Altered Pharmacodynamics Research Articles

Quantitative Analysis of Propofol Dosage in Cannabis Users: A Systematic Review and Meta-Analysis

Background: Rising cannabis use poses significant challenges in the administration of general anesthetics, particularly propofol, due to potential alterations in pharmacodynamics caused by tetrahydrocannabinol and its interactions with central nervous system receptors. This systematic review and meta-analysis aims to consolidate the existing literature to quantify propofol requirements in cannabis users, highlighting the complex relationship between cannabis use and anesthetic management. Methods: A systematic search of English-language literature was conducted to identify studies with data on propofol dosing in adult cannabis users. Propofol requirements were defined as the total intraoperative dose needed to achieve and maintain adequate sedation or anesthesia, assessed using parameters like monitoring and procedural tolerance. A random-effects model was used with DerSimonian–Laird estimations for pooled effect sizes and 95% confidence intervals. Heterogeneity was assessed using I2 and Cochran’s Q statistics, and sensitivity analysis was conducted by grouping publications by design, size, and quality. Results: Eight qualified studies were identified with 2268 patients included. Patients who used cannabis were typically younger and more likely to smoke tobacco than non-users. Propofol requirements were significantly higher in cannabis users, who required an average additional dose of 47.33 mg compared to non-users. Subgroup analyses revealed that cannabis users undergoing general anesthesia needed an additional 30.57 mg intraoperatively, while those undergoing sedation for endoscopic procedures required an additional 53.02 mg. Conclusions: These results underscore the need for personalized anesthetic plans to accommodate physiological variations in cannabis users. However, the lack of standardized definitions for propofol requirements and the heterogeneity across studies necessitate caution in interpretation. The observed increase in propofol requirements suggests altered central nervous system sensitivities and receptor changes in cannabis users, emphasizing the need for further research to establish clear definitions, elucidate underlying mechanisms, and refine clinical guidelines for anesthetic management in this population.

Geriatric anaesthesia: Challenges and recent updates – A review

Geriatric anaesthesia is a rapidly growing subspecialty due to the rising number of elderly individuals undergoing surgical procedures. Older adults present a unique set of challenges, including physiological changes, polypharmacy, and comorbidities, all of which can significantly influence anaesthetic management. Age-related alterations in pharmacokinetics and pharmacodynamics make dosing and drug selection more complex. Additionally, the elderly are at a higher risk of perioperative complications such as postoperative cognitive dysfunction (POCD) and delirium. Recent advancements in geriatric anaesthesia have focused on better preoperative assessments, personalized anaesthetic strategies, and enhanced recovery protocols to reduce postoperative morbidity. This review aims to explore the challenges faced in anaesthetizing the elderly and highlights recent updates in the field, including the development of frailty assessment tools, use of regional anaesthesia, and the role of multidisciplinary teams in perioperative care. By optimizing perioperative care, including pain management, anaesthetic depth monitoring, and the prevention of delirium, outcomes for elderly patients can be significantly improved. This article provides a comprehensive review of the current state of geriatric anaesthesia, with a focus on both the challenges faced and innovations that have emerged to improve patient care.

Long-acting growth hormones: innovations in treatment and guidance on patient selection in pediatric growth hormone deficiency.

Long-acting growth hormones (LAGHs) represent a significant advancement in the treatment of pediatric growth hormone deficiency (GHD), offering an alternative to daily recombinant human growth hormone (rhGH) therapy. Traditional rhGH treatments, while effective, require daily injections, often leading to poor adherence due to the frequency of dosing, injection pain, and difficulties with storage and travel. In contrast, LAGHs, such as somatrogon, somapacitan, and lonapegsomatropin, are designed for once-weekly administration, improving patient compliance and quality of life. LAGHs have demonstrated non-inferiority to daily rhGH in phase 3 clinical trials, showing similar efficacy in terms of growth velocity and safety profiles. Despite these advantages, there remain concerns regarding the altered pharmacodynamics of LAGHs, such as the lack of pulsatile secretion and the potential for antibody formation. While the overall safety of LAGHs has been confirmed, some side effects, like lipoatrophy at the injection site, may occur, especially with PEGylated formulations. Guidelines for prescribing LAGHs are still evolving.. They are not yet approved for other conditions traditionally treated with rhGH, such as Turner or Noonan syndrome. Pediatric endocrinologists must carefully consider which patient groups would benefit most from this therapy, particularly those at risk for poor adherence to daily injections, such as patients undergoing multi-drug therapy, patients with needle phobia or behavioral disorders, very young children, adolescents, patients with separated parents, families that travel frequently, or children involved in activities like scouting. LAGHs present an opportunity to enhance therapeutic outcomes and adherence, but careful patient selection remains critical to maximizing their potential benefits.

Influence of Ageing on the Pharmacodynamics and Pharmacokinetics of Chronically Administered Medicines in Geriatric Patients: A Review.

As people age, the efficiency of various regulatory processes that ensure proper communication between cells and organs tends to decline. This deterioration can lead to difficulties in maintaining homeostasis during physiological stress. This includes but is not limited to cognitive impairments, functional difficulties, and issues related to caregivers which contribute significantly to medication errors and non-adherence. These factors can lead to higher morbidity, extended hospital stays, reduced quality of life, and even mortality. The decrease in homeostatic capacity varies among individuals, contributing to the greater variability observed in geriatric populations. Significant pharmacokinetic and pharmacodynamic alterations accompany ageing. Pharmacokinetic changes include decreased renal and hepatic clearance and an increased volume of distribution for lipid-soluble drugs, which prolong their elimination half-life. Pharmacodynamic changes typically involve increased sensitivity to various drug classes, such as anticoagulants, antidiabetic and psychotropic medications. This review examines the primary age-related physiological changes in geriatrics and their impact on the pharmacokinetics and pharmacodynamics of medications.

Considerations for Anesthesia in Older Adults with Cannabis Use.

Over the past decade, legislative changes occurred in the USA and the western world that were followed by a substantial increase in reported use of cannabis among the general population. Among patients undergoing anesthesiafor surgery or interventional procedures, older patients-often defined as adults over 65 years-are one of the fastest-growing populations. Within this group, the prevalence of cannabis use almost tripled over the past decade. In addition to habitual cannabis use, recommendations for treatment of chronic pain with cannabinoids have become increasingly more common. The clinical relevance of cannabis use in older adults is supported by recent studies linking it to increased anesthetic requirements as well as respiratory, cardiovascular, and psychiatric complications following surgery. Still, evidence remains equivocal, as these associations may largely depend on the type, frequency, and route of cannabis administration, and current research is mostly limited to retrospective cohort studies. Multisystemic effects of cannabis can become especially relevant in patients of advanced age undergoing anesthesia, characterized by physiological and pharmacodynamic alterations as well as a higher risks of drug-to-drug interactions. Best-practice guidelines emphasize the need for detailed, systematic preoperative screening for habits of cannabis use, including the history, type, and frequency, to guide perioperative management in these patients. This review discusses considerations for anesthesia in older patients with habitual cannabis use while highlighting strategies and recommendations to ensure safe and effective anesthesia care.

Are We Dosing Correctly? Population Pharmacokinetics of Cefepime in Critically Ill Pediatric Patients

Abstract Background Dosing guidelines of cefepime are well defined in healthy pediatric and adult populations but have not been extensively studied in critically ill pediatric patients. Patients who are critically ill may have significant alterations in antibiotic pharmacokinetics (PK) and pharmacodynamics (PD) due to many factors. Receipt of ECMO or CRRT may further alter PK/PD due to changes in clearance and volume of distribution and the depletion of plasma proteins. Since critically ill pediatric patients are likely to receive multiple courses of antimicrobials, optimization of drug dosing and delivery is critically important for individual patient outcomes. This study will test the hypothesis that the PK of cefepime is substantially altered in critically ill pediatric patients. Methods We prospectively enrolled patients in VUMC pediatric ICUs receiving cefepime, including those receiving ECMO or CRRT. Plasma samples were collected at opportune timepoints enriched for specific PK/PD metrics. Cefepime plasma concentrations were measured by LC-MS/MS. Weight, dose, interval, and administration time were extracted from the medical record. Monolix was used to fit population PK models using one and two-compartment models with a proportional error model. Covariate modeling was performed with a priori selected covariates: ECMO, CRRT, sex, race, ethnicity, gestational age, and creatinine clearance (CrCl). The final covariate model was used to perform probability of target attainment (PTA) analysis using Monte Carlo simulation. 6,000 subjects were simulated for each dosing regimen, with 3 weight categories (≤9 kg, 9-25 kg, and >25 kg) and 2 CrCl categories (≤90 mL/min and >90 mL/min). PTA was calculated over a grid of possible MIC values based on three targets, 65% fT>MIC, 100% fT>MIC, and 100% fT>4×MIC. Results Preliminary data from 84 pediatric participants receiving cefepime were analyzed. Of these, 9 received CRRT and 10 received ECMO. An average of 3 samples were collected per participant. A two compartment with proportional error model was selected as the base model. Population PK parameter estimates for the base model, base model with weight, and final covariate model were calculated. Inclusion of weight and CrCl significantly improved model fit. CRRT, ethnicity, and gestational age did significantly improve model fit, but their inclusion in the model did not provide evidence of being significantly better than the model with only weight and CrCl. The results from the PTA analysis are seen in Figure 1. We observed an overall ordering of PTA by dosing regimen across all three targets, with q8h 3-hour infusion having the highest PTA and q12h 30-minute infusion having the lowest PTA. Increased CrCl led to reduced PTA and as weight increased, PTA also increased. Conclusion This study will be among the first and largest to characterize cefepime PK in the critically ill pediatric population. Clinicians should incorporate local antibiograms with these population PK models to determine optimal dosing in critically ill pediatric patients. The use of extended infusions may be beneficial for PK/PD target achievement, particularly for resistant pathogens. Since clinical covariates affect PK parameters, this population may also benefit from therapeutic drug monitoring. Figure 1. Comparison of PTA among four dosing regimens of cefepime at targets of 65% fT>MIC, 100% fT>MIC, and 100% fT>4×MIC.

Increased Cardiovascular Disease Risk in Adult Offspring with Prenatal Opioid Exposure Is Associated with Endogenous Opioid Peptide Dysregulation

Parental drug abuse and dysfunctional households during childhood increase the risk for cardiovascular disease (CVD) later in life. Chronic opioid exposure and opioid use disorder (OUD) are associated with a 2-fold increased risk of CVD and a 16% increase in coronary artery disease. OUD among pregnant women is an understudied area related to the opioid epidemic, causing a 5-fold increase in neonatal opioid withdrawal syndrome (NOWS) incidence. In former studies, we subjected female rats to two models of maternal opioid exposure: 1) morphine sulfate during gestation or 2) fentanyl citrate during preconception and gestation. At birth, female and male opioid-exposed offspring showed normal birth weight compared with vehicle-exposed offspring while displaying NOWS-like somatic withdrawal signs after parturition. As adults, in utero opioid-exposed offspring displayed increased mean arterial pressure, sympathetic activation, and CVD risk factors. Prenatal exposure to opioids has been shown to dysregulate the endogenous opioid peptides (EOPs) and alter behavioral outcomes later in life, but the transplacental effects of opioids on blood pressure regulation remain understudied. Therefore, this study aimed to assess whether adult offspring with prenatal opioid exposure display changes in 1) the expression of the EOP proenkephalin (PENK) in brain regions known to control the sympathetic outflow (Paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM)), heart, kidneys, and liver; 2) the plasma levels of EOPs (PENK, enkephalin, prodynorphin and dynorphin); and 3) the fentanyl plasma clearance (pharmacokinetics). Protein was extracted from tissues for western blot analysis using the primary antibody for PENK (1:1000, Invitrogen). In opioid-exposed offspring, PENK protein expression was reduced in RVLM (0.55±0.06 vs. 0.36±0.01, AU) and PVN (1.56±0.09 vs. 1.08±0.08, AU), showing a ~35% and ~31% reduction, respectively (n=4-5, p<0.05). In the heart, PENK protein expression was not statistically different in opioid-exposed offspring compared with vehicle-exposed offspring. However, in the kidneys (0.72±0.09 vs. 1.16±0.10, AU) and liver (0.40±0.06 vs. 0.60±0.05, AU), PENK protein expression showed a 61% and 50% increase only in male opioid-exposed offspring compared to vehicle-exposed offspring (n=6-8, p<0.05). None of the plasma circulating EOP levels measured by ELISA were affected by prenatal opioid exposure. Fentanyl clearance in plasma (0, 15, 30, 60, 120, 360,1440 mins) following a fentanyl injection (20ug/kg, sc.) was not different between adult vehicle and opioid-exposed offspring, indicating potential pharmacodynamic alterations secondary to prenatal opioid exposure. As EOPs exert inhibitory effects on adrenergic signaling, our data indicate that prenatal exposure to opioids may induce a permanent downregulation of EOPs in the central nervous system and thus contributing to increasing the sympathetic tone and desensitize the acute depressor responses to opioid peptides, suggesting that EOPs may be critical for blood pressure regulation. However, peripheral expression of PENK seems to reflect pathophysiological alterations in different tissues since elevated PENK level is used in clinical settings as a marker to assess the severity of tissue damage in the liver and kidneys. This study was funded by 1013177615 (NRPA-UK), 1013400001 (SUGAR-UK) and 1013171360 (DPNS-UK). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Updated antimicrobial dosing recommendations for obese patients.

The prevalence of obesity has increased considerably in the last few decades. Pathophysiological changes in obese patients lead to pharmacokinetic (PK) and pharmacodynamic (PD) alterations that can condition the correct exposure to antimicrobials if standard dosages are used. Inadequate dosing in obese patients can lead to toxicity or therapeutic failure. In recent years, additional antimicrobial PK/PD data, extended infusion strategies, and studies in critically ill patients have made it possible to obtain data to provide a better dosage in obese patients. Despite this, it is usually difficult to find information on drug dosing in this population, which is sometimes contradictory. This is a comprehensive review of the dosing of different types of antimicrobials (antibiotics, antifungals, antivirals, and antituberculosis drugs) in obese patients, where the literature on PK and possible dosing strategies in obese adults was critically assessed.

Pharmacokinetic-pharmacodynamic modeling of the active components of Shenkang injection in rats with chronic renal failure and its protective effect on damaged renal cells.

The study aimed to explore the pharmacokinetic and pharmacodynamic alterations of the active components of Shenkang injection (i.e. hydroxy saffron yellow pigment A [HSYA], tanshinol, rheum emodin, and astragaloside IV) in rats with chronic renal failure (CRF), and establish a pharmacokinetic-pharmacodynamic model (PK-PD model) in order to provide a scientific and theoretical basis for the rational clinical use of Shenkang injection. Sprague-Dawley (SD) rats were randomly divided into a normal group, model group, and Shenkang injection group. A rat model of CRF was induced by adenine gavage and then followed by drug administration via tail vein injection. Orbital blood was collected at different timepoints and the blood concentrations of the four active components were measured by UHPLC-Q-Orbitrap HRMS. Serum levels of creatinine (Scr), urea nitrogen (BUN), and uric acid (UA) were determined using an automatic biochemical analyzer. A PK-PD model was established, and DAS 3.2.6 software was used for model fitting as well as statistical analysis. TGF-β1 was utilized to induce normal rat kidney cells to construct a renal fibrosis model to investigate the protective effect of the pharmacological components on renal fibrosis. The pharmacokinetic analysis of hydroxy saffron yellow pigment A, tanshinol, rheum emodin, and astragaloside IV based on UHPLC-Q-Orbitrap HRMS was stable. The linear regression equations for the four active components were as follows: Y=0.031X+0.0091 (R2 =0.9986) for hydroxy saffron yellow pigment A, Y=0.0389X+0.164 (R2 =0.9979) for tanshinol, Y=0.0257X+0.0146 (R2 =0.9973) for rheum emodin, and Y=0.0763X+0.0139 (R2 =0.9993) for astragaloside IV, which indicated good linear relationships. The methodological investigation was stable, with the interday and intraday precision RSD <10%. Meanwhile, the recoveries ranged between 90% and 120%, in accordance with the requirements for in vivo analysis of drugs. Compared with the model group, the levels of Scr, BUN, and UA were significantly decreased after 20min in the Shenkang injection group (p<0.01). The PK-PD model showed that the four active components in the Shenkang injection group could fit well with the three effect measures (i.e. Scr, BUN, and UA), with the measured values similar to the predicted values. The cell model of renal fibrosis showed that the connective tissue growth factor and FN1 protein expression levels were significantly lower in the Shenkang injection group than those in the model group, and the cell fibrosis was improved. The established method for in vivo analysis of Shenkang injection was highly specific, with good separation of the components and simple operation. The total statistical moment could well integrate the pharmacokinetic parameters of the four active components. After treatment with Shenkang injection, all indexes in the administered group improved and showed significant inhibition of renal cell fibrosis in vitro. This study could provide scientific reference ideas for the clinical rational use of traditional Chinese medicine.

FIBROMYALGIA IN OLDER ADULTS

Fibromyalgia is a chronic pain condition. Mood disorders, sleep problems, fatigue, and temporomandibular disorders can accompany fibromyalgia. The hallmark of fibromyalgia is chronic generalized pain. Yet, numerous diseases can present with generalized pain in older adults. Careful anamnesis and a detailed physical examination are essential to rule out mimicking conditions. Treatment of fibromyalgia in elderly requires particular attention, as well. Older individuals are prone to experiencing adverse effects of certain drugs due to age-related alterations in pharmacokinetics and pharmacodynamics. The aim of this article was to review fibromyalgia in older adults; including its features, differential diagnosis, and management.

Effect of Capsaicin on Pharmacokinetics and Pharmacodynamics of Nateglinide in normal and diabetic rats

The Cytochrome P-450 (CYP) enzymes present in the human body are responsible for the metabolism of most antidiabetic drugs. These CYP enzymes may metabolize the drugs either to active metabolites or to inactive metabolites. Some phytoconstituents which are present in vegetables, fruits and ayurvedic products will alter the activity of CYP enzymes. In the present research, the alterations in pharmacokinetics and pharmacodynamics of Nateglinide in the presence of a phytochemical like Capsaicin were studied. The study was conducted both in normal and diabetic rats. Rats were divided into different groups. Drug was administered as alone in one group and administered in combination with Capsaicin to other groups. After 8 days of treatment, the blood samples were collected and analysed. The Pharmacokinetic parameters like Cmax, tmax, AUC, MRT, Vd and ClT were estimated for all groups and compared. The mean blood glucose levels before and after treatments were recorded and compared among the groups. From the results, it could be concluded that the Capsaicin has inhibited the activity of CYP 2C9 and CYP 3A4 enzymes, thereby decreased the metabolism of drug which ultimately resulted in the increase of Cmax and AUC. The Capsaicin could raise the antidiabetic effect of drug.

Recent overviews on the drug delivery aspects and applications of brinzolamide for the management of glaucoma

Brinzolamide (BRZ) is a highly selective carbonic anhydrase (CA) inhibitor which leads to decreases intraocular pressure (IOP) by slowing down the production of aqueous humour. It is indicated for the topical care of primary open-angle glaucoma (POAG) with ocular hypertension (OH), as 1% ocular suspension (Azopt) is applied twice or three times. A complex optic neuropathy known as POAG is characterized by the gradual loss of ganglion cells, including their axon. The main risk factor is elevated IOP, the only curable risk factor that can harm the optic head (ONH). To improve the absorption and bioavailability of BRZ in such eye-related complications, various drug delivery vehicles and nano-carriers such as Liposomes, In-situ Gelling systems, Nanofiber, TPGS-based nanoliposomes, Nanocapsules, Nanoemulsion, Niosomes and Nano lipid carrier are briefly suggested in the literature. Different strategies based on nano-carriers have shown to be successful for site-targeted delivery and demonstrate the basic structure with the altered pharmacodynamics property of BRZ. This review summarizes recent advancements in the management of glaucoma and the use of nano-carriers for molecular therapeutics of Glaucoma since it has distinct cellular targets, particularly the trabecular meshwork of the anterior portion of the eye.

Implications of rituximab pharmacokinetic and pharmacodynamic alterations in various immune-mediated glomerulopathies and potential anti-CD20 therapy alternatives.

The specific B-cell depleting anti-CD20 monoclonal antibody rituximab (RTX) is effective in terms of the treatment of various immune-mediated glomerulopathies. The administration of RTX has been shown to be reliable and highly effective particularly in patients with ANCA-associated vasculitis, which is manifested predominantly with non-nephrotic proteinuria. Stable long-term B-cell depletion is usually readily attained in such patients using standard dosing regimens. However, in patients with nephrotic syndrome and non-selective proteinuria, the RTX pharmacokinetics is altered profoundly and RTX does not maintain high enough levels for a sufficiently long period, which may render RTX treatment ineffective. Since complement-derived cytotoxicity is one of the important modes of action of RTX, hypocomplementemia, frequently associated with systemic lupus erythematodes, may act to hamper the efficacy of RTX in the treatment of patients with lupus nephritis. This review provides a description of RTX pharmacokinetics and pharmacodynamics in several selected glomerulopathies, as well as the impact of proteinuria, anti-drug antibodies and other clinical variables on the clearance and volume of distribution of RTX. The impact of plasmapheresis and peritoneal dialysis on the clearance of RTX is also discussed in the paper. A review is provided of the potential association between pharmacokinetic and pharmacodynamic alterations in various kidney-affecting glomerular diseases, the sustainability of B-cell depletion and the clinical efficacy of RTX, with proposals for potential dosing implications. The role of therapeutic drug monitoring in treatment tailoring is also discussed, and various previously tested RTX dosing schedules are compared in terms of their clinical and laboratory treatment responses. Since alternative anti-CD20 molecules may prove effective in RTX unresponsive patients, their pharmacokinetics, pharmacodynamics and current role in the treatment of glomerulopathies are also mentioned.

Nanoplasmonic Avidity-Based Detection and Quantification of IgG Aggregates.

Production of therapeutic monoclonal antibodies (mAbs) is a complex process that requires extensive analytical and bioanalytical characterization to ensure high and consistent product quality. Aggregation of mAbs is common and very problematic and can result in products with altered pharmacodynamics and pharmacokinetics and potentially increased immunogenicity. Rapid detection of aggregates, however, remains very challenging using existing analytical techniques. Here, we show a real-time and label-free fiber optical nanoplasmonic biosensor system for specific detection and quantification of immunoglobulin G (IgG) aggregates exploiting Protein A-mediated avidity effects. Compared to monomers, IgG aggregates were found to have substantially higher apparent affinity when binding to Protein A-functionalized sensor chips in a specific pH range (pH 3.8-4.0). Under these conditions, aggregates and monomers showed significantly different binding and dissociation kinetics. Reliable and rapid aggregate quantification was demonstrated with a limit of detection (LOD) and limit of quantification (LOQ) of about 9 and 30 μg/mL, respectively. Using neural network-based curve fitting, it was further possible to simultaneously quantify monomers and aggregates for aggregate concentrations lower than 30 μg/mL. Our work demonstrates a unique avidity-based biosensor approach for fast aggregate analysis that can be used for rapid at-line quality control, including lot/batch release testing. This technology can also likely be further optimized for real-time in-line monitoring of product titers and quality, facilitating process intensification and automation.

The focus on foods for special medical purposes and food supplements in age‐related disorders

AbstractThe number of people over 60 years of age is increasing worldwide, representing a population of one billion in 2019, which is predicted to nearly double by 2050. In old age, people are more prone to the development of chronic disorders, mainly due to altered body responses to intracellular and extracellular stresses, where overactive oxidative stress and inflammatory processes initiate and stimulate degenerative processes in the body, resulting in metabolic diseases, loss of muscle strength, bone and joint disorders, neurodegenerative disorders, cardiovascular pathologies, and carcinogenesis. Moreover, treatment of patients of advanced age is more complex, due to the simultaneous involvement of multiple disease mechanisms, and the nonlinear association between disease risk factors and their disease endpoints. Most people in their old age are receiving treatment with two or more pharmacological drugs for the management of old age ailments, but on other hand, this increases the occurrence of adverse events in this population, attributed to their pharmacokinetic and pharmacodynamic alterations. One of the better approaches is primary prevention that may postpone the onset of morbidity with an improvement in general quality of life. The use of food supplements by old aged subjects is proportionally increasing for this purpose. This short commentary is focused on the basis of the use of foods for special medical purposes, and food supplements in the prevention of age‐related disorders.

Analgesia and Sedation in Critically Ill Patients With Burns.

Analgesia and Sedation in Critically Ill Patients With Burns.

Therapeutic Drug Monitoring of Antifungal Agents in Critically Ill Patients: Is There a Need for Dose Optimisation?

Invasive fungal infections are an important cause of morbidity and mortality, especially in critically ill patients. Increasing resistance rates and inadequate antifungal exposure have been documented in these patients, due to clinically relevant pharmacokinetic (PK) and pharmacodynamic (PD) alterations, leading to treatment failure. Physiological changes such as third spacing (movement of fluid from the intravascular compartment to the interstitial space), hypoalbuminemia, renal failure and hepatic failure, as well as common interventions in the intensive care unit, such as renal replacement therapy and extracorporeal membrane oxygenation, can lead to these PK and PD alterations. Consequently, a therapeutic target concentration that may be useful for one patient may not be appropriate for another. Regular doses do not take into account the important PK variations in the critically ill, and the need to select an effective dose while minimising toxicity advocates for the use of therapeutic drug monitoring (TDM). This review aims to describe the current evidence regarding optimal PK/PD indices associated with the clinical efficacy of the most commonly used antifungal agents in critically ill patients (azoles, echinocandins, lipid complexes of amphotericin B, and flucytosine), provide a comprehensive understanding of the factors affecting the PK of each agent, document the PK parameters of critically ill patients compared to healthy volunteers, and, finally, make recommendations for therapeutic drug monitoring (TDM) of antifungals in critically ill patients.

Medication Appropriateness, Polypharmacy, and Drug-Drug Interactions in Ambulatory Elderly Patients with Cardiovascular Diseases at Tikur Anbessa Specialized Hospital, Ethiopia.

BackgroundAppropriate prescribing is often challenging in geriatric patients due to age-related pharmacokinetic and pharmacodynamic alterations. Elderly patients with cardiovascular diseases are frequently prescribed multiple medications. Hence, it is imperative to investigate medication appropriateness, polypharmacy, and drug-drug interactions in these groups of patients.ObjectiveTo assess medication appropriateness using the 2019 American Geriatric Society Beers and Medication Appropriateness Index criteria, polypharmacy and drug-drug interactions among elderly ambulatory patients with cardiovascular diseases at Tikur Anbessa Specialized Hospital.MethodsA hospital-based retrospective cross-sectional study was conducted among 384 elderly (60 years and older) ambulatory patients with cardiovascular diseases between May 01-August 30, 2021. Data was collected from the patient’s medical record using a data abstraction tool. The data were entered and analyzed using the SPSS program. Descriptive and logistic regression models were used to present the findings.ResultsThe most frequent diagnosis was hypertension (78.4%) followed by ischemic heart disease (31.3%). Averagely, 4.4 ± 2 medications were prescribed per patient. More than half of (53.1%) the patients received polypharmacy. According to Beer’s and medication appropriateness index criteria, over one-third (28.1%) and the majority (95.1%) of the patients were prescribed potentially inappropriate medications, respectively. In addition, 53.1% and 90.1% of patients had polypharmacy, and were exposed to potential drug-drug interactions ranging from mild to major interactions, respectively. Further, polypharmacy was significantly associated with inappropriate medication prescribing.ConclusionThe study found that more than half of the patients got one or more potentially inappropriate medications in both criteria. The medication appropriateness index tool identified more potentially inappropriate medication than the Beers criteria. In addition, more than half of the patients got polypharmacy and had potential drug-drug interactions. Further, polypharmacy was significantly associated with inappropriate medication prescriptions. These findings highlight the need for interventions to improve appropriate prescribing practice among elderly patients.

1092. Population Pharmacokinetics of Cephalexin in Non-Obese and Obese Hospitalized Patients with Infectious Diseases

Abstract Background Obesity is a significant global health problem and has been associated with altered pharmacokinetics (PK) and pharmacodynamics (PD) of many drugs. Cephalexin is a commonly prescribed antibiotic as an oral drug for the treatment of mild to moderate infections; however, little is known regarding cephalexin pharmacokinetics in obese patients. The objective of this study was to investigate the population PK of cephalexin in non-obese and obese patients. Methods Hospitalized patients who were 18 years or older with a suspected or documented infection were studied. Patients weighing &amp;lt; 120 kg were defined as non-obese patients whereas those weighing ≥ 120 kg as obese. All included patients received cephalexin 1000 mg every 6 hours orally. After ≥ 3 days of therapy, serial blood samples were collected. Ultrafiltration was used to separate the unbound drug from the protein-bound fractions, and both total and unbound serum concentrations were determined by HPLC. The concentration-time data for cephalexin were analyzed by a non-linear mixed effects modeling approach using NONMEM. Results Overall, 255 serum concentrations from 19 patients (10 males, 4 in an ICU) were included; ten patients were non-obese (total body weight [TBW] &amp;lt; 120 kg) and nine were obese (TBW ≥ 120 kg). A 1-compartment model with first-order absorption, absorption lag-time, first-order elimination, and linear protein binding best fit the concentration-time data. Creatinine clearance (CrCl) was the only covariate significantly associated with cephalexin PK, specifically systemic clearance (CL): CL (L/h) = 12.3 + [0.0837*(CRCL – 81.8)]. No other covariates significantly affected the model-derived PK parameters including CL, volume of distribution (V), first-order absorption rate constant (Ka), unbound fraction (fu) with the fixed estimate of 0.776, and absorption lag-time (Tlag). Conclusion In conclusion, cephalexin PK is comparable between non-obese and obese patients. Dosing adjustments based solely on body size may not be necessary. Further analyses are warranted to suggest optimal cephalexin dosages in obesity through large-scale population PK-PD modeling and simulation. Disclosures All Authors: No reported disclosures

Personalized Antibiotic Therapy for the Critically Ill: Implementation Strategies and Effects on Clinical Outcome of Piperacillin Therapeutic Drug Monitoring-A Descriptive Retrospective Analysis.

Therapeutic drug monitoring (TDM) is increasingly relevant for an individualized antibiotic therapy and subsequently a necessary tool to reduce multidrug-resistant pathogens, especially in light of diminishing antimicrobial capabilities. Critical illness is associated with profound pharmacokinetic and pharmacodynamic alterations, which challenge dose finding and the application of particularly hydrophilic drugs such as β-lactam antibiotics. Methods: Implementation strategy, potential benefit, and practicability of the developed standard operating procedures were retrospectively analyzed from January to December 2020. Furthermore, the efficacy of the proposed dosing target of piperacillin in critically ill patients was evaluated. Results: In total, 160 patients received piperacillin/tazobactam therapy and were subsequently included in the study. Of them, 114 patients received piperacillin/tazobactam by continuous infusion and had at least one measurement of piperacillin serum level according to the standard operating procedure. In total, 271 measurements were performed with an average level of 79.0 ± 46.0 mg/L. Seventy-one piperacillin levels exceeded 100 mg/L and six levels were lower than 22.5 mg/L. The high-level and the low-level group differed significantly in infection laboratory parameters (CRP (mg/dL) 20.18 ± 11.71 vs. 5.75 ± 5.33) and renal function [glomerular filtration rate (mL/min/1.75 m2) 40.85 ± 26.74 vs. 120.50 ± 70.48]. Conclusions: Piperacillin levels are unpredictable in critically ill patients. TDM during piperacillin/tazobactam therapy is highly recommended for all patients. Although our implementation strategy was effective, further strategies implemented into the daily clinical workflow might support the health care staff and increase the clinicians’ alertness.