Chrono-pharmaceutical approaches to optimize dosing regimens based on the circadian clock machinery

Daily rhythmic variations in biological functions affect the efficacy and/or toxicity of drugs: a large number of drugs cannot be expected to exhibit the same potency at different administration times. The “circadian clock” is an endogenous timing system that broadly regulates metabolism, physiology and behavior. In mammals, this clock governs the oscillatory expression of the majority of genes with a period length of approximately 24 h. Genetic studies have revealed that molecular components of the circadian clock regulate the expression of genes responsible for the sensitivity to drugs and their disposition. The circadian control of pharmacodynamics and pharmacokinetics enables ‘chrono-pharmaceutical’ applications, namely drug administration at appropriate times of day to optimize the therapeutic index (efficacy vs. toxicity). On the other hand, a variety of pathological conditions also exhibit marked day-night changes in symptom intensity. Currently, novel therapeutic approaches are facilitated by the development of chemical compound targeted to key proteins that cause circadian exacerbation of disease events. This review presents an overview of the current understanding of the role of the circadian biological clock in regulating drug efficacy and disease conditions, and also describes the importance of identifying the difference in the circadian machinery between diurnal and nocturnal animals to select the most appropriate times of day to administer drugs in humans.

Translational Modeling of Chloroquine and Hydroxychloroquine Dosimetry in Human Airways for Treating Viral Respiratory Infections

Purpose Chloroquine and hydroxychloroquine are effective against respiratory viruses in vitro. However, they lack antiviral efficacy upon oral administration. Translation of in vitro to in vivo exposure is necessary for understanding the disconnect between the two to develop effective therapeutic strategies. Methods We employed an in vitro ion-trapping kinetic model to predict the changes in the cytosolic and lysosomal concentrations of chloroquine and hydroxychloroquine in cell lines and primary human airway cultures. A physiologically based pharmacokinetic model with detailed respiratory physiology was used to predict regional airway exposure and optimize dosing regimens. Results At their reported in vitro effective concentrations in cell lines, chloroquine and hydroxychloroquine cause a significant increase in their cytosolic and lysosomal concentrations by altering the lysosomal pH. Higher concentrations of the compounds are required to achieve similar levels of cytosolic and lysosomal changes in primary human airway cells in vitro. The predicted cellular and lysosomal concentrations in the respiratory tract for in vivo oral doses are lower than the in vitro effective levels. Pulmonary administration of aerosolized chloroquine or hydroxychloroquine is predicted to achieve high bound in vitro-effective concentrations in the respiratory tract, with low systemic exposure. Achieving effective cytosolic concentrations for activating immunomodulatory effects and adequate lysosomal levels for inhibiting viral replication could be key drivers for treating viral respiratory infections. Conclusion Our analysis provides a framework for extrapolating in vitro effective concentrations of chloroquine and hydroxychloroquine to in vivo dosing regimens for treating viral respiratory infections. Graphical abstract

vCOMBAT: a novel tool to create and visualize a computational model of bacterial antibiotic target-binding

Background As antibiotic resistance creates a significant global health threat, we need not only to accelerate the development of novel antibiotics but also to develop better treatment strategies using existing drugs to improve their efficacy and prevent the selection of further resistance. We require new tools to rationally design dosing regimens from data collected in early phases of antibiotic and dosing development. Mathematical models such as mechanistic pharmacodynamic drug-target binding explain mechanistic details of how the given drug concentration affects its targeted bacteria. However, there are no available tools in the literature that allow non-quantitative scientists to develop computational models to simulate antibiotic-target binding and its effects on bacteria. Results In this work, we have devised an extension of a mechanistic binding-kinetic model to incorporate clinical drug concentration data. Based on the extended model, we develop a novel and interactive web-based tool that allows non-quantitative scientists to create and visualize their own computational models of bacterial antibiotic target-binding based on their considered drugs and bacteria. We also demonstrate how Rifampicin affects bacterial populations of Tuberculosis bacteria using our vCOMBAT tool. Conclusions The vCOMBAT online tool is publicly available at https://combat-bacteria.org/.

Pharmacokinetic/Pharmacodynamic Based Breakpoints of Polymyxin B for Bloodstream Infections Caused by Multidrug-Resistant Gram-Negative Pathogens

The latest PK/PD findings have demonstrated negligible efficacy of intravenous polymyxins against pulmonary infections. We investigated pharmacokinetic/pharmacodynamic (PK/PD)-based breakpoints of polymyxin B for bloodstream infections and the rationality of the recent withdrawal of polymyxin susceptibility breakpoints by the CLSI. Polymyxin B pharmacokinetic data were obtained from a phase I clinical trial in healthy Chinese subjects and population pharmacokinetic parameters were employed to determine the exposure of polymyxin B at steady state. MICs of 1,431 recent clinical isolates of Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae collected from across China were determined. Monte-Carlo simulations were performed for various dosing regimens (0.42–1.5 mg/kg/12 h via 1 or 2-h infusion). The probability of target attainment, PK/PD breakpoints and cumulative fraction of response were determined for each bacterial species. MIC90 of polymyxin B was 1 mg/L for P. aeruginosa and 0.5 mg/L for A. baumannii and K. pneumoniae. With the recommended polymyxin B dose of 1.5–2.5 mg/kg/day, the PK/PD susceptible breakpoints for P. aeruginosa, A. baumannii and K. pneumoniae were 2, 1 and 1 mg/L respectively for bloodstream infection. For Chinese patients, polymyxin B dosing regimens of 0.75–1.5 mg/kg/12 h for P. aeruginosa and 1–1.5 mg/kg/12 h for A. baumannii and K. pneumoniae were appropriate. Breakpoint determination should consider the antimicrobial PK/PD at infection site and delivery route. The recent withdrawal of polymyxin susceptible breakpoint by CLSI primarily based on poor efficacy against lung infections needs to be reconsidered for bloodstream infections.

Application of Population Pharmacokinetic Analysis to Characterize CYP2C19 Mediated Metabolic Mechanism of Voriconazole and Support Dose Optimization

Purpose: The aims of this study were to establish a joint population pharmacokinetic model for voriconazole and its N-oxide metabolite in immunocompromised patients, to determine the extent to which the CYP2C19 genetic polymorphisms influenced the pharmacokinetic parameters, and to evaluate and optimize the dosing regimens using a simulating approach.Methods: A population pharmacokinetic analysis was conducted using the Phoenix NLME software based on 427 plasma concentrations from 78 patients receiving multiple oral doses of voriconazole (200 mg twice daily). The final model was assessed by goodness of fit plots, non-parametric bootstrap method, and visual predictive check. Monte Carlo simulations were carried out to evaluate and optimize the dosing regimens.Results: A one-compartment model with first-order absorption and mixed linear and concentration-dependent-nonlinear elimination fitted well to concentration-time profile of voriconazole, while one-compartment model with first-order elimination well described the disposition of voriconazole N-oxide. Covariate analysis indicated that voriconazole pharmacokinetics was substantially influenced by the CYP2C19 genetic variations. Simulations showed that the recommended maintenance dose regimen would lead to subtherapeutic levels in patients with different CYP2C19 genotypes, and elevated daily doses of voriconazole might be required to attain the therapeutic range.Conclusions: The joint population pharmacokinetic model successfully characterized the pharmacokinetics of voriconazole and its N-oxide metabolite in immunocompromised patients. The proposed maintenance dose regimens could provide a rationale for dosage individualization to improve clinical outcomes and minimize drug-related toxicities.

Quantification of Fosfomycin in Combination with Nine Antibiotics in Human Plasma and Cation-Adjusted Mueller-Hinton II Broth via LCMS

Fosfomycin-based combination therapy has emerged as an attractive option in our armamentarium due to its synergistic activity against carbapenem-resistant Gram-negative bacteria (CRGNB). The ability to simultaneously measure fosfomycin and other antibiotic drug levels will support in vitro and clinical investigations to develop rational antibiotic combination dosing regimens against CRGNB infections. We developed an analytical assay to measure fosfomycin with nine important antibiotics in human plasma and cation-adjusted Mueller–Hinton II broth (CAMHB). We employed a liquid-chromatography tandem mass spectrometry method and validated the method based on accuracy, precision, matrix effect, limit-of-detection, limit-of-quantification, specificity, carryover, and short-term and long-term stability on U.S. Food & Drug Administration (FDA) guidelines. Assay feasibility was assessed in a pilot clinical study in four patients on antibiotic combination therapy. Simultaneous quantification of fosfomycin, levofloxacin, meropenem, doripenem, aztreonam, piperacillin/tazobactam, ceftolozane/tazobactam, ceftazidime/avibactam, cefepime, and tigecycline in plasma and CAMHB were achieved within 4.5 min. Precision, accuracy, specificity, and carryover were within FDA guidelines. Fosfomycin combined with any of the nine antibiotics were stable in plasma and CAMHB up to 4 weeks at −80 °C. The assay identified and quantified the respective antibiotics administered in the four subjects. Our assay can be a valuable tool for in vitro and clinical applications.

Enoxaparin Use in Hospitalized SARS-CoV-2-Positive Patients with Elevated D-Dimer: A Pilot Study

Introduction The SARS-CoV-2 is a human pathogenic coronavirus that causes a respiratory tract infection, which may lead to systemic hyper-inflammation that is associated with a hypercoagulable state. Anticoagulation as an adjunct may decrease thrombi formation. Objectives This study aims to evaluate the efficacy and safety of enoxaparin for the prevention of thrombotic events in hospitalized SARS-CoV-2 patients with elevated D-dimer. Methods A single-center retrospective cohort study was conducted to evaluate three enoxaparin dosing regimens: full treatment (1 mg/kg SC Q12H or 1.5 mg/kg SC Q24H), intermediate (.5 mg/kg SC Q12H or 1 mg/kg SC Q24H), and prophylaxis (40 mg SC Q24H). The primary endpoint evaluated the percentage of patients who developed a venous thromboembolism (VTE). The secondary endpoints evaluated the development of a major bleed, mechanical ventilation need, and death. Results Forty-five patients were included with 27, 8, and 10 participants in the full treatment, intermediate, and prophylaxis arms, respectively. Six patients developed a VTE: 3, 1, and 2 in the listed above groups, respectively ( P = .83). Twenty patients died: 11, 3, and 6, respectively ( P = .64). Four patients developed a major bleed: 1, 1, and 2, respectively ( P = .17). Six patients required intubation: 1, 2, and 3 in the arms, respectively ( P = .043). Conclusion The study did not find a difference in respect to the development of a VTE between the three investigated doses of anticoagulation. However, our findings suggest that treatment dose of enoxaparin might be associated with lower risk for mechanical ventilation in hospitalized COVID-19-positive patients with elevated D-dimer.

A Critical Review of the Pharmacokinetics and Pharmacodynamics of Opioid Medications Used in Avian Patients

Opioid drugs are used to manage moderate to severe pain in mammals and avian species. In dosing opioids for a particular species, it is optimal to use dosing regimens based on pharmacokinetics or pharmacodynamics studies conducted in the same species as variability in the physiology among different species may result in differences in drug pharmacokinetics and pharmacodynamics. Unfortunately, dosing regimens are typically extrapolated from closely related avian species or even mammals, which is unideal. Therefore, this critical review aims to collate and evaluate the dosing regimens of selected opioids: tramadol, hydromorphone, buprenorphine, butorphanol, and fentanyl, in avian species and its related safety, efficacy and pharmacokinetic data. Our review found specific dosing regimens not described in the Exotic Animal Formulary for tramadol used in Indian Peafowl (Pavo cristatus), Muscovy Duck (Cairina moschata) and Hispaniolan Parrot (Amazona ventralis); hydromorphone used in Orange-winged Parrot (Amazona amazonica); buprenorphine used in Cockatiel (Nymphicus hollandicus), American Kestrel (Falco sparverius) and Grey Parrot (Psittacus erithacus); and butorphanol used in Hispaniolan Parrot (Amazona ventralis), Broiler Chicken and Indian Peafowl (Pavo cristatus). Cockatiel appeared to not experience analgesic effects for hydromorphone and buprenorphine, and American Kestrel exhibited sex-dependent responses to opioids. The selected opioids were observed to be generally safe, with adverse effects being dose-dependent.

Is Dosing of Ethambutol as Part of a Fixed-Dose Combination Product Optimal for Mechanically Ventilated ICU Patients with Tuberculosis? A Population Pharmacokinetic Study

Background: Tuberculosis (TB) patients admitted to intensive care units (ICU) have high mortality rates. It is uncertain whether the pharmacokinetics of first-line TB drugs in ICU patients are different from outpatients. This study aims to compare the pharmacokinetics of oral ethambutol in TB patients in ICU versus TB outpatients and to determine whether contemporary dosing regimens achieve therapeutic exposures. Methods: A prospective population pharmacokinetic study of ethambutol was performed in Amazonas State, Brazil. Probability of target attainment was determined using AUC/MIC > 11.9 and Cmax/MIC > 0.48 values. Optimized dosing regimens were simulated at steady state. Results: Ten ICU patients and 20 outpatients were recruited. Ethambutol pharmacokinetics were best described using a two-compartment model with first-order oral absorption. Neither ICU patients nor outpatients consistently achieved optimal ethambutol exposures. The absorption rate for ethambutol was 2-times higher in ICU patients (p < 0.05). Mean bioavailability for ICU patients was >5-times higher than outpatients (p < 0.0001). Clearance and volume of distribution were 93% (p < 0.0001) and 53% (p = 0.002) lower in ICU patients, respectively. Conclusions: ICU patients displayed significantly different pharmacokinetics for an oral fixed-dose combination administration of ethambutol compared to outpatients, and neither patient group consistently achieved pre-defined therapeutic exposures.