2B7 by optimizing the insertion sites for the thermostabilized fusion protein apocytochrome b 562RIL (BRIL) and various mutations to improve the protein yields and homogeneity. Preparation of the recombinant proteins with high purity accelerated the measurement of pharmacokinetic parameters of UGT2B7. The dissociation constants (K D) of two classical substrates (zidovudine and androsterone) and two inhibitors (schisanhenol and hesperetin) of UGT2B7 were determined using the surface plasmon resonance spectroscopy (SPR) for the first time. Using negative-staining transmission electron microscopy (TEM), UGT2B7 protein particles were characterized, which could be useful for further exploring its three-dimensional structure. The methods described in this study could be broadly applied to other UGTs and are expected to provide the basis for the exploration of metabolic enzyme kinetics, the mechanisms of drug metabolisms and drug interactions, changes in pharmacokinetics, and pharmacodynamics studies in vitro.

Prediction of pharmacokinetics and pharmacodynamics of trelagliptin and omarigliptin in healthy humans and in patients with renal impairment using physiologically based pharmacokinetic combined DPP-4 occupancy modeling

BackgroundThis study aimed to build a mathematical model of physiologically based pharmacokinetic combined DPP-4 occupancy (PBPK-DO) in humans to provide some recommendations for dosing adjustment in patients with renal impairment. MethodsThe PBPK-DO model was built using physicochemical and biochemical properties and binding kinetics data of TRE and OMA, and then validated by the clinically observed pharmacokinetics (PK) and pharmacodynamics (PD). Finally, the model was applied to determine dose adjustment in patients with renal impairment. ResultsThe predicted PK and DPP-4 occupancy matched well with the clinically observed data, and all absolute average-folding errors (AAFEs) were within 2. The simulations showed that TRE and OMA were both suggested to only support dose reduction by half in patients with severe renal impairment based on this PBPK-DO model, which is different from the commendations only in terms of their AUC0–336 changes. These simulation results were in good agreement with clinical recommendations about dosage adjustment in patients. ConclusionThe present PBPK-DO model can simultaneously predict PK and PD of TRE and OMA in humans and also provide valuable recommendations for dosing adjustment in renal impairment patients, which cannot be achieved by alone depending on PK change.

Herb-drug interaction resources: The PHYDGI database

BackgroundAccording to the WHO, about 60% of the world's population currently uses traditional herbal remedies as complementary or alternative medicine and 80% of the population in developing countries depends almost totally on them for their primary health-care requirements. Due to a lack of knowledge on the action mechanisms of plant compounds or mixture, concerns regarding the safety of potential Herb-Drug Interactions (HDIs) have been raised. Over the past two decades and by 2018, 124 WHO Member States had implemented regulations on herbal medicines. However, databases of interactions between plants and modern allopathic drugs are still limited. MethodsThis study aims to build a database containing the information required for the proper concomitant use of chemical drugs and plant remedies. To develop the HDI database, scientific research articles were searched online using Medline, Scopus and Google scholar databases. Specific key-words, including plant names and “herb” “drug” “interactions” were questioned. Articles were then selected on the availability of required information including the fine identification of the plant extracts. Peculiar attention was paid on data reliability, and redundancies in interaction data increased their credibility. To inform about this reliability, a specific grade was applied. Besides, a grade based on the strength of pharmacokinetic changes was also given. ResultsAs of February 2022, the PHYDGI database allows health care professionals, researchers and manufacturers of plant-based remedies and dietary supplements to search an entity amongst 58 plants and its potential interactions with a given drug amongst 114 commonly used medical substances. ConclusionThe PHYDGI database integrates scientific data on HDI in well-structured forms including reference to the scientific sources. It provides herbal entities and their interactions as well as the level of strength for the pharmacokinetic interactions. This database which will be available for health practitioners, for phyto-drugs and food supplement manufacturers should help reducing potential HDI and developing safe use of plant-based remedies or supplements.

Interactions of the protease inhibitor, ritonavir, with common anesthesia drugs.

The protease inhibitor, ritonavir, is a strong inhibitor of CYP 3A. The drug is used for management of the human immunovirus and is currently part of an oral antiviral drug combination (nirmatrelvir–ritonavir) for the early treatment of SARS‐2 COVID‐19‐positive patients aged 12 years and over who have recognized comorbidities. The CYP 3A enzyme system is responsible for clearance of numerous drugs used in anesthesia (e.g., alfentanil, fentanyl, methadone, rocuronium, bupivacaine, midazolam, ketamine). Ritonavir will have an impact on drug clearances that are dependent on ritonavir concentration, anesthesia drug intrinsic hepatic clearance, metabolic pathways, concentration‐response relationship, and route of administration. Drugs with a steep concentration‐response relationship (ketamine, midazolam, rocuronium) are mostly affected because small changes in concentration have major changes in effect response. An increase in midazolam concentration is observed after oral administration because CYP 3A in the gastrointestinal wall is inhibited, causing a large increase in relative bioavailability. Fentanyl infusion may be associated with a modest increase in plasma concentration and effect, but the large between subject variability of pharmacokinetic and pharmacodynamic concentration changes suggests it will have little impact on an individual patient, especially when used with adverse effect monitoring. It has been proposed that drugs that have no or only a small metabolic pathway involving the CYP 3A enzyme be used during anesthesia, for example, propofol, atracurium, remifentanil, and the volatile agents. That anesthesia approach denies children of drugs with considerable value. It is better that the inhibitory changes in clearance of these drugs are understood so that rational drug choices can be made to tailor drug use to the individual patient. Altered drug dose, anticipation of duration of effect, timing of administration, use of reversal agents and perioperative monitoring would better behoove children undergoing anesthesia.

Clinical Pharmacist Intervention on Drug-Related Problems among Elderly Patients Admitted to Medical Wards of Northwest Ethiopia Comprehensive Specialized Hospitals: A Multicenter Prospective, Observational Study.

Background: Drug therapy in the elderly needs an emphasis on age-related changes in drug pharmacokinetics and pharmacodynamics profile. Hospitalized elderly patients are at risk of more than one disease and polypharmacy associated with these; they are at risk of drug-related problems. This study aimed to assess the role of clinical pharmacy on identifying and resolution of drug-related problems among elderly patients admitted to medical ward of Northwest Ethiopia comprehensive specialized hospitals. Methods: A multicenter prospective observational study was conducted. A systematic sampling technique was used. The identified drug-related problem was recorded and classified using Cipolle, and adverse drug reaction was assessed using Naranjo algorithm of adverse drug reaction probability scale, and Medscape was used for drug-drug interaction. Data were analyzed by using STATA software version 14.1. Logistic regression was used, and results were reported as odds ratios (ORs) with 95% Confidence intervals with P value < 0.05 statistically significant. Result: A total of 389 study participants were included in the study. About 266 (68.4%) of the participants had at least a single drug-related problem. About 503 drug-related problems were identified with a mean of 1.32 (CI: 1.27-1.36) drug-related problem per patient. The three-leading categories of drug-related problems were dose too high 108 (21.5%), nonadherence 105 (20.9%), and adverse drug reaction 96 (19.1%). Alcohol use (AOR = 2.2, 95CI%: 1.23-3.94), source of the drug (AOR = 2.85, 95CI%: 1.63-4.98), length of hospitalization (AOR = 2.32, 95CI%: 1.37-3.95), number of comorbidities (AOR = 1.48, 95CI%: 1.09-1.99), and polypharmacy (AOR = 3.06, 95CI%: 1.72-5.46) were important risk factors for drug-related problems. From the intervention provided, 84.7% were accepted by prescribers. Among the total drug-related problems 67.4% of the problem was totally solved. Conclusion: This study revealed that DRPs were high among elderly patients admitted to medical ward of Northwest Ethiopia. Comorbidity, length of hospitalization, ploy-pharmacy, payer, and alcohol drinker were more likely to developed drug-related problems. Treatment optimizations were also done by clinical pharmacists and interventions were well accepted by prescribers.

The Impact of Suboptimal 25-Hydroxyvitamin D Levels and Cholecalciferol Replacement on the Pharmacokinetics of Oral Midazolam in Control Subjects and Patients With Chronic Kidney Disease.

The aim of this study was to investigate the impact of suboptimal 25-hydroxyvitamin D (25-VitD) and cholecalciferol (VitD3 ) supplementation on the pharmacokinetics of oral midazolam (MDZ) in control subjects and subjects with chronic kidney disease (CKD). Subjects with CKD (n=14) and controls (n=5) with suboptimal 25-VitD levels (<30ng/mL) were enrolled in a 2-phase study. In phase 1 (suboptimal), subjects were administered a single oral dose of VitD3 (5000IU) and MDZ (2mg). In phase 2 (replete) subjects who achieved 25-VitD repletion after receiving up to 16 weeks of daily cholecalciferol were given the identical single oral doses of VitD3 and MDZ as in phase 1. Concentrations of MDZ and metabolites, 1'-hydroxymidazolam (1'-OHMDZ), and 1'-OHMDZ glucuronide (1'-OHMDZ-G) were measured by liquid chromatography-tandem mass spectrometry and pharmacokinetic analysis was performed. Under suboptimal 25-VitD, reductions in MDZ clearance and renal clearance of 47% and 87%, respectively, and a 72% reduction in renal clearance of 1'-OHMDZ-G were observed in CKD vs controls. In phase 1 versus phase 2, MDZ clearance increased in all control subjects, with a median (interquartile range) increase of 10.5 (0.62-16.7)L/h. No changes in MDZ pharmacokinetics were observed in subjects with CKD between phases 1 and 2. The effects of 25-VitD repletion on MDZ disposition was largely observed in subjects without kidney disease. Impaired MDZ metabolism and/or excretion alterations due to CKD in a suboptimal 25-VitD state may not be reversed by cholecalciferol therapy. Suboptimal 25-VitD may augment the reductions in MDZ and 1'-OHMDZ-G clearance values observed in patients with CKD.

Simulation of febuxostat pharmacokinetics in healthy subjects and patients with impaired kidney function using physiologically based pharmacokinetic modeling.

Febuxostat is recommended by the American College of Rheumatology Gout Management Guidelines as a first-line therapy for lowering the level of urate in patients with gout. At present, this drug is being prescribed mainly based on the clinical experience of doctors. The potential effects of clinical and demographic variables on the bioavailability and therapeutic effectiveness of febuxostat are not being considered. In this study a physiologically based pharmacokinetic (PBPK) model of febuxostat was developed, thereby providing a theoretical basis for the individualized dosing of this drug in gout patients. The plasma concentration-time profiles corresponding to healthy subjects and gout patients with normal kidney function were simulated and validated; then, the model was used to predict the pharmacokinetic (PK) data of the drug in gout patients suffering from varying degrees of impaired kidney function. The error values (the predicted value/observed value) were used to validate the simulated PK parameters predicted by the PBPK model, including the area under the plasma concentration-time curve, the maximum plasma concentration, and time to maximum plasma concentration. Considering that to all error fold changes were smaller than 2, the PBPK model was. In subjects suffering from mild kidney impairment, moderate kidney impairment, severe kidney impairment, and endstage kidney disease (ESRD), the predicted AUC0-24h values increased by 1.62, 1.74, 2.27, and 2.65-fold, respectively, compared to gout patients with normal kidney function. Overall, the results showed that the PBPK model constructed in this study predict the pharmacokinetic changes in gout patients suffering from varying degrees of impaired kidney function.

The complex issue of medication management in older persons: a challenge for nurses

With increasing life expectancy, the share of older persons with coexisting multiple chronic degenerative diseases (comorbidity / multimorbidity) is expanding. These conditions require the use of multiple drugs, leading to polypharmacy, which plays a central role in making the therapeutic approach to the elderly particularly complex, together with age-related changes in pharmacokinetics and pharmacodynamics.&#x0D; Physicians and nurses both are challenged by polypharmacy and by the other drug-related issues involving older patients, in all care settings. In particular, nurses should be aware of the main issues of pharmacotherapy in older persons, because they are often the frontline for older patients care, especially in nursing homes.&#x0D; This review addresses the main issues related to pharmacotherapy in late life, such as pharmacokinetics and pharmacodynamics changes, limitations of evidence-based medicine, polypharmacy, drug interactions, adverse drug reactions, and lack of adherence. Focus will be on how these problems may impact on nursing, and on what nurses should know and do to improve drug treatment of older patients.&#x0D; In the last decade, the role and responsibilities of nurses in the management of drug therapy have significantly changed in most countries. There is consensus in educational programs and legislation that the preparation and administration of medications are essential aspects of nursing practice. These are considered as collaborative tasks with physicians and not purely mechanistic tasks. The nurse must intervene in the event of a perceived error, and he/she must report doubts about congruity or relevance of the therapy.&#x0D; Although nursing students gain knowledge and develop skills on drug therapy during their education, these are often perceived as insufficient. The need for post-graduation continuing education should be also emphasized. Thus, graduate and post-graduate educational programs should be developed, in order to offer adequate answers to the increasing and challenging share of older patients seen in clinical practice.

Analgesia and Sedation in Critically Ill Patients With Burns.

Analgesia and Sedation in Critically Ill Patients With Burns.

971 PERIOPERATIVE MEDICINE PRESCRIBING IN OLDER ADULTS - IMPROVING PRESCRIBING ACCURACY USING QUALITY IMPROVEMENT METHODOLOGY

Abstract Introduction Accurate medication prescribing perioperatively is an essential component of peri-operative optimisation. Older adults are uniquely vulnerable due to polypharmacy and age-related changes in pharmacokinetics and pharmacodynamics. Barriers to this include the urgency of surgery, unclear drug history and poor knowledge of how to manage the patient’s medications. This quality improvement project aimed to improve the accuracy of regular medications prescribed in older adults undergoing emergency laparotomy. Method Multiple Plan, Do, Study, Act (PDSA) cycles were conducted at Southend University Hospital. Patients over 65 undergoing emergency laparotomy were included. Regular medications were retrospectively analysed to assess whether they were continued or suspended appropriately in the perioperative period, according to UKCPA guidelines. The initial cycle analysed prescribing practices for nine medications which were pre-defined as ‘high risk’ of causing adverse effects when prescribed inappropriately. Subsequent cycles scoped all regular medications. Our interventions aimed to increase conscious prescribing by improving prescriber education. Interventions included introducing joint Geriatrician &amp; Surgeon-led teaching sessions, and dissemination of a poster guide with links to resources to aid decision making. Results First cycle (September—November 2020): 32 patients included. Only 30% of all regular medications were within the ‘high risk’ group; 50% of which were prescribed appropriately. Second cycle (May—July 2021): 26 patients included. 72% appropriately prescribed regular medications. Third cycle (September—October 2021): 13 patients included. Sustained improvement in prescribing accuracy to 75%. Problems identified include 1) delay in prescribing 2) regular medications not prescribed 3) prescribed but not administered. Conclusion Improvement in prescribing accuracy amongst doctors is achievable following education-focused intervention. The goal is active decision making with every drug prescribed. Integrating this inter-departmental teaching session into Induction teaching is a sustainable method to improve prescribing practice. This can be translated to every surgical department.

Physiologically based pharmacokinetic combined JAK2 occupancy modelling to simulate PK and PD of baricitinib with kidney transporter inhibitors and in patients with hepatic/renal impairment

PurposeOur aim is to build a physiologically based pharmacokinetic and JAK2 occupancy model (PBPK-JO) to simultaneously predict pharmacokinetic (PK) and pharmacodynamic (PD) changes of baricitinib (BAR) in healthy humans when co-administrated with kidney transporters OAT3 and MATE2-K inhibitors, and in patients with hepatic and renal impairment. MethodsProbenecid and vandetanib were selected as OAT3 and MATE2-K competitive inhibitors, respectively. The PBPK-JO model was built using physicochemical and biochemical properties of BAR, and then verified by observed clinical PK. Finally, the model was applied to determine optimal dosing regimens in various clinical situations. ResultsHere, we have successfully simulated PK and JAK2 occupancy profiles in humans by PBPK-JO model. Moreover, this modelling reproduced every observed PK data, and every mean relative deviation (MRD) was below 2. The simulation suggested that PK of BAR had a significant change (2.22-fold increase), however PD only had a slight increase of 1.14-fold. Additionally, the simulation also suggested that vandetanib was almost unlikely to affect the PK and PD of BAR. In simulations of hepatic and renal impairment patients, the predictions suggested that significant changes in the PK and PD of BAR occurred. However, there was a lower fold increase in JAK2 occupancy than in PK in patients relative to healthy individuals. ConclusionAdministration dose adjustment of BAR when co-administrated with OAT3 inhibitors or in patients with hepatic or renal impairment should combine PK and PD changes of BAR, instead of only considering PK alteration.

Physiologically based pharmacokinetic combined BTK occupancy modeling for optimal dosing regimen prediction of acalabrutinib in patients alone, with different CYP3A4 variants, co-administered with CYP3A4 modulators and with hepatic impairment.

To develop a mathematical model combined between physiologically based pharmacokinetic and BTK occupancy (PBPK-BO) to simultaneously predict pharmacokinetic (PK) and pharmacodynamic (PD) changes of acalabrutinib (ACA) and active metabolite ACP-5862 in healthy humans as well as PD in patients. Next, to use the PBPK-BO to determine the optimal dosing regimens in patients alone, with different CYP3A4 variants, when co-administration with four CYP3A4 modulators and in patients with hepatic impairment, respectively. The PBPK-BO model was built using physicochemical and biochemical properties of ACA and ACP-5862 and then verified by observed PK and PD data from healthy humans and patients. Finally, the model was applied to determine optimal dosing regimens in various clinical situations. The simulations demonstrated that 100mg ACA twice daily (BID) was the optimal dosing regimen in patients alone. Additionally, dosage regimens might be reduced to 50mg BID in patients with five CYP3A4 variants. Moreover, the dosing regimen should be modified to 100mg (even to 50mg) once daily (QD) when co-administration with erythromycin or clarithromycin, and be increased to 200mg BID with rifampicin, and but be avoided co-administration with itraconazole. Furthermore, dosage regimen simulations showed that optimal dosing might be decreased to 50mg BID in patients with mild and moderate hepatic impairment, and be avoided taking ACA in severely hepatically impaired patients. This PBPK-BO model can predict PK and PD in healthy humans and patients and also predict the optimal dosing regimens in various clinical situations.

Ovarian cancer: Age, prognosis, and biologic underpinnings.

e17555 Background: The prognosis of ovarian cancer worsens markedly with age. Yet few data are available to explain this phenomenon. Two hypotheses can be made. Changes in pharmacokinetics (PK) and treatment tolerance limit the dosing of chemotherapy, and/or changes in tumor and host-tumor biology limit treatment efficacy. Objective:To identify PK, body composition, and biologic changes with age that may impact prognosis. We reported PK findings in a previous abstract (Extermann et al., ASCO 2021) In this abstract we focus on the biologic findings. Methods: We conducted a prospective cohort study of women with stage III/IV high-grade serous ovarian cancers treated with neoadjuvant intravenous carboplatin (C) AUC 5 every 3 weeks and paclitaxel (P) dosed either weekly at 80 mg/m2 or every 3 weeks at 175 mg/m2. Body composition was assessed using baseline CT scans at the L3 level. Pre- and post-chemotherapy plasma samples were assayed by ELISA for CRP, IL-6, TNF alpha, TNF-receptor 1 and 2, d-dimers, vitamins B12 and D, methylmalonic acid, and cortisol levels. Tissue samples pre- and post-chemotherapy were analyzed for gene expression, gene methylation, and immunohistochemistry for inflammatory markers and senescence. Toxicity was assessed as first cycle nadir ANC and G4 hematologic (H) or grade 3-4 non-hematologic (NH) toxicity by CTCAE 4.0 criteria over a 3 cycles follow-up. The correlation between continuous measures was assessed by Spearman correlation coefficient, and the association with toxicity was evaluated by Wilcoxon rank sum test. The association with relapse-free survival (RFS) and overall survival (OS) was calculated by Log-rank and Cox regression analyzes. Results: Seventeen patients, ages 38 to 86 (median 61) were eligible, 14 underwent surgery. Treatment delivery was high with a median relative dose intensity of 100%. The mean percentage of senescent cells (CAV-1 +) was 49.5% in the stroma, vs 12.8% in the tumor (p &lt; 0.001) prechemotherapy, and 15.7% in the stroma vs 21.4% in the tumor post-chemotherapy (pre-post stroma p &lt; 0.01). The percentage of PD-L1 positive cells and CTLA-4 positive cells was very low: mean &lt; 1% both pre-and post-chemotherapy. The results from gene expression and methylation showed an increase in the inflammatory pathways and a decrease in the apoptosis pathways over time. Vitamin D levels decreased with age. Prechemotherapy CD8 percentage in the stroma and post chemotherapy d-dimers were associated with RFS. Conclusions: Neoadjuvant treatment delivery was high in an academic setting. Our results provide insights in the underexplored area of biologic response to chemotherapy in patients with ovarian cancer. Although our results did not provide clear candidates to explain the worsening of prognosis with age, they offer clues to develop future research on this issue.

Lithium placental passage at delivery: an observational study

IntroductionLithium is used as a first-line treatment for bipolar disorder during perinatal period. Dosing of lithium can be challenging as a result of pharmacokinetic changes in renal physiology. Frequent monitoring of lithium blood levels during pregnancy is recommended in order remain within the therapeutic window (0.5 to 1.2 mEq/L). Lower neonatal lithium blood level (&lt;0.64 mEq/L) at time of delivery reduces the risk of lithium side effects in the neonate.ObjectivesThe aim of the present study was to quantify the rate of lithium placental passage in real word.MethodsWe included a total of 68 mother-infant pairs for which a lithium measurement was performed intrapartum. Lithium serum concentrations were determined by means of an AVL 9180 electrolyte analyzer. The limit of quantification (LoQ) was 0.20 mEq/L and detection limit was 0.10 mEq/L. Pearson analyse was performer to assess the correlation between mother and umbilical cord lithium serum concentrations.ResultsThe mean of umbilical cord serum concentration at delivery was 0.57 mEq/L (SD=0.26, range 0,20-1,42). The mean infant-mother lithium ratio at delivery for the 68 pairs was 1.12 (SD=0.24) across a wide range of maternal concentrations (range 0.14-1,40 mEq/L). There was a strong positive correlation between maternal and umbilical cord lithium blood levels (Peearson correlation coefficient 0.948, p&lt;0.001).ConclusionsLithium demostrates complete placental passage. This finding is consistent with the results of others studies (Newport 2005; Molenaar 2021).DisclosureNo significant relationships.

High-alert medications for hospitalised paediatric patients - a two-step survey among paediatric clinical expert pharmacists in Germany.

Paediatric patients are more vulnerable to be harmed by medication errors compared to adults due to pharmacokinetic and pharmacodynamic changes in their development, individual dosing calculations, and manipulation of ready to-use products intended for adult patients. According to the Institute of Safe Medication Practices, there are some "drugs that bear a heightened risk of causing significant patient harm when they are used in error"; these drugs are called high-alert medications (HAM). The two-step survey among paediatric clinical expert pharmacists presented here aimed to compile a nation-wide HAM list. To provide detailed guidance, this survey followed a drugbased approach, resulting in specific potential drug related problems (DRPs) and associated recommendations for prevention. In contrast to this approach, in the first round of the survey two drug classes were included that both were rated as HAM (i.e.chemotherapy and parenteral nutrition). Twenty single drugs were identified as HAM, 65% of which were cardiovascular or neurological drugs. The paediatric expert pharmacists mentioned in total 216 potential DRPs; in particular, they identified potential administration-related problems (28% of all DRPs), dosing-related problems (26%), and drug-choice-related problems (18%, e.g.drug confusion and drug monitoring). Moreover, they suggested 275 potential interventions to address these DRPs. Two thirds of all interventions dealt with the preparation by the hospital pharmacy, standardisation of processes (e.g.labelling), and education or training. In conclusion, this survey provided a German paediatric high-alert medication list from a paediatric pharmacist point of view. Moreover, the experts mentioned for the first time specific potential DRPs and associated interventions to guide a local multidisciplinary approach for preventing medication-related harm in children.

Gender Differences in Levodopa Pharmacokinetics in Levodopa-Naïve Patients With Parkinson's Disease.

BackgroundLevodopa (LD) is the most effective drug in the treatment of Parkinson’s disease (PD). Unfortunately, prolonged use of LD leads to complications, mainly motor/non-motor fluctuations (MNMF) and dyskinesias (DYS). Women seem more prone to develop such LD-related complications. Nonetheless, there is a paucity of prospective studies examining gender-related predictors of MNMF and DYS. Among several factors, which concur with a very complex scenario, changes in LD pharmacokinetics influence the drug’s effectiveness. The present study aimed to assess gender-related differences in LD pharmacokinetics in patients with PD at their first-ever intake of LD.Materials and MethodsThis is a multicentric study enrolling patients with PD, who were LD-naïve and received a single dose of LD/benserazide (100/25 mg) formulation. All participants gave their written informed consent, and the study was approved by the local Ethics Committees. To measure plasma LD concentrations and pharmacokinetic parameters (AUC, Cmax, Tmax, t1/2), fasting blood samples were collected before drug intake and then at 8-time points until 260 min. LD concentrations were measured by ultra-high-performance liquid chromatography coupled with mass spectrometry (UHPLC-MS). Multiple linear regression analyses were performed to identify the predictors of the parameters.ResultsThirty-five patients (16 women and 19 men) were consecutively enrolled. Area under curve (AUC) and maximum plasma concentration (Cmax) were significantly higher in women than men (p = 0.0006 and p = 0.0014, respectively). No statistically significant difference was found regarding Tmax and t1/2. Multiple linear regression analyses revealed that female sex (β = 1.559116, 95% CI 0.8314479 2.286785; p < 0.0001) and body mass index (BMI) (β = −0.0970631, 95% CI −0.1733004 −0.0208258; p = 0.014) significantly predicted AUC. Only female sex significantly predicted Cmax (β = 1,582.499, 95% CI 731.581 2,433.417; p = 0.001). Moreover, only BMI significantly predicted t1/2 (β = 0.0756267, 95% CI 0.0143407 0.1369126; p = 0.017). Stratifying by gender, BMI was confirmed to significantly predict t1/2 in women (β = 0.1300486, 95% CI 0.0172322 0.242865; p = 0.027), but not in men.ConclusionThis study provides novel insights on gender differences in LD pharmacokinetics, possibly contributing to the later development of motor complications and dyskinesia in PD.

Pharmacokinetic Pharmacodynamic Modelling Contributions to Improve Paediatric Anaesthesia Practice.

The use of pharmacokinetic-pharmacodynamic models has improved anaesthesia practice in children through a better understanding of dose-concentration-response relationships, developmental pharmacokinetic changes, quantification of drug interactions and insights into how covariates (e.g., age, size, organ dysfunction, pharmacogenomics) impact drug prescription. Simulation using information from these models has enabled the prediction and learning of beneficial and adverse effects and decision-making around clinical scenarios. Covariate information, including the use of allometric size scaling, age and consideration of fat mass, has reduced population parameter variability. The target concentration approach has rationalised dose calculation. Paediatric pharmacokinetic-pharmacodynamic insights have led to better drug delivery systems for total intravenous anaesthesia and an expectation about drug offset when delivery is stopped. Understanding concentration-dependent adverse effects have tempered dose regimens. Quantification of drug interactions has improved the understanding of the effects of drug combinations. Repurposed drugs (e.g., antiviral drugs used for COVID-19) within the community can have important effects on drugs used in paediatric anaesthesia, and the use of simulation educates about these drug vagaries.

Pharmacokinetics of asciminib in the presence of CYP3A or P-gp inhibitors, CYP3A inducers, and acid-reducing agents.

Asciminib is a first‐in‐class inhibitor of BCR::ABL1, specifically targeting the ABL myristoyl pocket. Asciminib is a substrate of CYP3A4 and P‐glycoprotein (P‐gp) and possesses pH‐dependent solubility in aqueous solution. This report summarizes the results of two phase I studies in healthy subjects aimed at assessing the impact of CYP3A and P‐gp inhibitors, CYP3A inducers and acid‐reducing agents (ARAs) on the pharmacokinetics (PK) of asciminib (single dose of 40 mg). Asciminib exposure (area under the curve [AUC]) unexpectedly decreased by ~40% when administered concomitantly with the strong CYP3A inhibitor itraconazole oral solution, whereas maximum plasma concentration (Cmax) decreased by ~50%. However, asciminib exposure was slightly increased in subjects receiving an itraconazole capsule (~3%) or clarithromycin (~35%), another strong CYP3A inhibitor. Macroflux studies showed that cyclodextrin (present in high quantities as excipient [40‐fold excess to itraconazole] in the oral solution formulation of itraconazole) decreased asciminib flux through a lipid membrane by ~80%. The AUC of asciminib was marginally decreased by concomitant administration with the strong CYP3A inducer rifampicin (by ~13–15%) and the strong P‐gp inhibitor quinidine (by ~13–16%). Concomitant administration of the ARA rabeprazole had little or no effect on asciminib AUC, with a 9% decrease in Cmax. The treatments were generally well tolerated. Taking into account the large therapeutic window of asciminib, the observed changes in asciminib PK following multiple doses of P‐gp, CYP3A inhibitors, CYP3A inducers, or ARAs are not considered to be clinically meaningful. Care should be exercised when administering asciminib concomitantly with cyclodextrin‐containing drug formulations.

A microfluidic system that replicates pharmacokinetic (PK) profiles in vitro improves prediction of in vivo efficacy in preclinical models.

Test compounds used on in vitro model systems are conventionally delivered to cell culture wells as fixed concentration bolus doses; however, this poorly replicates the pharmacokinetic (PK) concentration changes seen in vivo and reduces the predictive value of the data. Herein, proof-of-concept experiments were performed using a novel microfluidic device, the Microformulator, which allows in vivo like PK profiles to be applied to cells cultured in microtiter plates and facilitates the investigation of the impact of PK on biological responses. We demonstrate the utility of the device in its ability to reproduce in vivo PK profiles of different oncology compounds over multiweek experiments, both as monotherapy and drug combinations, comparing the effects on tumour cell efficacy in vitro with efficacy seen in in vivo xenograft models. In the first example, an ERK1/2 inhibitor was tested using fixed bolus dosing and Microformulator-replicated PK profiles, in 2 cell lines with different in vivo sensitivities. The Microformulator-replicated PK profiles were able to discriminate between cell line sensitivities, unlike the conventional fixed bolus dosing. In a second study, murine in vivo PK profiles of multiple Poly(ADP-Ribose) Polymerase 1/2 (PARP) and DNA-dependent protein kinase (DNA-PK) inhibitor combinations were replicated in a FaDu cell line resulting in a reduction in cell growth in vitro with similar rank ordering to the in vivo xenograft model. Additional PK/efficacy insight into theoretical changes to drug exposure profiles was gained by using the Microformulator to expose FaDu cells to the DNA-PK inhibitor for different target coverage levels and periods of time. We demonstrate that the Microformulator enables incorporating PK exposures into cellular assays to improve in vitro–in vivo translation understanding for early therapeutic insight.