Utility of Cytochrome P450 4F2 Genotyping to Assess Drug Interaction Risk for Brincidovovir, a Cytochrome P450 4F2 Substrate.

Smallpox was eradicated in 1980 but remains a biothreat due to the potential release of variola virus into the general population. Brincidofovir, the second medicine approved by the US Food and Drug Administration to treat smallpox, is metabolized by oxidative and hydrolytic pathways. The oxidative pathway is initiated by cytochrome P450 4F2 (CYP4F2), an enzyme lacking clinical probes for drug interaction studies.

Translational Population-Pharmacodynamic Modeling of a Novel Long-Acting siRNA Therapy, Inclisiran, for the Treatment of Hypercholesterolemia.

Inclisiran is a novel N-acetylgalactosamine (GalNAc) conjugated small-interfering ribonucleic acid (siRNA) therapy designed to specifically target proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA in the liver for the treatment of hypercholesterolemia. Inclisiran's GalNAc attachment results in a rapid uptake into the liver, and thus a short plasma half-life, but long duration of effects on PCSK9 inhibition and low-density lipoprotein cholesterol (LDL-C) lowering. The effects on PCSK9 inhibition and consequent LDL-C reduction are sustained for more than 6 months following a single subcutaneous (s.

Model-Informed Drug Development for Anti-Infectives: State of the Art and Future.

Model-informed drug development (MIDD) has a long and rich history in infectious diseases. This review describes foundational principles of translational anti-infective pharmacology, including choice of appropriate measures of exposure and pharmacodynamic (PD) measures, patient subpopulations, and drug-drug interactions. Examples are presented for state-of-the-art, empiric, mechanistic, interdisciplinary, and real-world evidence MIDD applications in the development of antibacterials (review of minimum inhibitory concentration-based models, mechanism-based pharmacokinetic/PD (PK/PD) models, PK/PD models of resistance, and immune response), antifungals, antivirals, drugs for the treatment of global health infectious diseases, and medical countermeasures.

Antibacterial Spiropyrimidinetriones with N-Linked Azole Substituents on a Benzisoxazole Scaffold Targeting DNA Gyrase.

Herein, we report spiropyrimidinetriones (SPTs) incorporating N-linked azole substituents on a benzisoxazole scaffold with improved Gram-positive antibacterial activity relative to previously described analogues. SPTs have an unusual spirocyclic architecture and represent a new antibacterial class of bacterial DNA gyrase and topoisomerase IV inhibitors. They are not cross-resistant to fluoroquinolones and other DNA gyrase/topoisomerase IV inhibitors used clinically.

A mathematical model-based analysis of the time-kill kinetics of ceftazidime/avibactam against Pseudomonas aeruginosa.

Objectives: To characterize quantitatively the effect of avibactam in potentiating ceftazidime against MDR Pseudomonas aeruginosa by developing a mathematical model to describe the bacterial response to constant concentration time-kill information and validating it using both constant and time-varying concentration-effect data from in vitro and in vivo infection systems.

Methods: The time course of the bacterial population dynamics in the presence of static concentrations of ceftazidime and avibactam was modelled using a two-state pharmacokinetic/pharmacodynamic (PK/PD) model, consisting of active and resting states, to account for bactericidal activities, bacteria-mediated ceftazidime degradation and inhibition of degradation by avibactam. Ceftazidime's effect on the bacterial population was described as an enhancement of the death rate of the active population, with the effect of avibactam being to increase ceftazidime potency.

Potentiation of ceftazidime by avibactam against β-lactam-resistant Pseudomonas aeruginosa in an in vitro infection model.

Objectives: This study evaluated the in vitro pharmacodynamics of combinations of ceftazidime and the non-β-lactam β-lactamase inhibitor, avibactam, against ceftazidime-, piperacillin/tazobactam- and meropenem-multiresistant Pseudomonas aeruginosa by a quantitative time-kill method.

Methods: MICs of ceftazidime plus 0-16 mg/L avibactam were determined against eight isolates of P. aeruginosa .

In vitro pharmacokinetics/pharmacodynamics of the combination of avibactam and aztreonam against MDR organisms.

Objectives: The combination of aztreonam and avibactam has been proposed for the treatment of infections caused by metallo-β-lactamase-producing Gram-negative organisms, given the stability of aztreonam against metallo-β-lactamases plus the broad coverage of avibactam against AmpC β-lactamases and ESBLs. This study aimed to evaluate the efficacy of the combination against four clinical isolates with defined but diverse β-lactamase profiles.

Methods: The MICs of aztreonam were determined without and with avibactam (1, 2, 4, 8 and 16 mg/L).

Pharmacodynamics of Ceftazidime and Avibactam in Neutropenic Mice with Thigh or Lung Infection.

Avibactam is a new non-β-lactam β-lactamase inhibitor that shows promising restoration of ceftazidime activity against microorganisms producing Ambler class A extended-spectrum β-lactamases (ESBLs) and carbapenemases such as KPCs, class C β-lactamases (AmpC), and some class D enzymes. To determine optimal dosing combinations of ceftazidime-avibactam for treating infections with ceftazidime-resistant Pseudomonas aeruginosa, pharmacodynamic responses were explored in murine neutropenic thigh and lung infection models. Exposure-response relationships for ceftazidime monotherapy were determined first.

Responding to the challenge of untreatable gonorrhea: ETX0914, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases.

With the diminishing effectiveness of current antibacterial therapies, it is critically important to discover agents that operate by a mechanism that circumvents existing resistance. ETX0914, the first of a new class of antibacterial agent targeted for the treatment of gonorrhea, operates by a novel mode-of-inhibition against bacterial type II topoisomerases. Incorporating an oxazolidinone on the scaffold mitigated toxicological issues often seen with topoisomerase inhibitors.

Translating slow-binding inhibition kinetics into cellular and in vivo effects.

Many drug candidates fail in clinical trials owing to a lack of efficacy from limited target engagement or an insufficient therapeutic index. Minimizing off-target effects while retaining the desired pharmacodynamic (PD) response can be achieved by reduced exposure for drugs that display kinetic selectivity in which the drug-target complex has a longer half-life than off-target-drug complexes. However, though slow-binding inhibition kinetics are a key feature of many marketed drugs, prospective tools that integrate drug-target residence time into predictions of drug efficacy are lacking, hindering the integration of drug-target kinetics into the drug discovery cascade.

Preclinical pharmacokinetic/pharmacodynamic modeling and simulation in the pharmaceutical industry: an IQ consortium survey examining the current landscape.

The application of modeling and simulation techniques is increasingly common in preclinical stages of the drug discovery and development process. A survey focusing on preclinical pharmacokinetic/pharmacodynamics (PK/PD) analysis was conducted across pharmaceutical companies that are members of the International Consortium for Quality and Innovation in Pharmaceutical Development. Based on survey responses, ~68% of companies use preclinical PK/PD analysis in all therapeutic areas indicating its broad application.

Novel DNA gyrase inhibiting spiropyrimidinetriones with a benzisoxazole scaffold: SAR and in vivo characterization.

The compounds described herein with a spirocyclic architecture fused to a benzisoxazole ring represent a new class of antibacterial agents that operate by inhibition of DNA gyrase as corroborated in an enzyme assay and by the inhibition of precursor thymidine into DNA during cell growth. Activity resided in the configurationally lowest energy (2S,4R,4aR) diastereomer. Highly active compounds against Staphylococcus aureus had sufficiently high solubility, high plasma protein free fraction, and favorable pharmacokinetics to suggest that in vivo efficacy could be demonstrated, which was realized with compound (-)-1 in S.

Model-based drug discovery: implementation and impact.

Model-based drug discovery (MBDDx) aims to build and continuously improve the quantitative understanding of the relation between drug exposure (target engagement) efficacy and safety, to support target validation; to define compound property criteria for lead optimization and safety margins; to set the starting dose; and to predict human dose and scheduling for clinical candidates alone, or in combination with other medicines. AstraZeneca has systematically implemented MBDDx within all drug discovery programs, with a focused investment to build a preclinical modeling and simulation capability and an in vivo information platform and architecture, the implementation, impact and learning of which are discussed here.

Comparative in vitro and in vivo efficacies of human simulated doses of ceftazidime and ceftazidime-avibactam against Pseudomonas aeruginosa.

The combination of ceftazidime and avibactam possesses potent activity against resistant Gram-negative pathogens, including Pseudomonas aeruginosa. We compared the efficacies of human simulated doses of ceftazidime and ceftazidime-avibactam using a hollow-fiber system and neutropenic and immunocompetent murine thigh infection models. Twenty-seven clinical P.

In vitro microdialysis sampling of docetaxel.

Microdialysis is a technique that allows sampling compounds from the extracellular fluid in different tissues, such as muscle, lung, and brain. However, the feasibility of using this technique with lipopohilic and high molecular weight compounds has been questioned, since these compounds are less likely to diffuse through the dialysis membrane. Therefore, it was the objective of this study to investigate the feasibility of doing microdialysis of docetaxel by determining its recovery by the microdialysis probe.