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Antimicrobial Agents and Chemotherapy May 2024The prevalence of obesity has increased considerably in the last few decades. Pathophysiological changes in obese patients lead to pharmacokinetic (PK) and...
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.
Topics: Humans; Anti-Bacterial Agents; Anti-Infective Agents; Antifungal Agents; Antitubercular Agents; Antiviral Agents; Critical Illness; Obesity
PubMed: 38526051
DOI: 10.1128/aac.01719-23 -
European Journal of Human Genetics :... Mar 2024The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate pharmacogenetics implementation in clinical practice by developing evidence-based guidelines to...
The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate pharmacogenetics implementation in clinical practice by developing evidence-based guidelines to optimize pharmacotherapy. A guideline describing the gene-drug interaction between the genes CYP2D6, CYP3A4 and CYP1A2 and antipsychotics is presented here. The DPWG identified gene-drug interactions that require therapy adjustments when respective genotype is known for CYP2D6 with aripiprazole, brexpiprazole, haloperidol, pimozide, risperidone and zuclopenthixol, and for CYP3A4 with quetiapine. Evidence-based dose recommendations were obtained based on a systematic review of published literature. Reduction of the normal dose is recommended for aripiprazole, brexpiprazole, haloperidol, pimozide, risperidone and zuclopenthixol for CYP2D6-predicted PMs, and for pimozide and zuclopenthixol also for CYP2D6 IMs. For CYP2D6 UMs, a dose increase or an alternative drug is recommended for haloperidol and an alternative drug or titration of the dose for risperidone. In addition, in case of no or limited clinical effect, a dose increase is recommended for zuclopenthixol for CYP2D6 UMs. Even though evidence is limited, the DPWG recommends choosing an alternative drug to treat symptoms of depression or a dose reduction for other indications for quetiapine and CYP3A4 PMs. No therapy adjustments are recommended for the other CYP2D6 and CYP3A4 predicted phenotypes. In addition, no action is required for the gene-drug combinations CYP2D6 and clozapine, flupentixol, olanzapine or quetiapine and also not for CYP1A2 and clozapine or olanzapine. For identified gene-drug interactions requiring therapy adjustments, genotyping of CYP2D6 or CYP3A4 prior to treatment should not be considered for all patients, but on an individual patient basis only.
Topics: Humans; Antipsychotic Agents; Aripiprazole; Clopenthixol; Clozapine; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Drug Interactions; Haloperidol; Olanzapine; Pharmacogenetics; Pimozide; Quetiapine Fumarate; Quinolones; Risperidone; Thiophenes
PubMed: 37002327
DOI: 10.1038/s41431-023-01347-3 -
Cannabis and Cannabinoid Research Aug 2023In this review, we provide an updated assessment of available evidence on the pharmacokinetics (PK) of CBD and explore the impact of different factors on PK outcomes....
In this review, we provide an updated assessment of available evidence on the pharmacokinetics (PK) of CBD and explore the impact of different factors on PK outcomes. This systematic review and meta-regression analysis was preregistered (PROSPERO: CRD42021269857). We systematically searched Medline, Embase, PsycInfo, and Web of Science Core Collection up to November 19, 2022. Trials of CBD in healthy adults were included if they reported at least one of the PK parameters of interest, including T, C, AUC, AUC, and T, in serum or plasma. Studies of patient populations or CBD co-administration with other medications were excluded. The was used. Random-effects multivariable meta-regression analysis was conducted. A total of 112 trial arms from 39 studies were included; 26 trial arms had a "Good" quality, 70 "Fair," and 16 "Poor." Eight arms used inhalation CBD, 29 oromucosal, 73 oral, and 2 intravenous. CBD formulations could be categorized to nanotech (=14), oil-based (=21), alcohol-based (=10), water-based (=12), Sativex (=17), and Epidiolex (=22). For single-dose studies, CBD doses ranged between 2 and 100 mg in inhalation, 5-50 mg in oromucosal, and 0.42-6000 mg in oral administration. Sixty-six trial arms had only male participants or a higher number of male than female participants. The duration of the PK session was between 4 and 164 h. A higher CBD dose was associated with higher C, AUC, and AUC. Compared with oral administration, oromucosal administration was associated with lower C, AUC, and AUC. Fed status was associated with higher C and AUC when compared with the fasting status. A higher ratio of female participants was associated with lower T in oral administration and higher C. As expected, CBD dose, route of administration, and diet were major determinants of CBD PK with oral routes providing higher bioavailability and nanotechnology formulations a faster onset. Although CBD appeared to have a faster onset and longer duration in women, more studies are required to delineate the role of biological sex. Factors that influence CBD PK have implications for medication development and appropriate dosing in clinical practice.
PubMed: 37643301
DOI: 10.1089/can.2023.0025 -
Drug Metabolism Reviews Nov 2023Nebivolol is a beta-1 receptor blocker used to treat hypertension, heart failure, erectile dysfunction, vascular disease, and diabetes mellitus. This review investigated... (Review)
Review
Nebivolol is a beta-1 receptor blocker used to treat hypertension, heart failure, erectile dysfunction, vascular disease, and diabetes mellitus. This review investigated the data regarding pharmacokinetic (PK) parameters, drug-drug interactions, dextrorotatory (D), and levorotatory (L) stereoisomers of nebivolol. The articles related to the PK of nebivolol were retrieved by searching the five databases; Google Scholar, PubMed, Cochrane Library, ScienceDirect, and EBSCO. A total of 20 studies comprising plasma concentration-time profile data following the nebivolol's oral and intravenous (IV) administration were included. The area under the concentration-time curve from zero to infinity (AUC) was 15 times greater in poor metabolizers (PMs) than in extensive metabolizers (EMs). In hypertensive patients, L-nebivolol expressed a higher maximum plasma concentration (C) than D-nebivolol, i.e. 2.5 ng/ml vs 1.2 ng/ml. The AUC of nebivolol was 3-fold greater in chronic kidney disease (CKD). The clearance (CL) was increased in obese than in controls from 51.6 ± 11.6 L/h to 71.6 ± 17.4 L/h when 0.5 mg/ml IV solution was infused. Nebivolol showed higher C, AUC and half-life (t) when co-administered with bupropion, duloxetine, fluvoxamine, paroxetine, lansoprazole, and fluoxetine. This concise review of nebivolol would be advantageous in assessing all PK parameters, which may be crucial for clinicians to avoid drug-drug interactions, prevent adverse drug events and optimize the dosage regimen in diseased patients diagnosed with hypertension and cardiovascular disorders.
Topics: Male; Humans; Nebivolol; Hypertension; Fluvoxamine; Lansoprazole; Drug Interactions
PubMed: 37849071
DOI: 10.1080/03602532.2023.2271195 -
Expert Review of Clinical Pharmacology Jan 2024Quetiapine exhibits notable pharmacokinetic and pharmacodynamic (PK/PD) variability, the origins of which are poorly understood. This systematic review summarizes... (Review)
Review
INTRODUCTION
Quetiapine exhibits notable pharmacokinetic and pharmacodynamic (PK/PD) variability, the origins of which are poorly understood. This systematic review summarizes published population PK/PD studies and identifies significant covariates accounting for this variability to inform precision dosing.
METHODS
We systematically searched the PubMed, Web of Science, and Embase databases and compared study characteristics, model parameters, and covariate effects. Visual predictive distributions were used to compare different models. Forest plots and Monte Carlo simulations were used to assess the influence of covariates.
RESULTS
Six population PK and three population PK/PD studies were included. The median apparent clearance in adults was 87.7 L/h. Strong and moderate cytochrome P450 3A4 inducers increased the apparent clearance approximately fourfold, while strong cytochrome P450 3A4 inhibitors reduced it by 93%. The half-maximum effect concentrations were 82.8 ng/mL for the Brief Psychiatric Rating Scale and 583 ng/mL for dopamine D receptor occupancy. Both treatment duration and quetiapine exposure were associated with weight gain.
CONCLUSIONS
Concurrent administration of potent or moderate CYP3A4 inducers and inhibitors need to be avoided in quetiapine-treated patients. When co-medication is required, it is recommended to adjust the dosage based on therapeutic drug monitoring. Additional research is warranted to delineate the dose-exposure-response relationships of quetiapine and active metabolite norquetiapine in pediatrics, geriatrics, hepatically-impaired patients, and women using contraceptives or are pregnant or menopausal.
PROSPERO REGISTRATION
CRD42023446654.
Topics: Adult; Humans; Female; Child; Quetiapine Fumarate; Cytochrome P-450 Enzyme System; Models, Biological
PubMed: 38108086
DOI: 10.1080/17512433.2023.2295428 -
Pharmacotherapy Nov 2023Prolonged intermittent renal replacement therapy (PIRRT) is gaining popularity as a renal replacement modality in intensive care units, but there is a relative lack of... (Review)
Review
Prolonged intermittent renal replacement therapy (PIRRT) is gaining popularity as a renal replacement modality in intensive care units, but there is a relative lack of guidance regarding antimicrobial clearance and dosing when compared with other modalities. The objectives of this systematic review were to: (1) identify and describe the pharmacokinetics (PK) of relevant antimicrobials used in critically ill adults receiving PIRRT, (2) evaluate the quality of evidence supporting these data, and (3) propose dosing recommendations based on the synthesis of these data. A search strategy for multiple databases was designed and executed to identify relevant published evidence describing the PK of antimicrobials used in critically ill adults receiving PIRRT. Quality assessment, evaluation of reporting, and relevant data extraction were conducted in duplicate. Synthesis of PK/pharmacodynamic (PD) outcomes, dosing recommendations from study authors, and physicochemical properties of included antibiotics were assessed by investigators in addition to the quality of evidence to develop dosing recommendations. Thirty-nine studies enrolling 452 patients met criteria for inclusion and provided PK and/or PD data for 20 antimicrobials in critically ill adults receiving PIRRT. Nineteen studies describe both PK and PD outcomes. Vancomycin (12 studies, 171 patients), meropenem (7 studies, 84 patients), and piperacillin/tazobactam (5 studies, 56 patients) were the most frequent antimicrobials encountered. The quality of evidence was deemed strong for 7/20 antimicrobials, and strong dosing recommendations were determined for 9/20 antimicrobials. This systematic review updates and addresses issues of quality in previous systematic reviews on this topic. Despite an overall low quality of evidence, strong recommendations were able to be made for almost half of the identified antimicrobials. Knowledge gaps persist for many antimicrobials, and higher quality studies (i.e., population PK studies with assessment of PD target attainment) are needed to address these gaps.
Topics: Humans; Adult; Intermittent Renal Replacement Therapy; Critical Illness; Anti-Bacterial Agents; Anti-Infective Agents; Vancomycin; Renal Replacement Therapy
PubMed: 37596844
DOI: 10.1002/phar.2861 -
Cureus Jul 2023Drugs that act on the calcitonin gene-related peptide (CGRP) pathway herald the dawn of a new era in the management of migraine headaches. The blockade of CGRP... (Review)
Review
Drugs that act on the calcitonin gene-related peptide (CGRP) pathway herald the dawn of a new era in the management of migraine headaches. The blockade of CGRP alleviates neural inflammation and has been associated with reduced pain sensitization. Zavegepant is a third-generation drug and is the first intranasal CGRP antagonist to be developed. This systematic review aims to assess the safety, efficacy, pharmacokinetics, and tolerability of Zavegepant as an abortive treatment for migraine. Studies that assessed the safety, tolerability, and efficacy of Zavegepant for migraine were identified through a systematic literature review of PubMed, Clinicaltrials.gov, and Cochrane databases in April 2023. Our systematic review yielded a total of six studies that fit our inclusion criteria. Of these, data from only two randomized control trials (RCTs) was homogenous; hence, forest plots of results pooled from the included studies were not reported. The included studies showed that Zavegepant is an efficacious and well-tolerated abortive treatment modality for episodic migraine in adult patients. Zavegepant showed safety and efficacy in migraine treatment according to various parameters throughout the six included studies. These parameters include adverse events, pharmacokinetic properties, CGRP inhibition, effect on blood pressure/electrocardiogram, pain freedom, and freedom from most bothersome symptoms.
PubMed: 37593294
DOI: 10.7759/cureus.41991 -
Frontiers in Immunology 2023Cytokines are pivotal mediators of cell communication in the tumor microenvironment. Multiple cytokines are involved in the host antitumor response, but the production... (Review)
Review
Cytokines are pivotal mediators of cell communication in the tumor microenvironment. Multiple cytokines are involved in the host antitumor response, but the production and function of these cytokines are usually dysregulated during malignant tumor progression. Considering their clinical potential and the early successful use of cytokines in cancer immunotherapy, such as interferon alpha-2b (IFNα-2b; IntronA) and IL-2 (Proleukin), cytokine-based therapeutics have been extensively evaluated in many follow-up clinical trials. Following these initial breakthroughs, however, clinical translation of these natural messenger molecules has been greatly limited owing to their high-degree pleiotropic features and complex biological properties in many cell types. These characteristics, coupled with poor pharmacokinetics (a short half-life), have hampered the delivery of cytokines via systemic administration, particularly because of severe dose-limiting toxicities. New engineering approaches have been developed to widen the therapeutic window, prolong pharmacokinetic effects, enhance tumor targeting and reduce adverse effects, thereby improving therapeutic efficacy. In this review, we focus on the recent progress and competitive landscape in cytokine engineering strategies and preclinical/clinical therapeutics for cancer. In addition, aiming to promote engineered cytokine-based cancer immunotherapy, we present a profound discussion about the feasibility of recently developed methods in clinical medicine translation.
Topics: Humans; Cytokines; Neoplasms; Immunotherapy; Tumor Microenvironment
PubMed: 37483629
DOI: 10.3389/fimmu.2023.1218082 -
Journal of Nanobiotechnology Jan 2024Exosomes are nanoscale extracellular vesicles secreted by cells and enclosed by a lipid bilayer membrane containing various biologically active cargoes such as proteins,... (Review)
Review
Exosomes are nanoscale extracellular vesicles secreted by cells and enclosed by a lipid bilayer membrane containing various biologically active cargoes such as proteins, lipids, and nucleic acids. Engineered exosomes generated through genetic modification of parent cells show promise as drug delivery vehicles, and they have been demonstrated to have great therapeutic potential for treating cancer, cardiovascular, neurological, and immune diseases, but systematic knowledge is lacking regarding optimization of drug loading and assessment of delivery efficacy. This review summarizes current approaches for engineering exosomes and evaluating their drug delivery effects, and current techniques for assessing exosome drug loading and release kinetics, cell targeting, biodistribution, pharmacokinetics, and therapeutic outcomes are critically examined. Additionally, this review synthesizes the latest applications of exosome engineering and drug delivery in clinical translation. The knowledge compiled in this review provides a framework for the rational design and rigorous assessment of exosomes as therapeutics. Continued advancement of robust characterization methods and reporting standards will accelerate the development of exosome engineering technologies and pave the way for clinical studies.
Topics: Humans; Exosomes; Tissue Distribution; Drug Delivery Systems; Extracellular Vesicles; Neoplasms; Pharmaceutical Preparations
PubMed: 38172932
DOI: 10.1186/s12951-023-02259-6 -
European Journal of Medicinal Chemistry Dec 2023Proteolysis-targeting chimeras (PROTACs) have been an area of intensive research with the potential to extend drug space not target to traditional molecules. In the last... (Review)
Review
Proteolysis-targeting chimeras (PROTACs) have been an area of intensive research with the potential to extend drug space not target to traditional molecules. In the last half decade, we have witnessed several PROTACs initiated phase I/II/III clinical trials, which inspired us a lot. However, the structure of PROTACs beyond "rule of 5" resulted in developing PROTACs with acceptable oral pharmacokinetic (PK) properties remain one of the biggest bottleneck tasks. Many reports have demonstrated that it is possible to access orally bioavailable PROTACs through rational ligand and linker modifications. In this review, we systematically reviewed and highlighted the most recent advances in orally bioavailable PROTACs development, especially focused on the medicinal chemistry campaign of discovery process and in vivo oral PK properties. Moreover, the constructive strategies for developing oral PROTACs were proposed comprehensively. Collectively, we believe that the strategies summarized here may provide references for further development of oral PROTACs.
Topics: Proteolysis Targeting Chimera; Chemistry, Pharmaceutical; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 37708797
DOI: 10.1016/j.ejmech.2023.115793