Pharmacodynamic Changes Research Articles

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.

An integrated strategy to reveal the potential anti-asthma mechanism of peimine by metabolite profiling, network pharmacology, and molecular docking.

Peimine, one of the major quality markers in Fritillaria Cirrhosae Bulbus, was expected to become a new anti-asthma drug. However, its metabolic profiles and anti-asthma mechanism have not been clarified previously. In this study, a method was developed for the detection of peimine metabolites in vitro by ultra-high-performance liquid chromatography coupled with hybrid triple quadrupole time-of-flight mass spectrometry. The potential anti-asthma mechanism was predicted by an integrated analysis of network pharmacology and molecular docking. A total of 19 metabolites were identified with the aid of software and molecular networking. The metabolic profiles of peimine elucidated that the metabolism was a multi-pathway process with characteristics of species difference. The network pharmacology results showed that peimine and its metabolites could regulate multiple asthma-related targets. The above targets were involved in various regulatory pathways linked to asthma. Moreover, the results of molecular docking showed that both peimine and its metabolites had a certain affinity with the β2 adrenergic receptor. The results provided not only important references to understand the metabolism and pharmacodynamic changes of peimine in vitro, but also supporting data for further pharmacological evaluation. It also provided a new perspective for clarifying the functional changes of traditional Chinese medicine in vitro.

First-in-human, phase 1, open-label, dose-escalation, dose-expansion study of ADCT-901 as monotherapy in patients with select advanced solid tumors.

TPS3157 Background: Kidney associated antigen 1 (KAAG1) is highly and selectively expressed on tumor cell surface, such as ovarian, prostate, and triple negative breast cancers (TNBC), and is rapidly internalized and co-localized with a lysosomal marker, making an ideal candidate for an antibody-drug conjugate (ADC) target. ADCT-901 is an ADC composed of a humanized monoclonal antibody IgG1 against KAAG1, conjugated through a cathepsin-cleavable linker to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxin. In mouse xenograft models of human-derived TNBC, ovarian, and renal cancers significant tumor reduction was observed after a single dose of ADCT-901, providing the rationale for clinical development of a PBD-based ADC to treat KAAG1 expressing tumors (Zammarchi et al, AACR 2019). This study aims to identify the recommended dose and schedule for expansion and to characterize safety and tolerability of ADCT-901 in patients (pts) with selected advanced solid tumors that generally express KAAG1. Methods: ADCT-901-101 is a phase 1, multicenter, 2-part, open-label study that will enroll ̃70 pts (NCT04972981). Part 1: pts will receive escalating doses of ADCT-901 guided by a 3+3 design (1st dose: 15 µg/kg every 3 weeks [Q3W]; highest dose: 290 µg/kg Q3W). Dose escalation will be evaluated by administering the lowest dose to first 3 pts, then increasing/decreasing the dose based on dose-limiting toxicity (DLT) experienced by pts. The dose and schedule of ADCT-901 identified in part 1 will be tested in part 2 to characterize safety, tolerability, and preliminary efficacy of ADCT-901. Primary endpoints include incidence of DLTs (part 1 only), frequency/severity of adverse events (AE) and serious AE, clinically significant changes in vitals, laboratory values, overall tolerability, and frequency of dose interruptions and reductions. Secondary endpoints include overall response rate, duration of response, progression-free and overall survival, pharmacokinetic parameters of ADCT-901 total antibody, PBD-conjugated antibody, unconjugated SG3199 in serum, and frequency of confirmed positive antidrug antibody responses. Exploratory endpoints include tumor modulation and potential pharmacodynamic changes. Key inclusion criteria: pathologic diagnosis of selected solid tumor (cholangiocarcinoma, renal cell carcinoma, ovarian/fallopian tube and prostate cancers, TNBC) locally advanced or metastatic at time of screening, pts refractory or intolerant to existing therapy, tissue biopsy or available tissue sample, ECOG of 0-2, and adequate organ function based on predefined laboratory parameters. Pts with symptomatic CNS metastases and clinically significant third space fluid accumulation will be excluded. The study opened for recruitment in September 2021; enrollment is ongoing. Funding: ADC Therapeutics; medical writing: CiTRUS Health Group. Clinical trial information: NCT04972981.

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.

Phase II study of the combination of daratumumab, ixazomib, pomalidomide, and dexamethasone as salvage therapy in relapsed/refractory multiple myeloma: Stage 2 interim results.

8041 Background: The combination of daratumumab (Dara), pomalidomide (POM), and dexamethasone (dex) (DPd) has previously demonstrated deep and durable responses including high rates of minimal residual disease (MRD) negativity, in patients with relapsed/refractory (R/R) MM. Quadruplet regimens may further improve results. We report updated findings from a phase 2 multicenter trial of the addition of ixazomib to DPd (DIPd) in patients with early R/R MM. Methods: This is a prospective, multi-center, open-label, single arm phase II trial with a primary objective to evaluate the overall response rate (ORR), safety, and efficacy of DIPd. Secondary endpoints include progression-free survival (PFS), overall survival (OS), and MRD-negativity rate. A Simon’s optimal 2-stage design was used, with 14 subjects in stage 1 to assess response and 32 patients for stage 2. Eligible patients may not have had exposure Dara or ixazomib, may not have progressed on POM, and may have received ≥1 and ≤3 prior lines of therapy. The first six patients in the safety run-in received Dara 16mg/kg IV weekly x 8 doses, biweekly x 8 doses, then monthly, POM 4mg orally on days 1-21 of a 28-day cycle, ixazomib 4mg orally on days 1,8,15 every 28 days, and dex 20-40mg weekly. Grade 3-4 neutropenia was observed in 100% of patients, prompting dose reduction to ixazomib 3 mg and POM 3 mg by the DSMB. An amendment allowed subcutaneous Dara administration. MRD assessments are being performed by EuroFlow for patients in VGPR or suspected CR. Pharmacodynamic changes in patients’ tumor microenvironments were established by custom panel mass cytometry to include T-cell memory and activated subpopulations, B-cell content, NK-cell subpopulations as well as MDSCs, Tregs and T-exhaustive markers, monocytes and dendritic cells. Results: To date, 14 subjects have been treated in stage 1, and 18 patients in stage 2. Median age was 61.5 (range 41-87) years, 50% were female and 72% white. Median number of prior regimens was 1 (range 1-3), all patients were lenalidomide-exposed, and 47% (11/23) had high-risk cytogenetic features. The most common grade 3-4 treatment emergent adverse events included neutropenia (78%), infection (30%), leukopenia (11%), respiratory conditions (7%), psychiatric disturbance (4%), and thrombosis (4%). Median time on treatment was 4 months (1-29), with 11 patients remaining on DIPd and 5 deaths (4 due to progressive disease and 1 due to sepsis). ORR to date was 84% (16/19), and the best responses included: 5 (26%) sCR; 4 (21%) VGPR; 7 (37%) PR. After a median follow up of 12 months, the median OS was 39 months and PFS was 9.5 months. Conclusions: The quadruplet regimen DIPd is a well-tolerated combination that has shown early safety, efficacy, and ORR in early R/R myeloma, including patients with high-risk genetic abnormalities. Clinical trial information: NCT03590652.

Early safety and efficacy from a phase I open-label clinical study of LVGN7409 (CD40 agonist antibody) in patients with advanced or metastatic malignancies.

e14501 Background: LVGN7409 is a recombinant monoclonal antibody against CD40. The modified Fc fragment binds FcγRIIB selectively. LVGN7409 activates CD40 in Fc-FcγRIIB cross-link dependent manner and thus optimally in CD40 and FcγRIIB enriched tumor microenvironment. LVGN7409 demonstrated more robust antitumor efficacy and superior safety profile than published CD40 agonist antibodies in preclinical models. An open-label, first in human phase 1 study of LVGN7409 as a single agent, combined with LVGN3616 (anti-PD-1 antibody), and combined with LVGN3616 and LVGN6051 (CD137 agonist antibody) is ongoing. Methods: LVGN7409 was given intravenously every 3 weeks. For single agent dose-finding, LVGN7409 accelerated doses from 0.01 to 0.1mg/kg, and then conventional “3 + 3” design from 0.3 mg/kg. The objectives evaluate LVGN7409 safety, RP2D in a single agent and combination therapy, PK, immunogenicity, preliminary antitumor activity, and exploratory PD biomarkers. Results: As date on January 24, 2022, 12 patients (5 males, 7 females; median age 56, range 29-76; all ECOG 1 at screening; median 6 lines of prior therapies, range 2-14) have been treated with LVGN7409 monotherapy into 6 cohorts (0.01-0.03mg/kg n=1, 0.1-0.3mg/kg n=3, 1mg/kg n=6, 2mg/kg n=2). They received a median of 3 (range 1-10) treatment cycles. No DLT event was observed up to 2mg/kg of LVGN7409. Treatment-related adverse events (TRAEs) of any grade occurred in 10 out of 12 patients (n=10) including infusion related reaction (n=7), amylase increased (n=5), lipase increased (n=5), ALT increased (n=5), AST increased (n=5), bilirubin increased (n=1), WBC or neutrophil decreased (n=1), nausea (n=1), and cytokine release syndrome (n=1). Two patients experienced grade 3 TRSAEs: amylase/lipase increased (n=1) and ALT/AST increased (n=1). Most TRAEs were transient, asymptomatic, self-limited, and occurred in the initial cycle without recurrence upon rechallenge. Four of nine evaluable patients (44%) hadstabledisease by RECIST1.1 and iRECIST, with one active patient being treated for more than 8 months. CD40 receptor occupancy was achieved at the dose of 0.3 mg/kg and above; preliminary pharmacodynamic marker changes were observed. Conclusions: Preliminary evidence showed LVGN7409 monotherapy was well tolerated up to 2mg/kg. Approximately 44% of stable diseases were observed in these heavily treated patients. The favorable safety profile and preliminary antitumor activity warrant further evaluation of LVGN7409 as a single agent and in combination with other cancer therapeutics in patients with advanced malignancies. Clinical trial information: NCT04635995.

On the perspective of an aging population and its potential impact on drug attrition and pre-clinical cardiovascular safety assessment

There is no refuting that America's population is growing older: for the first time in US history, by 2034 older adults (defined as >65 years of age) are projected to outnumber children under the age of 18, representing approximately 70 million people or almost 25% of the population (Lloyd-Jones et al., 2010). Described as the “silver tsunami”, this flood of older adults is driven by the baby boomers (people born after World War II, from 1946 to 1964): they are now reaching old age, living longer due to significant advances in healthcare coupled with a record low birth rate, resulting in a skewed elderly population demographic.Unfortunately, older adults are also becoming increasingly unhealthy. Many often suffer from several chronic disorders requiring the use of multiple medications at a level higher than any other age group, resulting in an increased risk of drug-drug interactions (DDIs) and adverse drug reactions (ADRs). Indeed, because of age-related changes in pharmacokinetics (PK) and pharmacodynamics (PD), older adults are also more vulnerable to drug toxicity. Prescribed drugs certainly improve a range of health outcomes, but also often cause considerable ADRs, leading to devastating consequences for patients, clinicians, and manufacturers. Therefore, safe and effective pharmacotherapy remains one of the greatest growing challenges in geriatric medicine.In this review we examine the effects of aging and its impact on the increased risk of experiencing ADRs, resulting in devastating consequences for patients and manufacturers. We assess the current regulatory considerations related to the development of drugs for this population and highlight issues, concerns, and propose alternatives to the standard battery of tests focused on assessing cardiovascular (CV) safety in an attempt to develop safer and efficient new drugs for the growing elderly demographic.

Central Nervous System Trial Failures: Using the Fragile X Syndrome-mGluR5 Drug Target to Highlight the Complexities of Translating Preclinical Discoveries Into Human Trials.

Drug trials of the central nervous system(CNS) have been plagued with uninformative failures, often because of the difficulties of knowing definitively whether dosing achieved was sufficient to modulate the intended CNS target at adequate concentrations to produce pharmacodynamic or dose-related changes in readouts of brain function. Key design elements can be introduced into early-stage trials to get at this issue. This commentary builds on a review of earlier clinical studies in Fragile X syndrome to explore the extent to which the chain of evidence is in place to allow for interpretation of the results as ruling in or out the utility of modulating one or another molecular target to treat this disorder. Recent and current biomarker studies in Fragile X syndrome occurring subsequent to the clinical studies are reviewed to see if they might address any chain of evidence gaps. Despite the strong preclinical basis for targeting molecular mechanisms, the lack of efficacy seen in clinical studies remains uninterpretable, with regard to ruling in or out the utility of targeting the mechanism in a clinical population, given the absence of studies, which address whether doses of administered drug impacted the targeted brain mechanism. The value of pursuing clinical studies of compounds targeted to novel mechanisms in the absence of clinical pharmacological evidence of some anticipated mediating pharmacokinetic/pharmacodynamic signals is questionable. One or more biomarkers of a drug effect on brain function are needed to establish dose dependent CNS effects that allow one to interpret clinical results as ruling in or out a mechanism and providing a firm basis for continuing or not, as well as informing dose selection in any clinical efficacy trials. Initiatives to address this general need in pediatric psychopharmacology are highlighted.

Biological impact of iberdomide in patients with active systemic lupus erythematosus

ObjectivesIberdomide is a high-affinity cereblon ligand that promotes proteasomal degradation of transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). Pharmacodynamics and pharmacokinetics of oral iberdomide were evaluated in a phase 2b...

An Up-to-Date Article Regarding Particularities of Drug Treatment in Patients with Chronic Heart Failure.

Since the prevalence of heart failure (HF) increases with age, HF is now one of the most common reasons for the hospitalization of elderly people. Although the treatment strategies and overall outcomes of HF patients have improved over time, hospitalization and mortality rates remain elevated, especially in developed countries where populations are aging. Therefore, this paper is intended to be a valuable multidisciplinary source of information for both doctors (cardiologists and general physicians) and pharmacists in order to decrease the morbidity and mortality of heart failure patients. We address several aspects regarding pharmacological treatment (including new approaches in HF treatment strategies [sacubitril/valsartan combination and sodium glucose co-transporter-2 inhibitors]), as well as the particularities of patients (age-induced changes and sex differences) and treatment (pharmacokinetic and pharmacodynamic changes in drugs; cardiorenal syndrome). The article also highlights several drugs and food supplements that may worsen the prognosis of HF patients and discusses some potential drug–drug interactions, their consequences and recommendations for health care providers, as well as the risks of adverse drug reactions and treatment discontinuation, as an interdisciplinary approach to treatment is essential for HF patients.

Psychosomatic or Psychotropic Polypharmacy? A Case Highlighting the Importance of Pharmacokinetics

<h3>Introduction</h3> Psychotropic drugs are among the most common medications prescribed to elderly patients. The number of psychotropic drugs has increased significantly over the past few decades with a proportional increase in adverse medication outcomes including drug-drug interactions. Advancing age is accompanied by changes in pharmacokinetics and pharmacodynamics that put older patients at greater risk for adverse medication outcomes. The majority of psychotropic agents are metabolized by hepatic enzymes with many drug-drug interactions of psychotropics involving the cytochrome P450 enzyme system. The activity of these enzymes can be inhibited or induced by several drugs resulting in clinically significant drug-drug interactions. This case highlights the importance of maintaining a comprehensive understanding of pharmacokinetics and considering the possibility of an adverse drug reaction when evaluating an older patient presenting with new and unexplained symptoms. <h3>Methods</h3> This case report focuses on a geriatric patient with depression and multiple medical comorbidities presenting with unexplained neurological symptoms thought to be psychosomatic in origin. Patient's clinical documents in our electronic medical records system were reviewed. A literature survey was performed on the topic of psychotropic polypharmacy, pharmacokinetics, and the increased risk of adverse medical outcomes in geriatric patients. <h3>Results</h3> A 69 year old female was referred by inpatient neurology to an outpatient geriatric psychiatry clinic for evaluation and management of psychogenic non-epileptic seizures/conversion disorder. She had been experiencing ongoing symptoms of dizziness, dysarthria, and gait instability with multiple serious falls requiring hospitalization. She underwent an extensive and uneventful medical and neurological workup. Immediately prior to onset of symptoms, the patient was taking the maximum dose of amitriptyline at 150mg when bupropion was added and increased to 300mg. Symptoms were suspected to be secondary to amitriptyline toxicity with bupropion (a potent CYP2D6 inhibitor) leading to supratherapeutic amitriptyline levels (a CYP2D6 substrate). Amitriptyline level was obtained and returned supratherapeutic at 362. Both amitriptyline and bupropion were discontinued with immediate resolution of the patient's neurological symptoms. <h3>Conclusions</h3> Polypharmacy is a disease simulator; patients may exhibit conditions caused by medications rather than organic illness. It is crucial for clinicians to be aware of drug interactions and consider whether the development of a new medical condition could be the presentation of an adverse drug event. Many drug interactions are the result of altered CYP450 metabolism, and therapeutic drug doses may cause adverse effects related to increased drug serum levels if a CYP450 enzyme inhibitor is added or if the patient is a genetically poor metabolizer. Knowledge of the most important drugs metabolized by cytochrome P450 enzymes, as well as the most potent inducers and inhibitors, can help to reduce the occurrence of adverse drug events and interactions.

Accelerating topical formulation development for inflammatory dermatoses; an ex vivo human skin culture model consistent with clinical therapeutics

Although animal models have been extensively used to evaluate human topical therapeutics, they exhibit marked physiological differences to human skin. Our objective was to develop a human ex vivo skin culture model to explore the pathophysiology of inflammatory dermatoses and for preclinical testing of potential therapeutic treatments. Ex vivo skin barrier integrity and metabolic activity was retained for 5 days and stimulation of T-helper cells (Th1), which produce proinflammatory cytokines, provided inflammatory responses similar to those reported from in vivo biopsy. Tissue responses to established therapies of pimecrolimus (Elidel) and clobetasol propionate (Dermovate) were evaluated using the human ex vivo skin culture, assessing pharmacodynamic changes in gene expression alongside the pharmacokinetics of drug penetration with both products showing time dependent efficacies. The translational utility of the human ex vivo skin culture model of inflammatory dermatoses was demonstrated through comparison with an in vivo clinical study, with similar reductions in inflammatory gene expression recorded for both drug treatments. Thus, this model can reduce, replace or refine animal testing and also mitigate the risk of failure in costly and time-consuming clinical trials associated with novel topical therapeutic development.

A nonrandomized phase I and biomarker trial of regorafenib in advanced myeloid malignancies.

We conducted a single‐center, open‐label, dose escalation, and expansion phase I trial of the antiangiogenic multikinase inhibitor regorafenib in patients with advanced myeloid neoplasms. We enrolled 16 patients with relapsed/refractory acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), chronic myelomonocytic leukemia (CMML), or myelodysplastic syndrome (MDS). A 3 + 3 dose escalation design was used with two planned dose levels (120 or 160 mg daily) and one de‐escalation level (80 mg daily). An additional 10 patients were treated on an expansion cohort. The recommended phase two dose of regorafenib was 160 mg daily, with no dose‐limiting toxicities. The best overall disease response by International Working Group criteria included one partial and stable disease in 11 patients. Tissue studies indicated no change in Ras/mitogen‐activated protein kinase (MAPK) pathway activation in responders. Pharmacodynamic changes in plasma VEGF, PlGF, and sVEGFR2 were detected during treatment. Baseline proinflammatory and angiogenic cytokine levels were not associated with clinical response. Single‐agent regorafenib demonstrated an acceptable safety profile in relapsed/refractory myeloid malignancy patients. Most patients achieved stable disease, with modest improvements in cell counts in some MDS patients. Biomarker studies were consistent with on‐target effects of regorafenib on angiogenesis. Future studies should investigate the role of regorafenib in combination therapy approaches.

Polypharmacy occurrence and the related risk of premature death among older adults in Denmark: A nationwide register-based cohort study.

Polypharmacy, defined as the concurrent use of ≥5 medications, increases the risk of drug-drug and drug-disease interactions as well as non-adherence to drug therapy. This may have negative health consequences particularly among older adults due to age-related pharmacokinetic and pharmacodynamic changes. This study aims to uncover the occurrence of polypharmacy among older adults in Denmark and investigate how polypharmacy relates to mortality. This nationwide register-based study included 1,338,058 adults aged 65+ years between January 2013 and December 2017 in Denmark. Polypharmacy prevalence was measured at time of inclusion while incidence and the association between polypharmacy and mortality were measured over the five-year follow-up using Cox regression. In an attempt to adjust for confounding by indication, propensity scores with overlap weighting were introduced to the regression model. At time of inclusion, polypharmacy prevalence was 29% and over the five years follow-up, 47% of the remaining adults transitioned into polypharmacy. Identified risk factors included multimorbidity (2+ morbidities: HR = 3.51; 95% CI = 3.48-3.53), age (95+ years: HR = 2.85; 95% CI = 2.74-2.96), socioeconomic factors (Highest income quartile: HR = 0.81; 95% CI = 0.80-0.81), region of birth region (Non-western migrants: HR = 0.77; 95% CI = 0.75-0.79), marital status (Divorced: HR = 1.10; 95% CI = 1.10-1.12) and year of inclusion (2017: HR = 1.19; 95% CI = 1.19-1.22). Further analyses showed that polypharmacy involves many different drug cocktails with medication for the cardiovascular system (95%), blood and blood-forming organs (69%), alimentary tract and metabolism (61%) and nervous system (54%) contributing the most. After adjustment for propensity scores with OW, both polypharmacy (HR = 3.48, CI95% = 3.41-3.54) and excessive polypharmacy (HR = 3.48, CI95% = 3.43-3.53) increased the risk of death substantially. A considerable proportion of older adults in Denmark were exposed to polypharmacy dependent on health status, socio-economic status, and societal factors. The associated three- to four-fold mortality risk indicate a need for further exploration of the appropriateness of polypharmacy among older adults.

Targeting Mcl-1 by AMG-176 During Ibrutinib and Venetoclax Therapy in Chronic Lymphocytic Leukemia.

B-cell receptor (BCR) signaling pathway and Bcl-2 family prosurvival proteins, specifically Bcl-2 and Mcl-1, are functional in the pathobiology of chronic lymphocytic leukemia (CLL). A pivotal and apical molecule in the BCR pathway is Bruton’s tyrosine kinase (BTK). Together, BTK, Bcl-2, and Mcl-1 participate in the maintenance, migration, proliferation, and survival of CLL cells. Several ongoing and published clinical trials in CLL reported high rates of remission, namely, undetectable measurable residual disease (u-MRD) status with combined BTK inhibitor ibrutinib and Bcl-2 antagonist, venetoclax. While the majority of patients achieve complete remission with undetectable-measurable residual disease, at least one third of patients do not achieve this milestone. We hypothesized that cells persistent during ibrutinib and venetoclax therapy may be sensitive to combined venetoclax and Mcl-1 inhibitor, AMG-176. To test this hypothesis, we took peripheral blood samples at baseline, after Cycle 1 and Cycle 3 of ibrutinib monotherapy, after one week and 1 cycle of ibrutinib plus venetoclax therapy. These serial samples were tested for pharmacodynamic changes and treated in vitro with AMG-176 or in combination with venetoclax. Compared to C1D1 cells, residual cells during ibrutinib and venetoclax treatment were inherently resistant to endogenous cell death. Single agent exposure induced some apoptosis but combination of 100 nM venetoclax and 100 or 300 nM of AMG-176 resulted in 40–100% cell death in baseline samples. Cells obtained after four cycles of ibrutinib and one cycle of venetoclax, when treated with such concentration of venetoclax and AMG-176, showed 10–80% cell death. BCR signaling pathway, measured as autophosphorylation of BTK was inhibited throughout therapy in all post-therapy samples. Among four anti-apoptotic proteins, Mcl-1 and Bfl-1 decreased during therapy in most samples. Proapoptotic proteins decreased during therapy. Collectively, these data provide a rationale to test Mcl-1 antagonists alone or in combination in CLL during treatment with ibrutinib and venetoclax.

An Fc-Competent Anti-Human TIGIT Blocking Antibody Ociperlimab (BGB-A1217) Elicits Strong Immune Responses and Potent Anti-Tumor Efficacy in Pre-Clinical Models.

TIGIT (T-cell immunoglobulin and ITIM domain) has emerged as a promising target in cancer immunotherapy. It is an immune “checkpoint” inhibitor primarily expressed on activated T cells, NK cells and Tregs. Engagement of TIGIT to its ligands PVR and PVR-L2 leads to inhibitory signaling in T cells, promoting functional exhaustion of tumor-infiltrating T lymphocytes. Here, we described the pre-clinical characterization of Ociperlimab (BGB-A1217), a novel humanized IgG1 anti-TIGIT antibody (mAb), and systemically evaluated the contribution of Fc functions in the TIGIT mAb-mediated anti-tumor activities. BGB-A1217 binds to the extracellular domain of human TIGIT with high affinity (KD = 0.135 nM) and specificity, and efficiently blocks the interaction between TIGIT and its ligands PVR or PVR-L2. Cell-based assays show that BGB-A1217 significantly enhances T-cell functions. In addition, BGB-A1217 induces antibody dependent cellular cytotoxicity (ADCC) against Treg cells, activates NK cells and monocytes, and removes TIGIT from T cell surfaces in an Fc-dependent manner, In vivo, BGB-A1217, either alone or in combination with an anti-PD-1 mAb elicits strong immune responses and potent anti-tumor efficacy in pre-clinical models. Moreover, the Fc effector function is critical for the anti-tumor activity of BGB-A1217 in a syngeneic human TIGIT-knock-in mouse model. The observed anti-tumor efficacy is associated with a pharmacodynamic change of TIGIT down-regulation and Treg reduction. These data support the selection of BGB-A1217 with an effector function competent Fc region for clinical development for the treatment of human cancers.

Heart failure as a risk factor of adverse drug reactions. Part 1: potential changes in pharmacokinetics

The use of many drugs is associated with the risk of adverse drug reactions (ADRs), including those that increase mortality and / or morbidity and / or seek medical help or hospitalization, so called «drug-induced diseases» (DID). There is a number of factors that increase the risk of DID (risk factors) including comorbid diseases (for example, chronic kidney disease, hepatic impairment, obesity etc.). These pathologic conditions induce changes in pharmacokinetics (PK) and pharmacodynamics of drugs, thereby increasing the risk of ADRs. One of these diseases is heart failure (HF). Most studies of PK changes were conducted among patients with LVEF from 40 to 45 %, and excluded patients with concomitant diseases that could affect the PK of drugs (for example, serious liver and / or kidney diseases), therefore in polymorbid patients, trial findings may not be applicable. HF may be associated with a decrease in bioavailability, a decrease in volume of distribution, a change in the activity of cytochrome P450 isoenzymes, etc. Individual dose and dosage regimen adjustment can significantly reduce risks, improve the quality of medical care and improve the prognosis in patients with heart failure.

Genetic Risk Factors for Adverse Drug Reactions

The use of medicines may in some cases be associated with the development of drug-induced diseases (DIDs) аnd other adverse drug reactions (ADRs), which leads to an increase in morbidity/mortality rates, and/or symptoms forcing a patient to seek medical attention or resulting in hospitalisation. ADRs may develop due to changes in a patient’s genotype, which entail an inadequate pharmacological response. The aim of the study was to analyse and summarise literature data on genetic risk factors that cause DIDs аnd other ADRs. It was shown that the polymorphism of genes encoding enzymes of drug metabolism (CYP, UGT, NAT, TPMT, EPHX, GST, etc.) or carriers (transporters) of drugs (P-gp, BCRP, MRP, OATP, OCT, etc.) can change the pharmacokinetics of drugs, affecting their activity. Polymorphism of RYR1, CACNA1S, MT-RNR1, VKORC1, and other genes encoding receptors targeted by drugs, and human leukocyte antigen (HLA) gene, may affect drug pharmacodynamics by modifying drug targets or changing the sensitivity of biological pathways to pharmacological effects of medicines. Changes in drug pharmacokinetics and pharmacodynamics may cause DIDs аnd other ADRs. The use of pharmacogenetic tests will allow a personalised approach to patients’ treatment and prevention or timely detection of potential ADRs during therapy. Before prescribing some medicines, clinicians should use recommendations on their dosing based on pharmacogenetic tests, which are posted on the official websites of Pharmacogenomics Research Network (PGRN), Pharmacogenomics Knowledgebase (PharmGKB), and Clinical Pharmacogenetics Implementation Consortium (CPIC). The results of ongoing clinical studies on the effect of gene polymorphism on drug safety will soon allow for higher personalisation of the choice of pharmacotherapy and prevention of many ADRs, including DIDs.

Inappropriate prescribing: hazards and solutions.

With population ageing, the number of older people is growing, which results in increasing number of people with multimorbidity and related polypharmacy. Polypharmacy in its turn leads to drug-related problems (DRPs) and potentially inappropriate prescribing (IP) in older people. In this commentary, susceptibility of older people to DRPs due to changes in pharmacokinetics and pharmacodynamics, plurality of prescribing physicians, inadequate consideration of patients' characteristics, polypharmacy and its consequences such as prescribing cascades, drug interactions and potentially IP have been discussed respectively. Consecutively, identifying DRPs and optimizing of IP, including drug reconciliation, application of criteria for identifying and preventing IP, implementation of computer-based prescribing systems, and comprehensive geriatric assessment and management have been elaborated as well. One of the main challenges regarding appropriate and tailored prescribing in older people is to evaluate whether the expected benefits of pharmacotherapy are bigger than the risks in a population with multimorbidity, decreased tolerance to vulnerability and limited life expectancy. Comprehensive geriatric assessment enables informed prescribing decisions in the context of such variables. A challenge for future research is how to integrate important clinical information obtained by existing methods into a comprehensive and wide-reaching approach targeting all potential factors involved in causing DRPs. Good prescribing in late life accommodates the needs of older patients with multimorbidity. Individualized, interactive, multidisciplinary, and multifaceted approach to geriatric pharmacotherapy should be promoted and encouraged. How to optimize pharmacological prescription in complex older patients is a major legacy of geriatrics to contemporary medicine/medical practice.