Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2D6, ADRB1, ADRB2, ADRA2C, GRK4, and GRK5 Genotypes and Beta-Blocker Therapy.

Beta-blockers are widely used medications for a variety of indications, including heart failure, myocardial infarction, cardiac arrhythmias, and hypertension. Genetic variability in pharmacokinetic (e.g., CYP2D6) and pharmacodynamic (e.g., ADRB1, ADRB2, ADRA2C, GRK4, GRK5) genes have been studied in relation to beta-blocker exposure and response. We searched and summarized the strength of the evidence linking beta-blocker exposure and response with the six genes listed above. The level of evidence was high for associations between CYP2D6 genetic variation and both metoprolol exposure and heart rate response. Evidence indicates that CYP2D6 poor metabolizers experience clinically significant greater exposure and lower heart rate in response to metoprolol compared with those who are not poor metabolizers. Therefore, we provide therapeutic recommendations regarding genetically predicted CYP2D6 metabolizer status and metoprolol therapy. However, there was insufficient evidence to make therapeutic recommendations for CYP2D6 and other beta-blockers or for any beta-blocker and the other five genes evaluated (updates at www.cpicpgx.org).

Maternal perceived stress and green spaces during pregnancy are associated with adult offspring gene (NR3C1 and IGF2/H19) methylation patterns in adulthood: A pilot study.

BACKGROUND: Changes in NR3C1 and IGF2/H19 methylation patterns have been associated with behavioural and psychiatric outcomes. Maternal mental state has been associated with offspring NR3C1 promotor and IGF2/H19 imprinting control region (ICR) methylation patterns. However, there is a lack of prospective studies with long-term follow-up. METHODS: 52 mother-offspring pairs were studied from 12 to 22 weeks of pregnancy and offspring was followed-up until 28-29 years-of-age. During pregnancy, mothers filled in a Life Event Scale and a Daily Hassles Scale measuring perceived stress; i.e., appraisal or subjectively experienced severity of impact of important life events and of daily hassles in several life domains during pregnancy, respectively. Green space was quantified around the residence, using high-resolution (1 m2) map data. Saliva and blood samples were obtained from the adult offspring. Absolute DNA methylation levels were determined in blood and saliva on four NR3C1 amplicons, and one IGF2/H19 ICR amplicon using a bisulfite PCR and sequencing method. Linear mixed effect models were used to test the associations between perceived stress and green spaces during pregnancy, and adult offspring methylation patterns. RESULTS: We found associations between maternal perceived stress during pregnancy and methylation patterns on two out of the four NR3C1 amplicons, measured in blood, from offspring in adulthood, but not with IGF2/H19 methylation. For an interquartile-range (IQR) increase in maternal perceived life event or daily hassles stress scores, absolute methylation levels on several NR3C1 CpG sites were significantly changed (-1.62 % to +5.89 %, p<0.05). Maternal perceived stress scores were not associated with IGF2/H19 methylation, neither in blood nor in saliva. Maternal exposure to green spaces surrounding the residence during the pregnancy was associated with IGF2/H19 ICR methylation (-0.80 % to -1.04 %, p<0.05) in saliva, but not with NR3C1 promotor methylation. CONCLUSION: We observed significant long-term effects of maternal perceived stress during pregnancy on the methylation patterns of the NR3C1 promotor in offspring well into adulthood. This may imply that maternal psychological distress during pregnancy may influence the regulation of the HPA-axis well into adulthood. Additionally, maternal proximity to green spaces was associated with IGF2/H19 ICR methylation patterns, which is a novel finding.

Real-world therapy management of patients with multiple sclerosis receiving cladribine tablets beyond year 4 - Results from a German cladribine cohort.

BACKGROUND: The current approval of oral cladribine covers four years, with two treatment courses in the first two years, followed by two treatment-free years. For decision-making in year 5, experts recommend three scenarios: Extending the treatment-free period, retreatment with cladribine, or therapy switch. OBJECTIVE: To assess the implementation of the three year-5-scenarios in clinical practice in a large multicentric real-world cohort in Germany. METHODS: Data from adult patients diagnosed with highly active RMS (first dose between 8/2017 and 8/2018) were included. The primary outcome was the percentages of patients who remained treatment-free in year 5, were retreated with cladribine, or switched to another therapy. RESULTS: In total, 187 patients (75 % female, mean age 38.6 years, median EDSS 2.5, 21 % DMT-naive) were evaluated. Overall, 27 (14 %) switched treatment within year 1-4, 36 (19 %) continued therapy with cladribine tablets in year 5, and 8 (4 %) switched therapy in year 5. All other patients (n = 118, 63 %) continued to be monitored without therapy in year 5. CONCLUSION: The recommended three treatment scenarios in year 5 appear to be feasible in clinical practice. Treatment-free structured monitoring is the most frequently applied strategy, highly likely due to the prospect of continuing low disease activity under cladribine treatment.

Association between prenatal glucocorticoid exposure and adolescent neurodevelopment: An observational follow-up study.

INTRODUCTION: Prenatal exposure to supraphysiological glucocorticoid (GC) levels may lead to long-lasting developmental changes in numerous biological systems. Our prior study identified an association between prenatal GC prophylaxis and reduced cognitive performance, electrocortical changes, and altered autonomic nervous system (ANS) activity in children aged 8-9 years. This follow-up study aimed to examine whether these findings persisted into adolescence. MATERIAL AND METHODS: Prospective observational follow-up study involving twenty-one 14- to 15-year-old adolescents born to mothers who received betamethasone for induction of fetal lung maturation in threatened preterm birth, but who were born with a normal weight appropriate for their gestational age (median 37+4 gestational weeks). Thirty-five children not exposed to betamethasone served as the reference group (median 37+6 gestational weeks). The primary endpoint was cognitive performance, measured by intelligence quotient (IQ). Key secondary endpoints included symptoms of attention-deficit/hyperactivity disorder (ADHD) and metabolic markers. Additionally, we determined electrocortical (electroencephalogram), hypothalamus-pituitary-adrenal axis (HPAA), and ANS activity in response to a standardized stress paradigm. RESULTS: No statistically significant group difference was observed in global IQ (adjusted mean: betamethasone 103.9 versus references 105.9, mean difference -2.0, 95% confidence interval [CI]: -7.12 to 3.12, p = 0.44). Similarly, ADHD symptoms, metabolic markers, the overall and stress-induced activity of the HPAA and the ANS did not differ significantly between groups. However, the betamethasone group exhibited reduced electrocortical activity in the frontal brain region (spectral edge frequency-adjusted means: 16.0 Hz versus 17.8 Hz, mean difference -1.83 Hz, 95% CI: -3.21 to -0.45, p = 0.01). CONCLUSIONS: In 14- to 15-year-old adolescents, prenatal GC exposure was not associated with differences in IQ scores or ANS activity compared to unexposed controls. However, decelerated electrocortical activity in the frontal region potentially reflects disturbances in the maturation of cortical and/or subcortical brain structures. The clinical significance of these changes remains unknown. Given the small sample size, selective participation/loss of follow-up and potential residual confounding, these findings should be interpreted cautiously. Further research is required to replicate these results in larger cohorts before drawing firm clinical conclusions.

A Semi-Mechanistic Population Pharmacokinetic Model of Noscapine in Healthy Subjects Considering Hepatic First-Pass Extraction and CYP2C9 Genotypes.

INTRODUCTION: Noscapine is a commonly used cough suppressant, with ongoing research on its anti-inflammatory and anti-tumor properties. The drug has a pronounced pharmacokinetic variability. OBJECTIVE: This evaluation aims to describe the pharmacokinetics of noscapine using a semi-mechanistic population pharmacokinetic model and to identify covariates that could explain inter-individual pharmacokinetic variability. METHODS: Forty-eight healthy volunteers (30 men and 18 women, mean age 33 years) were enrolled in a randomized, two-period, two-stage, crossover bioequivalence study of noscapine in two different liquid formulations. Noscapine plasma concentrations following oral administration of noscapine 50 mg were evaluated by a non-compartmental analysis and by a population pharmacokinetic model separately. RESULTS: Compared to the reference formulation, the test formulation exhibited ratios (with 94.12% confidence intervals) of 0.784 (0.662-0.929) and 0.827 (0.762-0.925) for peak plasma concentrations and area under the plasma concentration-time curve, respectively. Significant differences in p values (< 0.01) were both observed when comparing peak plasma concentrations and area under the plasma concentration-time curve between CYP2C9 genotype-predicted phenotypes. A three-compartmental model with zero-order absorption and first-order elimination process best described the plasma data. The introduction of a liver compartment was able to describe the profound first-pass effect of noscapine. Total body weight and the CYP2C9 genotype-predicted phenotype were both identified as significant covariates on apparent clearance, which was estimated as 958 ± 548 L/h for extensive metabolizers (CYP2C9*1/*1 and *1/*9), 531 ± 304 L/h for intermediate metabolizers with an activity score of 1.5 (CYP2C9*1/*2), and 343 ± 197 L/h for poor metabolizers and intermediate metabolizers with an activity score of 1.0 (CYP2C9*1/*3, *2/*3, and*3/*3). CONCLUSION: The current work is expected to facilitate the future pharmacokinetic/pharmacodynamic development of noscapine. This study was registered prior to starting at "Deutsches Register Klinischer Studien" under registration no. DRKS00017760.

mitoBKCa is functionally expressed in murine and human breast cancer cells and potentially contributes to metabolic reprogramming.

Alterations in the function of K+ channels such as the voltage- and Ca2+-activated K+ channel of large conductance (BKCa) reportedly promote breast cancer (BC) development and progression. Underlying molecular mechanisms remain, however, elusive. Here, we provide electrophysiological evidence for a BKCa splice variant localized to the inner mitochondrial membrane of murine and human BC cells (mitoBKCa). Through a combination of genetic knockdown and knockout along with a cell permeable BKCa channel blocker, we show that mitoBKCa modulates overall cellular and mitochondrial energy production, and mediates the metabolic rewiring referred to as the 'Warburg effect', thereby promoting BC cell proliferation in the presence and absence of oxygen. Additionally, we detect mitoBKCa and BKCa transcripts in low or high abundance, respectively, in clinical BC specimens. Together, our results emphasize, that targeting mitoBKCa could represent a treatment strategy for selected BC patients in future.

Differential gene expression in B cells and T helper cells following high-dose glucocorticoid therapy for multiple sclerosis relapse.

BACKGROUND: Despite remarkable advances in the therapy of multiple sclerosis (MS), patients with MS may still experience relapses. High-dose short-term methylprednisolone (MP) remains the standard treatment in the acute management of MS relapses due to its potent anti-inflammatory and immunosuppressive properties. However, there is a lack of studies on the cell type-specific transcriptome changes that are induced by this synthetic glucocorticoid (GC). Moreover, it is not well understood why some patients do not benefit adequately from MP therapy. METHODS: We collected peripheral blood from MS patients in relapse immediately before and after ∼3-5 days of therapy with MP at 4 study centers. CD19+ B cells and CD4+ T cells were then isolated for profiling the transcriptome with high-density arrays. The patients' improvement of neurological symptoms was evaluated after ∼2 weeks by the treating physicians. We finally analyzed the data to identify genes that were differentially expressed in response to the therapy and whose expression differed between clinical responders and non-responders. RESULTS: After MP treatment, a total of 33 genes in B cells and 55 genes in T helper cells were significantly up- or downregulated. The gene lists overlap in 10 genes and contain genes that have already been described as GC-responsive genes in the literature on other cell types and diseases. Their differential expression points to a rapid and coordinated modulation of multiple signaling pathways that influence transcription. Genes that were previously suggested as potential prognostic biomarkers of the clinical response to MP therapy could not be confirmed in our data. However, a greater increase in the expression of genes encoding proteins with antimicrobial activity was detected in CD4+ T cells from non-responders compared to responders. CONCLUSION: Our study delved into the cell type-specific effects of MP at the transcriptional level. The data suggest a therapy-induced ectopic expression of some genes (e.g., AZU1, ELANE and MPO), especially in non-responders. The biological consequences of this remain to be explored in greater depth. A better understanding of the molecular mechanisms underlying clinical recovery from relapses in patients with MS will help to optimize future treatment decisions.

Joint recommendations on cost calculation and estimation in paediatric clinical trials.

The conduct of clinical trials in paediatrics is essential to improve drug therapy in children. In Europe, paediatric clinical trials have been supported by the European Paediatric Regulation since 2007, but there is still a great need for high-quality clinical trials. The personnel and time required to conduct clinical trials in accordance with EU Regulations 536/2014 and 745/2017 is considerably higher compared to other studies, such as observational studies. It is important that this additional workload for the trial centre is fully compensated, also taking into account EU state aid rules. In paediatric trials, it is necessary to take into account the special requirements of paediatric and adolescent medicine when calculating the additional costs. Within the framework of the pan-European paediatric study network c4c/GermanNetPaeT, a working group dealt with specific aspects of cost calculation in order to support paediatric study centres in internal cost calculation as well as in the subsequent preparation of financing requirements for industrial sponsors or public funders. In several workshops the working group developed a cost calculation template with the content derived from the "Joint recommendations for a total services account as a factor in simplifying contracts" of the Deutsche Hochschulmedizin (DHM, German University Medicine), the Netzwerk der Koordinierungszentren für Klinische Studien (KKS Network, Network of Coordinating Centres for Clinical Trials) and the Verband Forschender Arzneimittelhersteller (vfa, German Association of Research-Based Pharmaceutical Companies). By estimating the specific time required for measures and investigations as part of a sample study, the background to the increased time required was discussed and a list with aspects to be considered for cost calculation was compiled together with the study centres. The paediatrics-specific aspects mentioned in detail are intended to increase understanding of the particular problem of higher costs for clinical trials involving children and adolescents and the need for correspondingly appropriate remuneration. This transparent and comprehensible presentation of the higher financial requirements for both the study centres and the financial supporters is intended to promote the high-quality conduct of clinical trials in paediatric study centres in the long term.

A physiologically-based pharmacokinetic precision dosing approach to manage dasatinib drug-drug interactions.

Dasatinib, a second-generation tyrosine kinase inhibitor, is approved for treating chronic myeloid and acute lymphoblastic leukemia. As a sensitive cytochrome P450 (CYP) 3A4 substrate and weak base with strong pH-sensitive solubility, dasatinib is susceptible to enzyme-mediated drug-drug interactions (DDIs) with CYP3A4 perpetrators and pH-dependent DDIs with acid-reducing agents. This work aimed to develop a whole-body physiologically-based pharmacokinetic (PBPK) model of dasatinib to describe and predict enzyme-mediated and pH-dependent DDIs, to evaluate the impact of strong and moderate CYP3A4 inhibitors and inducers on dasatinib exposure and to support optimized dasatinib dosing. Overall, 63 plasma profiles from perorally administered dasatinib in healthy volunteers and cancer patients were used for model development. The model accurately described and predicted plasma profiles with geometric mean fold errors (GMFEs) for area under the concentration-time curve from the first to the last timepoint of measurement (AUClast) and maximum plasma concentration (Cmax) of 1.27 and 1.29, respectively. Regarding the DDI studies used for model development, all (8/8) predicted AUClast and Cmax ratios were within twofold of observed ratios. Application of the PBPK model for dose adaptations within various DDIs revealed dasatinib dose reductions of 50%-80% for strong and 0%-70% for moderate CYP3A4 inhibitors and a 2.3-3.1-fold increase of the daily dasatinib dose for CYP3A4 inducers to match the exposure of dasatinib administered alone. The developed model can be further employed to personalize dasatinib therapy, thereby help coping with clinical challenges resulting from DDIs and patient-related factors, such as elevated gastric pH.

Fluorescence-Guided Laparoscopy after Oral Hypericin Administration for Staging of Locally Advanced Gastric Cancer-A Pilot Study.

(1) Background: Laparoscopic staging is essential in gastric cancer (GC) to rule out peritoneal metastasis (PM). Hypericin, a plant-derived fluorescent compound, has been suggested to improve laparoscopic visualization of PM from GC. This prospective, single-arm, open-label clinical trial aimed to assess the feasibility and safety of oral hypericin administration as well as the suitability of fluorescence-guided laparoscopy (FGL) for improving the sensitivity and specificity of staging in GC patients (EudraCT-Number: 2015-005277-21; clinicaltrials.gov identifier: NCT-02840331). (2) Methods: GC patients received Laif® 900, an approved hypericin-containing phytopharmaceutical, once orally two to four hours before white light and ultraviolet light laparoscopy. The peritoneal cancer index was evaluated, biopsies taken and hypericin concentrations in serum and peritoneal tissue were determined by mass spectrometry. (3) Results: Between 2017 and 2021, out of 63 patients screened for eligibility, 50 patients were enrolled and treated per protocol. The study intervention was shown to be feasible and safe in all patients. Standard laparoscopy revealed suspicious lesions in 27 patients (54%), among whom 16 (59%) were diagnosed with PM. FGL identified suspicious areas in 25 patients (50%), among whom PM was confirmed in 13 cases (52%). Although hypericin concentrations in serum reached up to 5.64 ng/mL, no hypericin was detectable in peritoneal tissue biopsies. (4) Conclusions: FGL in patients with GC was shown to be feasible but futile in this study. Sufficient levels of hypericin should be ensured in target tissue prior to reassessing FGL with hypericin.

Genetic associations of cardiovascular risk genes in European patients with coronary artery spasm.

BACKGROUND: Coronary artery spasm (CAS) is a frequent finding in patients presenting with angina pectoris. Although the pathogenesis of CAS is incompletely understood, previous studies suggested a genetic contribution. Our study aimed to elucidate genetic variants in a cohort of European patients with angina and unobstructed coronary arteries who underwent acetylcholine (ACh) provocation testing. METHODS: A candidate association analysis of 208 genes previously associated with cardiovascular conditions was performed using genotyped and imputed variants in patients grouped in epicardial (focal, diffuse) CAS (n = 119) and microvascular CAS (n = 87). Patients with a negative ACh test result (n = 45) served as controls. RESULTS: We found no association below the genome-wide significance threshold of p < 5 × 10-8, thus not confirming variants in ALDH2, NOS3, and ROCK2 previously reported in CAS patients of Asian ancestry. However, the analysis identified suggestive associations (p < 10-05) for the groups of focal epicardial CAS (CDH13) and diffuse epicardial CAS (HDAC9, EDN1). Downstream analysis of the potential EDN1 risk locus showed that CAS patients have significantly increased plasma endothelin-1 levels (ET-1) compared to controls. An EDN1 haplotype comprising rs9349379 and rs2070698 was significantly associated to ET-1 levels (p = 0.01). CONCLUSIONS: In summary, we suggest EDN1 as potential genetic risk loci for patients with diffuse epicardial CAS, and European ancestry. Plasma ET-1 levels may serve as a potential cardiac marker.

A high performance liquid chromatography-tandem mass spectrometry assay for therapeutic drug monitoring of 10 drug compounds commonly used for antimicrobial therapy in plasma and serum of critically ill patients: Method optimization, validation, cross-validation and clinical application.

BACKGROUND AND AIMS: Intensive care antibiotic treatment faces challenges due to substantial pharmacokinetic differences in critically ill patients. Individualized antibiotic dosing guided by therapeutic drug monitoring (TDM) is considered to minimize the risk of treatment failure and toxicity. This study aimed to develop a valid method for simultaneous LC-MS/MS quantification of 10 drugs frequently used in intensive care antibiotic therapy for which TDM-guided dosing is recommended: piperacillin, meropenem, flucloxacillin, cefuroxime, vancomycin, colistin A and B, linezolid, ciprofloxacin and tazobactam. METHODS AND RESULTS: Thorough optimization of sample preparation and chromatography resulted in a fast and simple method based on protein precipitation of 50 µL plasma or serum and gradient elution using an Acquity UPLC HSS-T3 column. Electrospray ionization-triple quadrupole mass spectrometry in dynamic multiple reaction monitoring was used for quantification, covering the therapeutic range of each drug compound. Validation following EMA and FDA recommendations, including inter-platform validation and inter-laboratory comparison, demonstrated high accuracy, precision and robustness of the new method. The assay was successfully used to monitor plasma antibiotic levels of critically ill patients (n = 35). CONCLUSION: The established multiplex method covers major drug classes with documented dosing challenges, provides a reliable basis for the implementation of high-throughput TDM, and its application confirmed the clinical impact of TDM in a real-world setting.

Consequences of Amyloid-ß Deficiency for the Liver.

The hepatic content of amyloid beta (Aß) decreases drastically in human and rodent cirrhosis highlighting the importance of understanding the consequences of Aß deficiency in the liver. This is especially relevant in view of recent advances in anti-Aß therapies for Alzheimer's disease (AD). Here, it is shown that partial hepatic loss of Aß in transgenic AD mice immunized with Aß antibody 3D6 and its absence in amyloid precursor protein (APP) knockout mice (APP-KO), as well as in human liver spheroids with APP knockdown upregulates classical hallmarks of fibrosis, smooth muscle alpha-actin, and collagen type I. Aß absence in APP-KO and deficiency in immunized mice lead to strong activation of transforming growth factor-ß (TGFß), alpha secretases, NOTCH pathway, inflammation, decreased permeability of liver sinusoids, and epithelial-mesenchymal transition. Inversely, increased systemic and intrahepatic levels of Aß42 in transgenic AD mice and neprilysin inhibitor LBQ657-treated wild-type mice protect the liver against carbon tetrachloride (CCl4)-induced injury. Transcriptomic analysis of CCl4-treated transgenic AD mouse livers uncovers the regulatory effects of Aß42 on mitochondrial function, lipid metabolism, and its onco-suppressive effects accompanied by reduced synthesis of extracellular matrix proteins. Combined, these data reveal Aß as an indispensable regulator of cell-cell interactions in healthy liver and a powerful protector against liver fibrosis.

Nonlinear Mixed-Effects Model of Z-Endoxifen Concentrations in Tamoxifen-Treated Patients from the CEPAM Cohort.

Tamoxifen is widely used in patients with hormone receptor-positive breast cancer. The polymorphic enzyme CYP2D6 is primarily responsible for metabolic activation of tamoxifen, resulting in substantial interindividual variability of plasma concentrations of its most important metabolite, Z-endoxifen. The Z-endoxifen concentration thresholds below which tamoxifen treatment is less efficacious have been proposed but not validated, and prospective trials of individualized tamoxifen treatment to achieve Z-endoxifen concentration thresholds are considered infeasible. Therefore, we aim to validate the association between Z-endoxifen concentration and tamoxifen treatment outcomes, and identify a Z-endoxifen concentration threshold of tamoxifen efficacy, using pharmacometric modeling and simulation. As a first step, the CYP2D6 Endoxifen Percentage Activity Model (CEPAM) cohort was created by pooling data from 28 clinical studies (> 7,000 patients) with measured endoxifen plasma concentrations. After cleaning, data from 6,083 patients were used to develop a nonlinear mixed-effect (NLME) model for tamoxifen and Z-endoxifen pharmacokinetics that includes a conversion factor to allow inclusion of studies that measured total endoxifen but not Z-endoxifen. The final parent-metabolite NLME model confirmed the primary role of CYP2D6, and contributions from body weight, CYP2C9 phenotype, and co-medication with CYP2D6 inhibitors, on Z-endoxifen pharmacokinetics. Future work will use the model to simulate Z-endoxifen concentrations in patients receiving single agent tamoxifen treatment within large prospective clinical trials with long-term survival to identify the Z-endoxifen concentration threshold below which tamoxifen is less efficacious. Identification of this concentration threshold would allow personalized tamoxifen treatment to improve outcomes in patients with hormone receptor-positive breast cancer.

REBISTART: Adherence of Patients with Multiple Sclerosis to Treatment with Subcutaneous Interferon Beta in the Context of a Patient Support Program.

INTRODUCTION: Treatment adherence is a critical success factor in the disease-modifying therapy (DMT) of multiple sclerosis (MS). The REBISTART study prospectively evaluated adherence in patients using components of a patient support program (PSP). METHODS: The 12-month non-interventional multicenter study examined the real-world adherence to subcutaneously (sc) injected interferon beta-1a (Rebif®). Patient-assessed adherence was measured by a visual analog scale (VAS) and the Morisky Medication Adherence Scale (MMAS). Objective adherence data were obtained by readouts from the RebiSmart® injection device. RESULTS: Of 333 patients, 70.9% used the nursing service as the core component of the PSP. Self-assessed VAS-based adherence was stable over time at 94.0-96.3%. Similarly, MMAS score (maximum 4) was 3.8-3.9 at all visits, also reflecting high self-assessed adherence. In 269 patients using the RebiSmart® injection device, mean readout-based objective adherence was similarly high (93.0-98.4% throughout visits). At last available visit, VAS-based adherence was independent of participation in the PSP nursing service (93.1% with participation versus 91.7% without it). Adherence was also independent of injection method or disease-related measures, including fatigue, depression, cognition, and quality of life. The most frequent reason for the premature discontinuations (38.7% of patients) was "change of treatment" (10.0%). DISCUSSION: We suggest that subgroups that may specifically benefit from PSP include patients who live alone, use multiple comedications, and are affected by cognitive impairment, depression, and/or fatigue. Further studies should investigate the potential usefulness of PSPs in these populations. CONCLUSIONS: Very high adherence rates independent of the PSP nursing service over 1 year of treatment indicate that IFN beta-1a sc is an easy-to-use and well-tolerated disease-modifying drug. TRIAL REGISTRATION NUMBER: Vfa.de: No. 892. https://www.vfa.de/de/arzneimittel-forschung/datenbanken-zu-arzneimitteln/nisdb/nis-details/_892 .

First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure.

Diminished hepatocyte regeneration is a key feature of acute and chronic liver diseases and after extended liver resections, resulting in the inability to maintain or restore a sufficient functional liver mass. Therapies to restore hepatocyte regeneration are lacking, making liver transplantation the only curative option for end-stage liver disease. Here, we report on the structure-based development and characterization (nuclear magnetic resonance [NMR] spectroscopy) of first-in-class small molecule inhibitors of the dual-specificity kinase MKK4 (MKK4i). MKK4i increased liver regeneration upon hepatectomy in murine and porcine models, allowed for survival of pigs in a lethal 85% hepatectomy model, and showed antisteatotic and antifibrotic effects in liver disease mouse models. A first-in-human phase I trial (European Union Drug Regulating Authorities Clinical Trials [EudraCT] 2021-000193-28) with the clinical candidate HRX215 was conducted and revealed excellent safety and pharmacokinetics. Clinical trials to probe HRX215 for prevention/treatment of liver failure after extensive oncological liver resections or after transplantation of small grafts are warranted.

Physiologically based pharmacokinetic modeling of imatinib and N-desmethyl imatinib for drug-drug interaction predictions.

The first-generation tyrosine kinase inhibitor imatinib has revolutionized the development of targeted cancer therapy and remains among the frontline treatments, for example, against chronic myeloid leukemia. As a substrate of cytochrome P450 (CYP) 2C8, CYP3A4, and various transporters, imatinib is highly susceptible to drug-drug interactions (DDIs) when co-administered with corresponding perpetrator drugs. Additionally, imatinib and its main metabolite N-desmethyl imatinib (NDMI) act as inhibitors of CYP2C8, CYP2D6, and CYP3A4 affecting their own metabolism as well as the exposure of co-medications. This work presents the development of a parent-metabolite whole-body physiologically based pharmacokinetic (PBPK) model for imatinib and NDMI used for the investigation and prediction of different DDI scenarios centered around imatinib as both a victim and perpetrator drug. Model development was performed in PK-Sim® using a total of 60 plasma concentration-time profiles of imatinib and NDMI in healthy subjects and cancer patients. Metabolism of both compounds was integrated via CYP2C8 and CYP3A4, with imatinib additionally transported via P-glycoprotein. The subsequently developed DDI network demonstrated good predictive performance. DDIs involving imatinib and NDMI were simulated with perpetrator drugs rifampicin, ketoconazole, and gemfibrozil as well as victim drugs simvastatin and metoprolol. Overall, 12/12 predicted DDI area under the curve determined between first and last plasma concentration measurements (AUClast) ratios and 12/12 predicted DDI maximum plasma concentration (Cmax) ratios were within twofold of the respective observed ratios. Potential applications of the final model include model-informed drug development or the support of model-informed precision dosing.

Genome-Wide Association Study of Atorvastatin Pharmacokinetics: Associations With SLCO1B1, UGT1A3, and LPP.

In a genome-wide association study of atorvastatin pharmacokinetics in 158 healthy volunteers, the SLCO1B1 c.521T>C (rs4149056) variant associated with increased area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) of atorvastatin (P = 1.2 × 10-10), 2-hydroxy atorvastatin (P = 4.0 × 10-8), and 4-hydroxy atorvastatin (P = 2.9 × 10-8). An intronic LPP variant, rs1975991, associated with reduced atorvastatin lactone AUC0-∞ (P = 3.8 × 10-8). Three UGT1A variants linked with UGT1A3*2 associated with increased 2-hydroxy atorvastatin lactone AUC0-∞ (P = 3.9 × 10-8). Furthermore, a candidate gene analysis including 243 participants suggested that increased function SLCO1B1 variants and decreased activity CYP3A4 variants affect atorvastatin pharmacokinetics. Compared with individuals with normal function SLCO1B1 genotype, atorvastatin AUC0-∞ was 145% (90% confidence interval: 98-203%; P = 5.6 × 10-11) larger in individuals with poor function, 24% (9-41%; P = 0.0053) larger in those with decreased function, and 41% (16-59%; P = 0.016) smaller in those with highly increased function SLCO1B1 genotype. Individuals with intermediate metabolizer CYP3A4 genotype (CYP3A4*2 or CYP3A4*22 heterozygotes) had 33% (14-55%; P = 0.022) larger atorvastatin AUC0-∞ than those with normal metabolizer genotype. UGT1A3*2 heterozygotes had 16% (5-25%; P = 0.017) smaller and LPP rs1975991 homozygotes had 34% (22-44%; P = 4.8 × 10-5) smaller atorvastatin AUC0-∞ than noncarriers. These data demonstrate that genetic variation in SLCO1B1, UGT1A3, LPP, and CYP3A4 affects atorvastatin pharmacokinetics. This is the first study to suggest that LPP rs1975991 may reduce atorvastatin exposure. [Correction added on 6 April, after first online publication: An incomplete sentence ("= 0.017) smaller in heterozygotes for UGT1A3*2 and 34% (22%, 44%; P × 10-5) smaller in homozygotes for LPP noncarriers.") has been corrected in this version.].

The effect of genetic variants in the transcription factor TSPYL family on the CYP3A4 mediated cyclosporine metabolism in kidney transplant patients.

CYP3A4 activity shows considerable interindividual variability. Although studies indicate 60%-80% is heritable, common single nucleotide variants (SNVs) in CYP3A4 together only explain ~10%. Transcriptional factors, such as the testis-specific Y-encoded-like proteins (TSPYLs) family, have been reported to regulate the expression of CYP enzymes including CYP3A4 in vitro. Here, we investigated the effect of genetic variants in TSPYL on CYP3A4 activity using data from a clinical study and a human liver bank. Five SNVs (rs3828743, rs10223646, rs6909133, rs1204807, and rs1204811) in TSPYL were selected because of a reported effect on CYP3A4 expression in vitro or suggested clinical effect. For the clinical study, whole blood concentrations, clinical data, and DNA were available from 295 kidney transplant recipients participating in the prospective MECANO study. A multivariate pharmacokinetic model adjusted for body weight, steroid treatment, and CYP3A4 genotype was used to assess the effect of the genetic variants on cyclosporine clearance. In multivariate analysis, homozygous carriers of rs3828743 had a 18% lower cyclosporin clearance compared to the wild-type and heterozygous patients (28.72 vs. 35.03 L/h, p = 0.018) indicating a lower CYP3A4 activity and an opposite direction of effect compared to the previously reported increased CYP3A4 expression. To validate, we tested associations between rs3828743 and CYP3A4 mRNA and protein expression as well as enzyme activity with data from a liver bank (n = 150). No association with any of these end points was observed. In conclusion, the totality of evidence is not in support of a significant role for TSPYL SNV rs3828743 in explaining variability in CYP3A4 activity.