Pharmacodynamic Considerations Research Articles

Structure of Medication Therapy in Patients with Complex Hand Bone Fractures in Kyrgyz Republic

This article analyzes the structure of medication therapy in patients with complex hand bone fractures in the Kyrgyz Republic. Complex hand fractures are common injuries requiring a multi-stage treatment approach, including surgery, immobilization, and adequate medication therapy. The article examines various therapeutic regimens used at different stages of treatment: the first-line therapy includes analgesics and anti-inflammatory drugs, the second-line therapy adds hormonal medications and tissue regeneration stimulants, and alternative methods incorporate biologically active agents and physiotherapy. Effectiveness was evaluated based on clinical indicators such as pain level, bone healing rate, complication frequency, and restoration of hand function. The article also discusses gender-specific differences in therapeutic approaches, necessitating the consideration of pharmacokinetics and pharmacodynamics in men and women. This study highlights the need for the development of standardized treatment protocols adapted to local healthcare conditions to improve treatment efficacy and reduce complications.

Pharmacokinetic and Pharmacodynamic Considerations in Personalized Medicine: Optimizing Drug Therapy

Pharmacokinetic and Pharmacodynamic Considerations in Personalized Medicine: Optimizing Drug Therapy

Pharmacokinetic and pharmacodynamic considerations with psychiatric disorders and migraines.

Pharmacokinetic and pharmacodynamic considerations with psychiatric disorders and migraines.

Central Nervous System Medications: Pharmacokinetic and Pharmacodynamic Considerations for Older Adults.

Most drugs have not been evaluated in the older population. Recognizing physiological alterations associated with changes in drug disposition and with the ultimate effect, especially in central nervous system-acting drugs, is fundamental. While considering pharmacokinetics, it should be noted that the absorption of most drugs from the gastrointestinal tract does not change in advanced age. There are only few data about the effect of age on the transdermal absorption of medications such as fentanyl. Absorption from an intramuscular injection may be similar in older adults as in younger patients. The distribution of lipophilic drugs (such as diazepam) is increased owing to a relative increase in the percentage of body fat, causing drug accumulation and prolonged drug elimination following cessation. Phase I drug biotransformation is variably decreased in aging, impacting elimination, and hepatic drug clearance has been shown to decrease in older individuals by 10-40% for most drugs studied. Lower doses of phenothiazines, butyrophenones, atypical antipsychotics, antidepressants (citalopram, mirtazapine, and tricyclic antidepressants), and benzodiazepines (such as diazepam) achieve the same extent of exposure. For renally cleared drugs with no prior metabolism (such as gabapentin), the glomerular filtration rate appropriately estimates drug clearance. Important pharmacodynamic changes in older adults include an increased sedative effect of benzodiazepines at a given drug exposure, and a higher sensitivity to mu opiate receptor agonists and to opioid adverse effects. Artificial intelligence, physiologically based pharmacokinetic modeling and simulation, and concentration-effect modeling enabling a differentiation between the pharmacokinetic and the pharmacodynamic effects of aging might help to close some of the gaps in knowledge.

Bipolar Disorder in the Elderly: Clinical Insights and Therapeutic Challenges

IntroductionBipolar Disorder (BD) is a mood disorder characterized by recurrent episodes of mania, hypomania, and depression. While it often manifests in early adulthood, it can persist or emerge in later life, posing unique diagnostic and therapeutic challenges in the elderly population. This abstract explores the clinical aspects, diagnostic intricacies, and therapeutic considerations of BD in older adults.ObjectivesThis study aims to shed light on the epidemiology and clinical presentation of BD in the elderly, discuss the diagnostic challenges, and address the complexities of treatment and management in this age group.Methods A comprehensive review of the literature was conducted, encompassing epidemiological studies, clinical trials, case reports, and expert guidelines from the past decade. The search was performed using medical databases such as PubMed and Medline.Results BD in the elderly presents with a range of clinical complexities that differentiate it from presentations in younger adults. These complexities include atypical features as elderly individuals may exhibit less overt manic or hypomanic symptoms, resembling irritability rather than euphoria; depressive episodes can be more prevalent and prolonged, leading to potential misdiagnosis as unipolar depression; medical comorbidities: older adults with BD often have more medical conditions, complicating treatment; cognitive impairment: cognitive decline, including mild cognitive impairment and dementia, is common and distinguishing it from neurodegenerative conditions requires specialized assessment; mixed episodes, in older adults may experience mixed episodes, requiring intensive treatment; diagnostic challenges: overlapping symptoms with other disorders make accurate diagnosis challenging. Treatment includes mood stabilizers like lithium, valproate, or lamotrigine, and atypical antipsychotics like quetiapine or aripiprazole. Treatment response varies, requiring consideration of age-related pharmacokinetics, pharmacodynamics, and drug interactions. Non-pharmacological interventions, including psychoeducation, tailored cognitive-behavioural therapies, and psychosocial support, are essential.ConclusionsIn summary, BD in the elderly demands a customized, multidisciplinary approach to navigate diagnostic complexities and optimize treatment, considering comorbidities and cognitive factors. Enhanced clinical awareness and holistic care are essential for effective management in this population.Disclosure of InterestNone Declared

Pharmacokinetic and pharmacodynamic considerations of antibiotic therapy among critically ill adult patients with sepsis

A szepszis életet veszélyeztető, komplex klinikai állapot, melynek kezelése jelentős kihívást és számottevő költségráfordítást jelent a betegellátás számára. A szepszis által előidézett patofiziológiai változások jelentős mértékben megváltoztatják a gyógyszerek és a szervezet kölcsönhatását, megnehezítve az optimális gyógyszerelést. A kapillárisszivárgás jelensége, valamint az ellátás során alkalmazott folyadékterápia hatására megemelkedhet egyes antibiotikumok megoszlási térfogata. A hypalbuminaemia következtében megnövekedett szabad frakció a nagy fehérjekötődésű antibiotikumok gyorsabb eliminációját okozhatja. A megnövekedett perctérfogat és a vascularis ellenállás csökkenése a fiatalabb betegpopulációkban megnövekedett renalis clearance-t idézhet elő. A betegek nagyobb hányadában azonban a hipoperfúzió miatt szepszis indukálta akut veseelégtelenség jellemző, melynek hatására a renalis clearance csökken. A klinikai képet tovább árnyalja, ha vesepótló vagy extracorporalis membránoxigenizációs kezelést alkalmazunk. Az antibiotikumok fizikai-kémiai jellemzői meghatározzák, hogy a patofiziológiai változások milyen mértékben befolyásolják az egyes gyógyszermolekulák farmakokinetikai paramétereit. A várttól eltérő gyógyszer-expozíciót előidéző folyamatok ellensúlyozására a farmakokinetikai-farmakodinamikai indexek, valamint a fizikokémiai értékek ismeretében többféle klinikai stratégia áll rendelkezésre. A terápia racionális szempontok szerint történő személyre szabásával és a terápiás gyógyszerszint monitorozásával növelhető a hatékonyság, és csökkenthető az antibiotikumrezisztencia kialakulásának esélye. Orv Hetil. 2024; 165(11): 403–415.

Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Moderate-to-Severe Psoriasis.

Psoriasis is a common inflammatory immune disorder due to chronic activation of the adaptive and innate immune responses. Therapies for psoriasis target reducing inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-17, and interleukin-22. Patients with inflammatory disorders have reduced metabolism by cytochrome P450 enzymes in the liver. The pharmacokinetic and pharmacodynamic changes due to psoriasis also have an impact on reaching therapeutic concentrations of the drug. Pharmacokinetic and pharmacodynamic data help determine the safety and clinical considerations necessary when utilizing drugs for plaque psoriasis. A literature search was performed on PubMed and Ovid MEDLINE for the pharmacokinetic and pharmacodynamic data of oral therapies and biologics utilized for moderate-to-severe plaque psoriasis. The findings from the literature search were organized into two sections: oral therapies and biologics. The pharmacokinetic and pharmacodynamic parameters in healthy patients, patients with psoriasis, and special populations are discussed in each section. The oral therapies described in this review include methotrexate, cyclosporine, apremilast, tofacitinib, and deucravacitinib. Biologics include tumor necrosis factor-alpha inhibitors, interleukin-17 inhibitors, ustekinumab, and interleukin-23 inhibitors. Clinical considerations for these therapies include drug toxicities, dosing frequency, and anti-drug antibodies. Methotrexate and cyclosporine have a risk for hepatoxicity and renal impairment, respectively. Moreover, drugs metabolized via cytochrome P450, including tofacitinib and apremilast have decreased clearance in patients with psoriasis, requiring dose adjustments. Patients treated with therapies such as adalimumab can develop anti-drug antibodies that reduce the long-term efficacy of the drug. Additionally, overweight patients benefit from more frequent dosing to achieve better psoriasis clearance.

Pharmacokinetic and Pharmacodynamic Considerations of Antibiotic Use in Neonates.

The selection of an appropriate dose of a given antibiotic for a neonate not only requires knowledge of the drug's basic pharmacokinetic (PK) and pharmacodynamic (PD) properties but also the profound effects that organ development might have on the volume of distribution and clearance, both of which may affect the PK/PD of a drug. Interest has grown in alternative antibiotic dosing strategies that are better aligned with the antibiotic's PK and PD properties. These strategies should be used in conjunction with minimum inhibitory concentration measurements and therapeutic drug monitoring to measure their potential success. They can also guide the clinician in tailoring the delivery of antibiotics to suit an individual patient's needs. Model-informed precision dosing, such as Bayesian forecasting dosing software (which incorporates PK/PD population models), may be utilized to optimize antibiotic exposure in neonatal populations. Consequently, optimizing the antibiotic dose and exposure in each newborn requires expertise in different fields. It drives the collaboration of physicians together with lab technicians and quantitative clinical pharmacologists.

Time-Dependent Differences in Vancomycin Sensitivity of Macrophages Underlie Vancomycin-Induced Acute Kidney Injury.

Although vancomycin (VCM)-frequently used to treat drug-resistant bacterial infections-often induces acute kidney injury (AKI), discontinuation of the drug is the only effective treatment; therefore, analysis of effective avoidance methods is urgently needed. Here, we report the differences in the induction of AKI by VCM in 1/2-nephrectomized mice depending on the time of administration. Despite the lack of difference in the accumulation of VCM in the kidney between the light (ZT2) and dark (ZT14) phases, the expression of AKI markers due to VCM was observed only in the ZT2 treatment. Genomic analysis of the kidney suggested that the time of administration was involved in VCM-induced changes in monocyte and macrophage activity, and VCM had time-dependent effects on renal macrophage abundance, ATP activity, and interleukin (IL)-1β expression. Furthermore, the depletion of macrophages with clodronate abolished the induction of IL-1β and AKI marker expression by VCM administration at ZT2. This study provides evidence of the need for time-dependent pharmacodynamic considerations in the prevention of VCM-induced AKI as well as the potential for macrophage-targeted AKI therapy. SIGNIFICANCE STATEMENT: There is a time of administration at which vancomycin (VCM)-induced renal injury is more and less likely to occur, and macrophages are involved in this difference. Therefore, there is a need for time-dependent pharmacodynamic considerations in the prevention of VCM-induced acute kidney injury as well as the potential for macrophage-targeted acute kidney injury therapy.

Pharmcokinetic and pharmacodynamic considerations for the anticholinergic burden scale of drugs.

Older adults frequently have many systemic diseases that require treatment with multiple drugs, and thus anticholinergic adverse effect by polypharmacy is a significant concern in the management of older adults. The accuracy of the anticholinergic burden rating may be increased by considering pharmacokinetic and pharmacodynamic factors such as biophase drug concentrations, the pharmacologically active metabolites formed after drug administration, and muscarinic receptor-mediated effects. Therefore, a pharmacological evidence-based burden scale that considers pharmacokinetic and pharmacodynamic factors is expected to be a more optimal tool for precisely assessing the anticholinergic burden, specifically risk reductions in anticholinergic adverse events in the poly-medicated elderly. Geriatr Gerontol Int 2024; 24: 81-87.

Pharmacokinetic and Pharmacodynamic Considerations of Novel Antibiotic Agents for Pediatric Infections: A Narrative Review.

Background: Currently, the escalation of microbial resistance poses a significant global challenge. Children are more susceptible to develop infections and therefore are prescribed antibiotics more frequently. The overuse and misuse of antibiotics in pediatric patients can play a considerable role in developing microbial resistance. Accordingly, many policies, including research into new antibiotic agents have been recommended to combat microbial resistance. Recent developments in novel antibiotics have shown promising results against multi-drug resistant (MDR) and extensive drug resistance (XDR) pathogens. However, as pediatric patients are typically excluded from the clinical trials of new medications, labeling and information about approved antibiotics should be improved. This study aimed to evaluate antibiotics having been introduced to the market in the last decade focusing on pediatric population. Methods: This study reviewed the published literatures on novel FDA-approved antibiotics released between 2010 and 2022. Results: Finally, seven newly approved antibiotics including ceftaroline fosamil, ceftazidime-avibactam, ceftolozane-tazobactam, ceftobiprole, imipenem-cilastatin-relebactam, meropenem-vaborbactam, and tedizolid were considered in the present review-article. All relevant data extracted from literatures, were discussed in different subtitles of "Pharmacology", "Mechanism of action", "Indication", "Dosage regimen and pharmacokinetic and pharmacodynamic properties", "Dosage adjustment in renal/liver failure", "Resistance pattern", and "Adverse drug events". Conclusion: This study reviewed available data on seven new antibiotic agents and their pharmacodynamic and pharmacokinetic properties, with a particular focus on their use in pediatric patients. The information presented in this review will be useful for healthcare professionals in selecting appropriate antibiotics for pediatric patients and for researchers in achieving the ideal therapeutic regimens.

Dual pathway inhibition in patients with atherosclerotic disease: pharmacodynamic considerations and clinical implications

Introduction The persistence of elevated rates of ischemic recurrences despite the use of antiplatelet therapy among patients with atherosclerotic disease together with the understanding of the pivotal role of coagulation in the thrombo-inflammatory processes involved in the pathogenesis of atherosclerosis and its complications has fostered the development of treatments targeting both platelets and coagulation, a strategy known as dual-pathway inhibition (DPI). Areas covered In this review we discuss the recent advancements in the understanding of the interplay between coagulation, platelets and inflammation involved in the pathophysiology of atherosclerosis and atherothrombosis, as the rationale for the implementation of a DPI strategy. We also discuss the available pharmacodynamic (PD) evidence and clinical implications with the use of DPI in patients with atherosclerotic disease. Expert opinion The implementation of a DPI by adding the so-called “vascular dose of rivaroxaban” (i.e., 2.5 mg bis in die), on top of antiplatelet therapy has consistently been associated with reduced levels of thrombin generation in PD studies and with reduced ischemic event rates at the cost of increased bleeding compared to antiplatelet therapy alone. Further research is warranted to best define patients in whom a DPI regimen has the best safety and efficacy profile.

Pharmacodynamic Biomarkers Evidentiary Considerations for Biosimilar Development and Approval.

A biosimilar is a biological product that is highly similar to and has no clinically meaningful differences from a US Food and Drug Administration (FDA)-approved reference product. The development and approval of biosimilars is critical to enhancing the availability of safe, effective, and affordable treatment options for patients. Utilization of pharmacodynamic (PD) biomarkers can help streamline biosimilar development programs as the current process can be costly and time-consuming. Whereas PD biomarkers have not been prominently used across biosimilar approvals to date, moving forward, there is ample opportunity to increase the use of PD biomarkers in biosimilar development programs in place of comparative clinical studies with efficacy end point(s). This includes utilizing PD biomarkers that were not used as surrogate end points in approval of reference products. This mini-review summarizes how PD biomarkers have been used in biosimilar development programs to date and then discusses evidentiary considerations for PD biomarkers. In addition, study design considerations for clinical pharmacokinetic and PD assessment of proposed biosimilars are discussed. Finally, the FDA's applied regulatory science activities related to PD biomarkers for biosimilars conducted in support of the FDA's Biosimilars Action Plan are reviewed. This included conducting three clinical studies to address information gaps about PD biomarkers for biosimilars and inform general methodological best practices. In summary, enhancing our understanding of key evidentiary considerations and optimal study designs for incorporating PD biomarkers in the evaluation of proposed biosimilars can help bring more treatment options to patients faster.

Pharmacokinetic and pharmacodynamic considerations of antibiotics and antifungals in liver transplantation recipients.

The liver plays a major role in drug metabolism. Liver transplantation impacts the intrinsic metabolic capability and extrahepatic mechanisms of drug disposition and elimination. Different levels of inflammation and oxidative stress during transplantation, the process of liver regeneration, and the characteristics of the graft alter the amount of functional hepatocytes and activity of liver enzymes. Binding of drugs to plasma proteins is affected by the hyperbilirubinemia status and abnormal synthesis of albumin and alpha-1-acid glycoproteins. Postoperative intensive care complications such as biliary, circulatory, and cardiac also impact drug distribution. Renally eliminated antimicrobials commonly present reduced clearance due to hepatorenal syndrome and the use of nephrotoxic immunosuppressants. In addition, liver transplantation recipients are particularly susceptible to multidrug-resistant infections due to frequent manipulation, multiple hospitalizations, invasive devices, and frequent use of empiric broad-spectrum therapy. The selection of appropriate anti-infective therapy must consider the pathophysiological changes after transplantation that impact the pharmacokinetics and pharmacodynamics of antibiotics and antifungal drugs.

COVID-19 vaccination: a possible trigger for Addisonian crisis in a patient with Addison’s disease

Infection with COVID-19 disease is caused by the SARS-CoV-2 virus. Following its identification, the pursuit of the rapid development of effective vaccines became a pandemic-period international public health priority. This report describes the case of an older woman with Addison’s disease who developed acute clinical symptoms and signs indicative of an Addisonian crisis following each of two consecutive doses of the Pfizer BioNTech Covid-19 vaccines. Both presentations (with nausea, vomiting, hypotension, tachycardia, and transient hypoglycaemia) occurred within 24 hours of receipt of the vaccines. In each instance, she responded well to treatment with intravenous fluids, and temporarily changing her maintenance oral steroid regimen to higher dose intravenous steroids. She successfully completed a period of rehabilitation and was discharged home. Some pharmacokinetic and pharmacodynamic considerations of the Pfizer BioNTech COVID-19 vaccines are discussed. An overview is presented of Addison’s disease and Addisonian crisis. The discussion also applies two causality assessment systems to derive a classification of ‘probable’ adverse drug reactions for the index case report.

Comparison of Piperacillin and Tazobactam Pharmacokinetics in Critically Ill Patients with Trauma or with Burn.

Critical illness caused by burn and sepsis is associated with pathophysiologic changes that may result in the alteration of pharmacokinetics (PK) of antibiotics. However, it is unclear if one mechanism of critical illness alters PK more significantly than another. We developed a population PK model for piperacillin and tazobactam (pip-tazo) using data from 19 critically ill patients (14 non-burn trauma and 5 burn) treated in the Military Health System. A two-compartment model best described pip-tazo data. There were no significant differences found in the volume of distribution or clearance of pip-tazo in burn and non-burn patients. Although exploratory in nature, our data suggest that after accounting for creatinine clearance (CrCl), doses would not need to be increased for burn patients compared to trauma patients on consideration of PK alone. However, there is a high reported incidence of augmented renal clearance (ARC) in burn patients and pharmacodynamic (PD) considerations may lead clinicians to choose higher doses. For critically ill patients with normal kidney function, continuous infusions of 13.5–18 g pip-tazo per day are preferable. If ARC is suspected or the most stringent PD targets are desired, then continuous infusions of 31.5 g pip-tazo or higher may be required. This approach may be reasonable provided that therapeutic drug monitoring is enacted to ensure pip-tazo levels are not supra-therapeutic.

Applications of Model-Based Target Pharmacology Assessment in Defining Drug Design and DMPK Strategies: GSK Experiences.

Many critical decisions faced in early discovery require a thorough understanding of the dynamic behavior of pharmacological pathways following target engagement. From fundamental decisions on the optimal target to pursue and the ultimate drug product profile (combination of modality, potency, and compound properties) expected to elicit the desired clinical outcome to tactical program decisions such as what chemical series to pursue, what chemical properties require optimization, and what compounds to synthesize and progress, all demand detailed consideration of pharmacodynamics. Model-based target pharmacology assessment (mTPA) is a computational approach centered around large-scale virtual exploration of pharmacokinetic and pharmacodynamic models built early in discovery to guide these decisions. The present work summarizes several examples (use cases) from programs at GlaxoSmithKline that demonstrate the utility of mTPA throughout the drug discovery lifecycle.

Recommendations for the diagnosis and treatment of urinary tract infection in pediatrics. Part 2: Working group associated with the Antimicrobial Committee, Chilean Society of Infectology

The urinary tract infection (UTI) is one of the most common bacterial infections in childhood. An adequate diagnosis is essential to be able to carry out a rational, efficient and effective treatment, however, there is great heterogeneity in diagnostic methods, specifically in the study of antimicrobial susceptibility. The aim of these recommendations is to provide tools to homogenize the diagnosis criteria, susceptibility study and antimicrobial treatment of urinary tract infection in the pediatric population, with a rational use of antibiotics approach. In the first part, the recommendations regarding diagnosis were presented, such as sampling and cut-off points, as well as microbiological considerations for susceptibility study and management of UTI in pediatrics. This second part details the management of complications, UTI in special situations, and pharmacokinetic and pharmacodynamic considerations of antimicrobials to be prescribed in UTI.

Recommendations for the diagnosis and treatment of urinary tract infection in pediatrics. Part 1: Working group associated with the Antimicrobial Committee, Chilean Society of Infectology

The urinary tract infection (UTI) is one of the most common bacterial infections in childhood. An adequate diagnosis is essential to be able to carry out a rational, efficient and effective treatment, however, there great heterogeneity in diagnostic methods, specifically in the study of antimicrobial susceptibility. The aim of these recommendations is to provide tools to homogenize the diagnosis criteria, susceptibility study and antimicrobial treatment of urinary tract infection in the pediatric population, with a rational use of antibiotics approach. In the first part, the recommendations regarding diagnosis are presented, such as sampling and cut-off points, as well as microbiological considerations for susceptibility study and management of UTI in pediatrics. The second part details the management of complications, UTI in special situations, and pharmacokinetic and pharmacodynamic considerations of antimicrobials to be prescribed in UTI.

A Review of the Selected and Newer Antiseizure Medications Used in Childhood Epilepsies.

There have been additions of newer antiseizure medications in the armamentarium of clinicians for the management of epilepsy. The newer antiseizure medications have advantages of better tolerability, lesser adverse effects, and minimal drug interactions in comparison with conventional antiseizure medications. However, high cost and availability are concerns. There are also peculiar pharmacokinetic and pharmacodynamic considerations for thepediatric age, particularly in the context of age-dependent electroclinical syndromes and precision-based medicine. Thisreview attempts to provide a comprehensiveand pragmatic update on newer antiseizure medications.