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  Subjects -> PHARMACY AND PHARMACOLOGY (Total: 575 journals)
Showing 1 - 200 of 253 Journals sorted by number of followers
Nature Reviews Drug Discovery     Full-text available via subscription   (Followers: 331)
International Journal of Drug Policy     Hybrid Journal   (Followers: 253)
Journal of Clinical Oncology     Hybrid Journal   (Followers: 243)
Journal of Medicinal Chemistry     Hybrid Journal   (Followers: 158)
Journal of Pharmaceutical Sciences     Hybrid Journal   (Followers: 155)
Drugs     Full-text available via subscription   (Followers: 146)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 98)
Pharmaceutical Research     Hybrid Journal   (Followers: 94)
European Journal of Pharmaceutical Sciences     Hybrid Journal   (Followers: 86)
Drug Safety     Full-text available via subscription   (Followers: 83)
Annals of Pharmacotherapy     Hybrid Journal   (Followers: 56)
Biomaterials     Hybrid Journal   (Followers: 54)
Clinical Pharmacology & Therapeutics     Hybrid Journal   (Followers: 44)
Regulatory Toxicology and Pharmacology     Hybrid Journal   (Followers: 42)
Journal of Controlled Release     Hybrid Journal   (Followers: 38)
Annual Review of Pharmacology and Toxicology     Full-text available via subscription   (Followers: 38)
International Journal of Pharmaceutics     Hybrid Journal   (Followers: 37)
Clinical Therapeutics     Hybrid Journal   (Followers: 34)
European Journal of Pharmaceutics and Biopharmaceutics     Hybrid Journal   (Followers: 34)
Pharmacoepidemiology and Drug Safety     Hybrid Journal   (Followers: 33)
British Journal of Clinical Pharmacology     Hybrid Journal   (Followers: 32)
Journal of Pharmacy and Pharmacology     Full-text available via subscription   (Followers: 31)
Drug Development and Industrial Pharmacy     Hybrid Journal   (Followers: 29)
PharmacoEconomics     Full-text available via subscription   (Followers: 27)
Clinical Pharmacokinetics     Full-text available via subscription   (Followers: 27)
AAPS Journal     Hybrid Journal   (Followers: 26)
Critical Reviews in Toxicology     Hybrid Journal   (Followers: 25)
Journal of Clinical Psychopharmacology     Hybrid Journal   (Followers: 24)
International Journal of Pharmacy Practice     Full-text available via subscription   (Followers: 24)
Toxicology and Applied Pharmacology     Hybrid Journal   (Followers: 24)
Chemical Research in Toxicology     Hybrid Journal   (Followers: 22)
Journal of Pharmacokinetics and Pharmacodynamics     Hybrid Journal   (Followers: 22)
Journal of Pain & Palliative Care Pharmacotherapy     Hybrid Journal   (Followers: 21)
Trends in Pharmacological Sciences     Full-text available via subscription   (Followers: 20)
Journal of Applied Toxicology     Hybrid Journal   (Followers: 19)
Journal of Clinical Pharmacology     Hybrid Journal   (Followers: 19)
Pharmaceutical Development and Technology     Hybrid Journal   (Followers: 19)
American Journal of Cardiovascular Drugs     Hybrid Journal   (Followers: 19)
Clinical Trials     Hybrid Journal   (Followers: 18)
Toxicology     Hybrid Journal   (Followers: 18)
Journal of Pharmaceutical and Biomedical Analysis     Hybrid Journal   (Followers: 18)
Clinical Toxicology     Hybrid Journal   (Followers: 18)
International Journal of Toxicology     Hybrid Journal   (Followers: 17)
Critical Reviews in Clinical Laboratory Sciences     Hybrid Journal   (Followers: 16)
Journal of Clinical Pharmacy and Therapeutics     Hybrid Journal   (Followers: 16)
Journal of Natural Products     Hybrid Journal   (Followers: 16)
Pharmaceutical Statistics     Hybrid Journal   (Followers: 15)
Toxicology Letters     Hybrid Journal   (Followers: 15)
Journal of Pharmacy Practice     Hybrid Journal   (Followers: 15)
Psychopharmacology     Hybrid Journal   (Followers: 15)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 14)
Cardiovascular Drugs and Therapy     Hybrid Journal   (Followers: 14)
European Journal of Clinical Pharmacology     Hybrid Journal   (Followers: 14)
Current Medicinal Chemistry     Hybrid Journal   (Followers: 13)
American Journal of Therapeutics     Hybrid Journal   (Followers: 13)
Drug and Chemical Toxicology     Hybrid Journal   (Followers: 13)
Journal of the American Pharmacists Association     Full-text available via subscription   (Followers: 13)
Clinical Research and Regulatory Affairs     Hybrid Journal   (Followers: 12)
Seminars in Hematology     Hybrid Journal   (Followers: 12)
Drug Discovery Today: Technologies     Full-text available via subscription   (Followers: 12)
Current Pharmaceutical Design     Hybrid Journal   (Followers: 12)
Journal of Oncology Pharmacy Practice     Hybrid Journal   (Followers: 12)
Journal of Psychopharmacology     Hybrid Journal   (Followers: 11)
Biopharmaceutics and Drug Disposition     Hybrid Journal   (Followers: 11)
Toxicology in Vitro     Hybrid Journal   (Followers: 11)
Drug Development Research     Hybrid Journal   (Followers: 11)
Drug Metabolism and Disposition     Hybrid Journal   (Followers: 11)
Seminars in Oncology Nursing     Full-text available via subscription   (Followers: 10)
Biochemical Pharmacology     Hybrid Journal   (Followers: 10)
Journal of Separation Science     Hybrid Journal   (Followers: 10)
CNS Drugs     Full-text available via subscription   (Followers: 10)
Current Pharmaceutical Biotechnology     Hybrid Journal   (Followers: 10)
Journal of Medical Marketing     Hybrid Journal   (Followers: 10)
Drugs & Aging     Full-text available via subscription   (Followers: 10)
European Neuropsychopharmacology     Hybrid Journal   (Followers: 9)
Food Additives & Contaminants Part A     Hybrid Journal   (Followers: 9)
Journal of Pharmacology and Experimental Therapeutics     Hybrid Journal   (Followers: 9)
Environmental Toxicology and Pharmacology     Hybrid Journal   (Followers: 9)
Medicinal Chemistry     Hybrid Journal   (Followers: 9)
Biometrical Journal     Hybrid Journal   (Followers: 9)
Drugs & Therapy Perspectives     Full-text available via subscription   (Followers: 9)
Prescriber     Hybrid Journal   (Followers: 9)
ChemMedChem     Hybrid Journal   (Followers: 9)
Current Opinion in Pharmacology     Hybrid Journal   (Followers: 9)
European Journal of Pharmacology     Hybrid Journal   (Followers: 8)
Inhalation Toxicology     Hybrid Journal   (Followers: 8)
Antiviral Research     Hybrid Journal   (Followers: 8)
Drug Metabolism Reviews     Hybrid Journal   (Followers: 8)
Progress in Neuro-Psychopharmacology and Biological Psychiatry     Hybrid Journal   (Followers: 8)
Human & Experimental Toxicology     Hybrid Journal   (Followers: 8)
Drug Delivery     Open Access   (Followers: 8)
BioDrugs     Full-text available via subscription   (Followers: 8)
Frontiers in Drug Design & Discovery     Hybrid Journal   (Followers: 8)
Expert Review of Pharmacoeconomics & Outcomes Research     Full-text available via subscription   (Followers: 8)
Experimental and Clinical Psychopharmacology     Full-text available via subscription   (Followers: 7)
Toxicology Mechanisms and Methods     Hybrid Journal   (Followers: 7)
Journal of Pharmacological and Toxicological Methods     Hybrid Journal   (Followers: 7)
Clinical and Experimental Pharmacology and Physiology     Hybrid Journal   (Followers: 7)
Scandinavian Journal of Clinical and Laboratory Investigation     Hybrid Journal   (Followers: 7)
Epilepsy Research     Hybrid Journal   (Followers: 7)
Clinical Drug Investigation     Full-text available via subscription   (Followers: 7)
Journal of Veterinary Pharmacology and Therapeutics     Hybrid Journal   (Followers: 6)
Toxicology and Industrial Health     Hybrid Journal   (Followers: 6)
Skin Pharmacology and Physiology     Full-text available via subscription   (Followers: 6)
Journal of Cardiovascular Pharmacology     Hybrid Journal   (Followers: 6)
AAPS PharmSciTech     Hybrid Journal   (Followers: 6)
Current Drug Discovery Technologies     Hybrid Journal   (Followers: 6)
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry     Hybrid Journal   (Followers: 6)
Current Therapeutic Research     Open Access   (Followers: 6)
Expert Review of Cardiovascular Therapy     Full-text available via subscription   (Followers: 6)
Current Drug Delivery     Hybrid Journal   (Followers: 6)
Expert Review of Anti-infective Therapy     Full-text available via subscription   (Followers: 5)
Neuropharmacology     Hybrid Journal   (Followers: 5)
Current Drug Metabolism     Hybrid Journal   (Followers: 5)
Fitoterapia     Hybrid Journal   (Followers: 5)
Expert Review of Molecular Diagnostics     Full-text available via subscription   (Followers: 5)
Anti-Infective Agents     Hybrid Journal   (Followers: 5)
Toxicon     Hybrid Journal   (Followers: 5)
Medicinal Research Reviews     Hybrid Journal   (Followers: 5)
Investigational New Drugs     Hybrid Journal   (Followers: 5)
Current Cancer Therapy Reviews     Hybrid Journal   (Followers: 5)
Reviews of Physiology, Biochemistry and Pharmacology     Hybrid Journal   (Followers: 4)
Planta Medica     Hybrid Journal   (Followers: 4)
Current Vascular Pharmacology     Hybrid Journal   (Followers: 4)
Pharmaceutical Medicine     Full-text available via subscription   (Followers: 4)
Journal of Child and Adolescent Psychopharmacology     Hybrid Journal   (Followers: 4)
CNS Drug Reviews     Open Access   (Followers: 4)
Inpharma Weekly     Full-text available via subscription   (Followers: 4)
Journal of Labelled Compounds and Radiopharmaceuticals     Hybrid Journal   (Followers: 4)
Immunopharmacology and Immunotoxicology     Hybrid Journal   (Followers: 4)
International Journal of Pharmaceutical and Healthcare Marketing     Hybrid Journal   (Followers: 4)
Inflammation Research     Hybrid Journal   (Followers: 4)
Cancer Chemotherapy and Pharmacology     Hybrid Journal   (Followers: 4)
International Journal of Neuropsychopharmacology     Open Access   (Followers: 3)
Pharmacology & Therapeutics     Hybrid Journal   (Followers: 3)
Physiology International     Full-text available via subscription   (Followers: 3)
Cardiovascular Therapeutics     Open Access   (Followers: 3)
ASSAY and Drug Development Technologies     Hybrid Journal   (Followers: 3)
Pharmacopsychiatry     Hybrid Journal   (Followers: 3)
Chemotherapy     Full-text available via subscription   (Followers: 3)
Therapeutic Drug Monitoring     Hybrid Journal   (Followers: 3)
Current Drug Therapy     Hybrid Journal   (Followers: 3)
Research in Social and Administrative Pharmacy     Hybrid Journal   (Followers: 3)
PharmacoEconomics & Outcomes News     Full-text available via subscription   (Followers: 3)
Journal of Aerosol Medicine and Pulmonary Drug Delivery     Hybrid Journal   (Followers: 3)
Journal of Ethnopharmacology     Hybrid Journal   (Followers: 3)
Drug Resistance Updates     Hybrid Journal   (Followers: 3)
Journal of Pain Management & Medicine     Open Access   (Followers: 3)
Journal of Infection and Chemotherapy     Hybrid Journal   (Followers: 3)
Journal of Cardiovascular Pharmacology and Therapeutics     Hybrid Journal   (Followers: 3)
Current Pharmacogenomics and Personalized Medicine     Hybrid Journal   (Followers: 3)
Acta Pharmacologica Sinica     Hybrid Journal   (Followers: 3)
Microbial Drug Resistance     Hybrid Journal   (Followers: 3)
Frontiers in Medicinal Chemistry     Hybrid Journal   (Followers: 3)
Human Psychopharmacology Clinical and Experimental     Hybrid Journal   (Followers: 3)
BMC Pharmacology     Open Access   (Followers: 2)
The Brown University Psychopharmacology Update     Hybrid Journal   (Followers: 2)
International Clinical Psychopharmacology     Hybrid Journal   (Followers: 2)
Canadian Journal of Physiology and Pharmacology     Hybrid Journal   (Followers: 2)
Journal of Drug Targeting     Hybrid Journal   (Followers: 2)
Inflammopharmacology     Hybrid Journal   (Followers: 2)
Journal of Inflammation     Open Access   (Followers: 2)
Fundamental & Clinical Pharmacology     Hybrid Journal   (Followers: 2)
Behavioural Pharmacology     Hybrid Journal   (Followers: 2)
Vascular Pharmacology     Hybrid Journal   (Followers: 2)
Pulmonary Pharmacology & Therapeutics     Hybrid Journal   (Followers: 2)
Biomedicine & Pharmacotherapy     Full-text available via subscription   (Followers: 2)
Clinical Neuropharmacology     Hybrid Journal   (Followers: 2)
Drugs in R & D     Full-text available via subscription   (Followers: 2)
International Immunopharmacology     Hybrid Journal   (Followers: 2)
Pharmacology Biochemistry and Behavior     Hybrid Journal   (Followers: 2)
Letters in Drug Design & Discovery     Hybrid Journal   (Followers: 2)
Archiv der Pharmazie     Hybrid Journal   (Followers: 2)
Pharmacological Reviews     Hybrid Journal   (Followers: 2)
Molecular Pharmacology     Hybrid Journal   (Followers: 2)
Journal of Microencapsulation: Microcapsules, Liposomes, Nanoparticles, Microcells, Microspheres     Hybrid Journal   (Followers: 2)
Toxicological & Environmental Chemistry     Hybrid Journal   (Followers: 2)
Particulate Science and Technology: An International Journal     Hybrid Journal   (Followers: 1)
Pharmacological Research     Hybrid Journal   (Followers: 1)
Current Enzyme Inhibition     Hybrid Journal   (Followers: 1)
Journal of Neuroimmune Pharmacology     Hybrid Journal   (Followers: 1)
Current Pharmaceutical Analysis     Hybrid Journal   (Followers: 1)
Current Neuropharmacology     Hybrid Journal   (Followers: 1)
Pharmacogenetics and Genomics     Hybrid Journal   (Followers: 1)
Journal of Texture Studies     Hybrid Journal   (Followers: 1)
Pharmaceutical Biology     Open Access  
Journal of Liposome Research     Hybrid Journal  
Toxin Reviews     Hybrid Journal  
Kaohsiung Journal of Medical Sciences     Open Access  
Redox Report     Open Access  
Pharmacology     Full-text available via subscription  
Pharmaceutical Chemistry Journal     Hybrid Journal  
NeuroMolecular Medicine     Hybrid Journal  
Journal of Ocular Pharmacology and Therapeutics     Hybrid Journal  
Harm Reduction Journal     Open Access  
Current Nanoscience     Hybrid Journal  
Infectious Disorders - Drug Targets     Hybrid Journal  
Current Bioactive Compounds     Hybrid Journal  
Cancer Biotherapy & Radiopharmaceuticals     Hybrid Journal  
Autonomic & Autacoid Pharmacology     Hybrid Journal  

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Journal Cover
Clinical Pharmacokinetics
Journal Prestige (SJR): 1.482
Citation Impact (citeScore): 4
Number of Followers: 27  
 
  Full-text available via subscription Subscription journal
ISSN (Print) 0312-5963 - ISSN (Online) 1179-1926
Published by Adis Homepage  [21 journals]
  • Acknowledgement to Referees

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      PubDate: 2022-11-23
       
  • Evaluation of Neonatal and Paediatric Vancomycin Pharmacokinetic Models
           and the Impact of Maturation and Serum Creatinine Covariates in a Large
           Multicentre Data Set

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      Abstract: Background and Objective Infants and neonates present a clinical challenge for dosing drugs with high interindividual variability due to these patients’ rapid growth and the interplay between maturation and organ function. Model-informed precision dosing (MIPD), which can account for interindividual variability via patient characteristics and Bayesian forecasting, promises to improve individualized dosing strategies in this complex population. Here, we assess the predictive performance of published population pharmacokinetic models describing vancomycin in neonates and infants, and analyze the robustness of these models in the face of clinical uncertainty surrounding covariate values. Methods The predictive precision and bias of nine pharmacokinetic models were compared in a large multi-site data set (N = 2061 patients, 5794 drug levels, 28 institutions) of patients aged 0–365 days. The robustness of model predictions to errors in serum creatinine measurements and gestational age was assessed by using recorded values or by replacing covariate values with 0.3, 0.5 or 0.8 mg/dL or with 40 weeks, respectively. Results Of the nine models, two models (Dao and Jacqz-Aigrain) resulted in predicted concentrations within 2.5 mg/L or 15% of the measured values for at least 60% of population predictions. Within individual models, predictive performance often 2 differed in neonates (0–4 weeks) versus older infants (15–52 weeks). For preterm neonates, imputing gestational age as 40 weeks reduced the accuracy of model predictions. Measured values of serum creatinine improved model predictions compared to using imputed values even in neonates ≤1 week of age. Conclusions Several available pharmacokinetic models are suitable for MIPD in infants and neonates. Availability and accuracy of model covariates for patients will be important for guiding dose decision-making.
      PubDate: 2022-11-21
       
  • Physiologically Based Modelling Framework for Prediction of Pulmonary
           Pharmacokinetics of Antimicrobial Target Site Concentrations

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      Abstract: Background and Objectives Prediction of antimicrobial target-site pharmacokinetics is of relevance to optimize treatment with antimicrobial agents. A physiologically based pharmacokinetic (PBPK) model framework was developed for prediction of pulmonary pharmacokinetics, including key pulmonary infection sites (i.e. the alveolar macrophages and the epithelial lining fluid). Methods The modelling framework incorporated three lung PBPK models: a general passive permeability-limited model, a drug-specific permeability-limited model and a quantitative structure–property relationship (QSPR)-informed perfusion-limited model. We applied the modelling framework to three fluoroquinolone antibiotics. Incorporation of experimental drug-specific permeability data was found essential for accurate prediction. Results In the absence of drug-specific transport data, our QSPR-based model has generic applicability. Furthermore, we evaluated the impact of drug properties and pathophysiologically related changes on pulmonary pharmacokinetics. Pulmonary pharmacokinetics were highly affected by physiological changes, causing a shift in the main route of diffusion (i.e. paracellular or transcellular). Finally, we show that lysosomal trapping can cause an overestimation of cytosolic concentrations for basic compounds when measuring drug concentrations in cell homogenate. Conclusion The developed lung PBPK model framework constitutes a promising tool for characterization of pulmonary exposure of systemically administrated antimicrobials.
      PubDate: 2022-11-19
       
  • Assessment of Aging-Related Function Variations of P-gp Transporter in
           Old-Elderly Chinese CHF Patients Based on Modeling and Simulation

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      Abstract: Background and Objectives P-glycoprotein (P-gp) is one of the most intensely studied transporters owing to its broad tissue distribution and substrate specificity. Existing research suggests that the risk of systemic exposure to dabigatran etexilate (DABE) and digoxin, two P-gp probe substrates in vivo, has significantly increased in elderly patients. We applied a model-based quantitative pharmacological approach to assess aging-related P-gp changes in the Chinese old-elderly population. Methods Population pharmacokinetic (PopPK) modeling was first performed using clinical pharmacokinetic data to explore the effect of age on the pharmacokinetic characteristics of dabigatran (DAB, the active principle of DABE) and digoxin in elderly Chinese patients. Corresponding physiologically based pharmacokinetic (PBPK) models were established to further explain the elevated systemic exposure to these two drugs. Eventually, standard dosing regimens of DABE and digoxin were assessed in Chinese old-elderly patients with chronic heart failure (CHF) with different stages of renal impairment. Results PopPK analysis suggested that age as a covariate had an additional effect on the apparent clearance of these two drugs after correcting for creatinine clearance. PBPK simulation results suggested that disease-specific pathophysiological changes could explain DAB exposure in the young elderly. In the elderly population, 17.1% of elevated DAB exposure remained unexplained, and 25.5% of the reduced P-gp function associated with aging was ultimately obtained using sensitivity analysis. This value was further validated using digoxin data obtained by PBPK modeling. The simulation results suggest that CHF patients with advanced age and moderate-to-severe renal impairment require heightened vigilance for elevated exposure risk during the use of DABE and digoxin. Conclusions Aging might be a significant risk factor for elevated systemic exposure to DAB and digoxin by reducing P-gp-mediated efflux in the Chinese old elderly population.
      PubDate: 2022-11-15
       
  • DeepIDC: A Prediction Framework of Injectable Drug Combination Based on
           Heterogeneous Information and Deep Learning

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      Abstract: Background and Objective In clinical practice, injectable drug combination (IDC) usually provides good therapeutic effects for patients. Numerous clinical studies have directly indicated that inappropriate IDC generates adverse drug events (ADEs). The clinical application of injections is increasing, and many injections lack relevant combination information. It is still a significant need for experienced clinical pharmacists to participate in evidence-based drug decision making, monitor medication safety, and manage drug interactions. Meanwhile, a large number of injection pairs and dosage combinations limit exhaustive screening. Here, we present a prediction framework, called DeepIDC, that can expediently screen the feasibility of IDCs using heterogeneous information with deep learning. This is the first specific prediction framework to identify IDCs. Methods Since the interaction between the injected drugs may occur in the direct physical and chemical reactions at the time of mixing or may be the indirect interaction of their drug targets and pathways, we used molecular fingerprints, drug-target associations, and drug-pathway associations to convert injections into a string of digital vectors. Then, based on these injection vectors, we combined a bidirectional long short-term memory and a feed-forward neural network to build a prediction model for accurate and instructive prediction of IDC. Results In three realistic evaluation scenarios, DeepIDC has achieved ideal prediction results. Furthermore, compared with the other five machine-learning methods, the proposed predictor is more efficient and robust. Among the top 30 potential IDCs of each IDC class predicted by DeepIDC, we found that 9 cases were experimentally verified in the literature or available on Drug.com. Conclusion The information we extracted in vivo and in vitro can effectively characterize injectable drugs. DeepIDC developed based on deep learning algorithm provides a valuable unified framework for new IDC discovery, which can make up for the lack of IDC information and predict potential IDC events.
      PubDate: 2022-11-11
       
  • Feasibility of a Pragmatic PBPK Modeling Approach: Towards Model-Informed
           Dosing in Pediatric Clinical Care

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      Abstract: Background and Objective More than half of all drugs are still prescribed off-label to children. Pharmacokinetic (PK) data are needed to support off-label dosing, however for many drugs such data are either sparse or not representative. Physiologically-based pharmacokinetic (PBPK) models are increasingly used to study PK and guide dosing decisions. Building compound models to study PK requires expertise and is time-consuming. Therefore, in this paper, we studied the feasibility of predicting pediatric exposure by pragmatically combining existing compound models, developed e.g. for studies in adults, with a pediatric and preterm physiology model. Methods Seven drugs, with various PK characteristics, were selected (meropenem, ceftazidime, azithromycin, propofol, midazolam, lorazepam, and caffeine) as a proof of concept. Simcyp® v20 was used to predict exposure in adults, children, and (pre)term neonates, by combining an existing compound model with relevant virtual physiology models. Predictive performance was evaluated by calculating the ratios of predicted-to-observed PK parameter values (0.5- to 2-fold acceptance range) and by visual predictive checks with prediction error values. Results Overall, model predicted PK in infants, children and adolescents capture clinical data. Confidence in PBPK model performance was therefore considered high. Predictive performance tends to decrease when predicting PK in the (pre)term neonatal population. Conclusion Pragmatic PBPK modeling in pediatrics, based on compound models verified with adult data, is feasible. A thorough understanding of the model assumptions and limitations is required, before model-informed doses can be recommended for clinical use.
      PubDate: 2022-11-11
       
  • Correction to: Predicting Drug–Drug Interactions between Rifampicin and
           Ritonavir-Boosted Atazanavir Using PBPK Modelling

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      PubDate: 2022-11-01
       
  • Clinical Pharmacokinetics and Pharmacodynamics of Rucaparib

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      Abstract: Abstract Rucaparib is an oral small-molecule poly(ADP-ribose) polymerase inhibitor indicated for patients with recurrent ovarian cancer in the maintenance and treatment settings and for patients with metastatic castration-resistant prostate cancer associated with a deleterious BRCA1 or BRCA2 mutation. Rucaparib has a manageable safety profile; the most common adverse events reported were fatigue and nausea in both indications. Accumulation in plasma exposure occurred after repeated administration of the approved 600-mg twice-daily dosage. Steady state was achieved after continuous twice-daily dosing for a week. Rucaparib has moderate oral bioavailability and can be dosed with or without food. Although a high-fat meal weakly increased maximum concentration and area under the curve, the effect was not clinically significant. A mass balance analysis indicated almost a complete dose recovery of rucaparib over 12 days, with metabolism, renal, and hepatic excretion as the elimination routes. A population pharmacokinetic analysis of rucaparib revealed no effect of age, sex, race, or body weight. No starting dose adjustments were necessary for patients with mild-to-moderate hepatic or renal impairment; the effect of severe organ impairment on rucaparib exposure has not been evaluated. In patients, rucaparib moderately inhibited cytochrome P450 (CYP) 1A2 and weakly inhibited CYP3As, CYP2C9, and CYP2C19. Rucaparib weakly increased systemic exposures of oral contraceptives and oral rosuvastatin and marginally increased the exposure of oral digoxin (a P-glycoprotein substrate). In vitro studies suggested that rucaparib inhibits transporters MATE1, MATE2-K, OCT1, and OCT2. No clinically meaningful drug interactions with rucaparib as a perpetrator were observed. An exposure–response analysis revealed dose-dependent changes in selected clinical efficacy and safety endpoints. Overall, this article provides a comprehensive review of the clinical pharmacokinetics, pharmacodynamics, drug–drug interactions, effects of intrinsic and extrinsic factors, and exposure–response relationships of rucaparib.
      PubDate: 2022-11-01
       
  • Semi-mechanistic Modeling of Hypoxanthine, Xanthine, and Uric Acid
           Metabolism in Asphyxiated Neonates

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      Abstract: Background and Objective Previously, we developed a pharmacokinetic-pharmacodynamic model of allopurinol, oxypurinol, and biomarkers, hypoxanthine, xanthine, and uric acid, in neonates with hypoxic-ischemic encephalopathy, in which high initial biomarker levels were observed suggesting an impact of hypoxia. However, the full pharmacodynamics could not be elucidated in our previous study. The current study included additional data from the ALBINO study (NCT03162653) placebo group, aiming to characterize the dynamics of hypoxanthine, xanthine, and uric acid in neonates with hypoxic-ischemic encephalopathy. Methods Neonates from the ALBINO study who received allopurinol or placebo mannitol were included. An extended population pharmacokinetic-pharmacodynamic model was developed based on the mechanism of purine metabolism, where synthesis, salvage, and degradation via xanthine oxidoreductase pathways were described. The initial level of the biomarkers was a combination of endogenous turnover and high disease-related amounts. Model development was accomplished by nonlinear mixed-effects modeling (NONMEM®, version 7.5). Results In total, 20 neonates treated with allopurinol and 17 neonates treated with mannitol were included in this analysis. Endogenous synthesis of the biomarkers reduced with 0.43% per hour because of precursor exhaustion. Hypoxanthine was readily salvaged or degraded to xanthine with rate constants of 0.5 1/h (95% confidence interval 0.33–0.77) and 0.2 1/h (95% confidence interval 0.09–0.31), respectively. A greater salvage was found in the allopurinol treatment group consistent with its mechanism of action. High hypoxia-induced initial levels of biomarkers were quantified, and were 1.2-fold to 2.9-fold higher in neonates with moderate-to-severe hypoxic-ischemic encephalopathy compared with those with mild hypoxic-ischemic encephalopathy. Half-maximal xanthine oxidoreductase inhibition was achieved with a combined allopurinol and oxypurinol concentration of 0.68 mg/L (95% confidence interval 0.48–0.92), suggesting full xanthine oxidoreductase inhibition during the period studied. Conclusions This extended pharmacokinetic-pharmacodynamic model provided an adequate description of the complex hypoxanthine, xanthine, and uric acid metabolism in neonates with hypoxic-ischemic encephalopathy, suggesting a positive allopurinol effect on these biomarkers. The impact of hypoxia on their dynamics was characterized, underlining higher hypoxia-related initial exposure with a more severe hypoxic-ischemic encephalopathy status.
      PubDate: 2022-11-01
       
  • Optimising the Nadroparin Dose for Thromboprophylaxis During Hemodialysis
           by Developing a Population Pharmacodynamic Model Using Anti-Xa Levels

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      Abstract: Introduction The optimal nadroparin dose in patients undergoing hemodialysis is difficult to determine in clinical practice. Anti-Xa levels ≥ 0.4 IU/mL and < 2.0 IU/mL are suggested to prevent thrombus formation within the extracorporeal circuit whilst minimizing bleeding risk. We aimed to characterize the variability in the association between dose and anti-Xa levels, identify patient and dialysis characteristics that explained this variability, and optimize nadroparin dosing based on the identified characteristics. Methods Anti-Xa samples were collected in patients who received intravenous nadroparin as thromboprophylaxis during routine dialysis sessions. A population pharmacodynamic model was developed using non-linear mixed-effects modelling. The percentage of patients ≥ 0.4 IU/mL (efficacy) and < 2.0 IU/mL (safety) was simulated for different doses, patient and dialysis characteristics. Results Patients (n = 137) were predominantly receiving standard hemodialysis (84.7% vs. hemodiafiltration 15.3%) and had a mean bodyweight of 76.3 kg (± 16.9). Lean body mass (LBM), mode of dialysis, and dialyzer partially explained between-subject variability in anti-Xa levels. Patients on hemodiafiltration and those receiving hemodialysis with a high LBM (≥ 80 kg) had a low probability (< 29%) of anti-Xa levels ≥ 0.4 IU/mL during the entire dialysis session. All patients, except hemodialysis patients with a low LBM (< 50 kg), had a high probability (> 70%) of peak anti-Xa levels < 2.0 IU/mL. Conclusion Mainly patients receiving hemodiafiltration and those receiving hemodialysis with a high LBM can benefit from a higher nadroparin dose than currently used in clinical practice, while having anti-Xa levels < 2.0 IU/mL.
      PubDate: 2022-11-01
       
  • The Cytokine Release Syndrome and/or the Proinflammatory Cytokines as
           Underlying Mechanisms of Downregulation of Drug Metabolism and Drug
           Transport: A Systematic Review of the Clinical Pharmacokinetics of Victim
           Drugs of this Drug–Disease Interaction Under Different Clinical
           Conditions

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      Abstract: Background and Objective An ever-growing body of evidence supports the impact of cytokine modulation on the patient’s phenotypic drug response. The aim of this systematic review was to analyze the clinical studies that assessed the pharmacokinetics of victim drugs of this drug–disease interaction in the presence of different scenarios of cytokine modulation in comparison with baseline conditions. Methods We conducted a systematic review by searching the PubMed-MEDLINE database from inception until February 2022 to retrieve prospective and/or retrospective observational studies, population pharmacokinetic studies, phase I studies, and/or case series/reports that investigated the impact of cytokine modulation on the pharmacokinetic behavior of victim drugs. Only studies providing quantitative pharmacokinetic data of victim drugs by comparing normal status versus clinical conditions with documented cytokine modulation or by assessing the influence of anti-inflammatory biological agents on metabolism and/or transport of victim drugs were included. Results Overall, 26 studies were included. Rheumatoid arthritis (6/26; 23.1%) and sepsis (5/26; 19.2%) were the two most frequently investigated pro-inflammatory clinical scenarios. The victim drug most frequently assessed was midazolam (14/26; 53.8%; as a probe for cytochrome P450 [CYP] 3A4). Cytokine modulation showed a moderate inhibitory effect on CYP3A4-mediated metabolism (area under the concentration–time curve increase and/or clearance decrease between 1.98-fold and 2.59-fold) and a weak-to-moderate inhibitory effect on CYP1A2, CYP2C9, and CYP2C19-mediated metabolism (in the area under the concentration–time curve increase or clearance decrease between 1.29-fold and 1.97-fold). Anti-interleukin-6 agents showed remarkable activity in counteracting downregulation of CYP3A4-mediated activity (increase in the area under the concentration–time curve between 1.75-fold and 2.56-fold). Conclusions Cytokine modulation may cause moderate or weak-to-moderate downregulation of metabolism/transport of victim drugs, and this may theoretically have relevant clinical consequences.
      PubDate: 2022-11-01
       
  • A Survey of Population Pharmacokinetic Reports Submitted to the USFDA: An
           Analysis of Common Issues in NDA and BLA from 2012 to 2021

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      Abstract: Background and Objective Population pharmacokinetic (PopPK) analysis is one of the important components of regulatory submission. The purpose of this study was to survey PopPK analysis reports in new drug applications (NDAs) and biological licensing applications (BLAs) submitted to the US Food and Drug Administration (FDA) and to retrieve the information regarding PopPK-related issues in the US FDA review reports. Methods We surveyed NDAs and BLAs over the period from 2012 to 2022 from Drug@FDA databases and extracted the review reports from the website. We explored the issues identified in these reports and sorted them into four categories: (i) data used for PopPK analysis, (ii) base model development, (iii) final model development, and (iv) model evaluation. The percentage of the issues in each category and the total issues were calculated. Results Data from a total of 317 applications were analyzed. Of these, 122 applications had at least one PopPK-related issue, and the count went up to 168 issues. The proportion of issues for each category was ranked as follows: model evaluation (39%, 65 of 168), final model development (34%, 57 of 168), data used for PopPK analysis (14%, 24 of 168), and base model development (13%, 22 of 168). The most common issues were related to the goodness-of-fit plots, covariate selection, and high shrinkage of ETA, accounting for 17.9%, 15.5%, and 11.3% of the total issues, respectively. Conclusion The findings from this study may help the applicant understand the FDA’s thinking on the PopPK analysis.
      PubDate: 2022-10-31
       
  • Evaluation of Absorption and Metabolism-Based DDI Potential of
           Pexidartinib in Healthy Subjects

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      Abstract: Background and Objective Pexidartinib is a novel oral small-molecule inhibitor that selectively targets colony-stimulating factor 1 receptor, KIT proto-oncogene receptor tyrosine kinase, and FMS-like tyrosine kinase 3 harboring an internal tandem duplication mutation. It is approved in the United States for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Pexidartinib in vitro data indicate the potential for absorption- and metabolism-related drug–drug interactions (DDIs). The objective was to present a comprehensive DDI risk assessment of agents that can impact pexidartinib exposure by altering its absorption and metabolism potentially affecting efficacy and safety of pexidartinib. Methods Four open-label crossover studies were performed to assess the effects of a pH modifier (esomeprazole), a strong cytochrome P450 (CYP) 3A4 inhibitor (itraconazole), a strong CYP3A/5′-diphospho-glucuronosyltransferase (UGT) inducer (rifampin), and a UGT inhibitor (probenecid) on the single-dose pharmacokinetics of pexidartinib. In addition, a physiologically based pharmacokinetic model was developed to predict the effect of a moderate CYP3A4 inhibitor (fluconazole) and a moderate CYP3A inducer (efavirenz) on the pharmacokinetics of pexidartinib. Results Co-administration of pexidartinib with esomeprazole modestly decreased pexidartinib exposure (maximum plasma concentration [Cmax], ng/mL: geometric mean ratio [90% confidence interval (CI)], 45.4% [36.8–55.9]; area under the drug plasma concentration–time curve from time 0 to infinity [AUC∞], ng•h/mL: geometric mean ratio [90% CI], 53.1% [47.4–59.3]), likely related to decreased solubility of pexidartinib at increased pH levels. As expected, the strong CYP3A4 inhibitor itraconazole increased pexidartinib exposure (Cmax, ng/mL: geometric mean ratio [90% CI], 148.3% [127.8–172.0]; AUC∞, ng•h/mL: geometric mean ratio [90% CI], 173.0% [160.7–186.3]) while the strong CYP3A/UGT inducer rifampin decreased exposure (Cmax, ng/mL: geometric mean ratio [90% CI], 67.1% [53.1–84.8]; AUC∞, ng•h/mL: geometric mean ratio [90% CI], 37.0% [30.6–44.8]). In addition, UGT inhibition increased pexidartinib exposure (Cmax, ng/mL: geometric mean ratio [90% CI], 105.8% [92.4–121.0]; AUC∞, ng•h/mL: geometric mean ratio [90% CI], 159.8% [143.4–178.0]), consistent with the fact that pexidartinib is a substrate of the UGT1A4 enzyme, which is responsible for the generation of the major metabolite, ZAAD-1006a. Conclusions The physiologically based pharmacokinetic model predicted that a moderate CYP3A4 inhibitor and a moderate CYP3A inducer would produce modest increases and decreases, respectively, in pexidartinib exposure. These results provide a basis for pexidartinib dosing recommendations when administered concomitantly with drugs with drug–drug interaction potential, including dose adjustments when concomitant administration cannot be avoided. Clinical Trial Registration Probenecid: phase I trial, NCT03138759, 3 May, 2017; esomeprazole, itraconazole, rifampin: phase I trials, not registered with ClinicalTrials.gov.
      PubDate: 2022-10-20
       
  • Meropenem Population Pharmacokinetics and Dosing Regimen Optimization in
           Critically Ill Children Receiving Continuous Renal Replacement Therapy

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      Abstract: Background and Objective We aimed to develop a meropenem population pharmacokinetic model in critically ill children receiving continuous renal replacement therapy and simulate dosing regimens to optimize patient exposure. Methods Meropenem plasma concentration was quantified by high-performance liquid chromatography. Meropenem pharmacokinetics was investigated using a non-linear mixed-effect modeling approach. Monte Carlo simulations were performed to compute the optimal scheme of administration, according to the target of a 100% inter-dose interval time in which concentration is one to four times above the minimum inhibitory concentration (100% fT>1–4×MIC). Results A total of 27 patients with a median age of 4 [interquartile range 0–11] years, a median body weight of 16 [range 7–35] kg receiving continuous renal replacement therapy were included. Concentration–time courses were best described by a one-compartment model with first-order elimination. Body weight (BW) produced significant effects on volume of distribution (V) and BW and continuous renal replacement therapy effluent flow rate (Qeff) produced significant effects on clearance (CL): \({V}_{i}={V}_{pop }{x (\frac{BWi}{70})}^{1}\) and \({CL}_{i}={CL}_{pop }x ({\frac{BWi}{70})}^{0.75} x ({\frac{Qeffi}{1200})}^{0.337}\) , where Vpop and CLpop estimates were 32.5 L and 5.88 L/h, respectively, normalized to a 70-kg BW and median Qeff at 1200 mL/h. Using this final model and Monte Carlo simulations, for patients with Qeff over 1200 mL/h, meropenem continuous infusion was adequate in most cases to attain 100% fT>1–4xMIC. For bacterial infections with a low minimum inhibitory concentration (≤2 mg/L), meropenem intermitent administration was appropriate for patients weighing more than 20 kg with Qeff <500 mL/h and for patients weighing more than 10 kg with Qeff <100 mL/h. Conclusions Meropenem exposure in critically ill children receiving continuous renal replacement therapy needs dosing adjustments to the minimum inhibitory concentration that take into account body weight and the continuous renal replacement therapy effluent flow rate.
      PubDate: 2022-10-17
       
  • Pharmacokinetics and Pharmacodynamics of PARP Inhibitors in Oncology

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      Abstract: Abstract Olaparib, niraparib, rucaparib, and talazoparib are poly (ADP-ribose) polymerase (PARP) inhibitors approved for the treatment of ovarian, breast, pancreatic, and/or prostate cancer. Poly (ADP-ribose) polymerase inhibitors are potent inhibitors of the PARP enzymes with comparable half-maximal inhibitory concentrations in the nanomolar range. Olaparib and rucaparib are orally dosed twice a day, extensively metabolized by cytochrome P450 enzymes, and inhibitors of several enzymes and drug transporters with a high risk for drug–drug interactions. Niraparib and talazoparib are orally dosed once a day with a lower risk for niraparib and a minimal risk for talazoparib to cause drug–drug interactions. All four PARP inhibitors show moderate-to-high interindividual variability in plasma exposure. Higher exposure is associated with an increase in toxicity, mostly hematological toxicity. For talazoparib, exposure–efficacy relationships have been described, but for olaparib, niraparib, and rucaparib this relationship remains inconclusive. Further studies are required to investigate exposure–response relationships to improve dosing of PARP inhibitors, in which therapeutic drug monitoring could play an important role. In this review, we give an overview of the pharmacokinetic properties of the four PARP inhibitors, including considerations for patients with renal dysfunction or hepatic impairment, the effect of food, and drug–drug interactions. Furthermore, we focus on the pharmacodynamics and summarize the available exposure–efficacy and exposure–toxicity relationships.
      PubDate: 2022-10-11
       
  • Rivaroxaban Pharmacokinetics in Obese Subjects: A Systematic Review

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      Abstract: Introduction Venous thromboembolism (VTE) is a leading cause of morbidity and mortality globally. The direct oral anticoagulants, including rivaroxaban, are relatively novel therapeutic options in the treatment and prevention of VTE. There is a conflicting and inconclusive evidence surrounding the pharmacokinetics (PK) of rivaroxaban in patients with VTE who are obese. Objectives We conducted a systematic review to provide an overview, and to synthesize the available evidence in the current literature pertaining to rivaroxaban PK in obese subjects who are healthy or diseased. Methods The PubMed, Embase, ScienceDirect, Rayyan, and Cochrane Library databases were systematically searched from 1 May 2021 through 28 February 2022. Studies investigating rivaroxaban PK in adult obese subjects were included in the review. Pertinent data, including anthropometric parameters, rivaroxaban dosage regimen, PK parameters, PK model, and outcome measures were extracted. Reference values of rivaroxaban PK parameters in the general population were used for comparison purposes. The review protocol was registered in the PROSPERO database (CRD42020177770). Results In the 11 studies included in this systematic review, over 7140 healthy or diseased subjects received rivaroxaban therapy, with varying clinical indications in the diseased population. The reported PK parameters of rivaroxaban in obese subjects compared with reference values in the general population were variable. The reported values of the volume of distribution (Vd) among obese subjects (73.4–82.8 L) fell within the range of values reported/calculated for the general population (59.4–104 L), assuming complete bioavailability. However, some of the reported values of clearance (CL) in obese subjects (7.86–16.8 L.h−1) do not fall within the range of values reported/calculated for the general population (5.57–11.3 L.h−1). The reported maximum plasma concentrations in obese subjects versus the general population following a 10 mg dose were 149 vs. 143–180 µg.L−1, and following a 20 mg dose were 214–305 vs. 299–360 µg.L−1, respectively. The area under the plasma concentration versus time curves (AUC) over different intervals in obese subjects versus the general population following a 10 mg dose were 1155 (AUC from time zero to infinity [AUC∞]) vs. 1029 (AUC∞) µg.h.L−1; and 1204–2800 (AUC from time zero to 24 h [AUC24]) vs. 3200 (AUC24) µg.h.L−1, respectively, following a 20 mg dose. The reported values of half-life and time to reach the maximum plasma concentration in obese subjects versus the general population were not consistent across studies. Conclusion Variable changes and inconsistencies in different rivaroxaban PK parameters were reported in obese subjects. Further well-designed studies are warranted to better characterize the PK and clinical outcomes of rivaroxaban in subjects with obesity.
      PubDate: 2022-10-06
       
  • Quantification of the Time Course of CYP3A Inhibition, Activation, and
           Induction Using a Population Pharmacokinetic Model of Microdosed Midazolam
           Continuous Infusion

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      Abstract: Background Cytochrome P450 (CYP) 3A contributes to the metabolism of many approved drugs. CYP3A perpetrator drugs can profoundly alter the exposure of CYP3A substrates. However, effects of such drug-drug interactions are usually reported as maximum effects rather than studied as time-dependent processes. Identification of the time course of CYP3A modulation can provide insight into when significant changes to CYP3A activity occurs, help better design drug-drug interaction studies, and manage drug-drug interactions in clinical practice. Objective We aimed to quantify the time course and extent of the in vivo modulation of different CYP3A perpetrator drugs on hepatic CYP3A activity and distinguish different modulatory mechanisms by their time of onset, using pharmacologically inactive intravenous microgram doses of the CYP3A-specific substrate midazolam, as a marker of CYP3A activity. Methods Twenty-four healthy individuals received an intravenous midazolam bolus followed by a continuous infusion for 10 or 36 h. Individuals were randomized into four arms: within each arm, two individuals served as a placebo control and, 2 h after start of the midazolam infusion, four individuals received the CYP3A perpetrator drug: voriconazole (inhibitor, orally or intravenously), rifampicin (inducer, orally), or efavirenz (activator, orally). After midazolam bolus administration, blood samples were taken every hour (rifampicin arm) or every 15 min (remaining study arms) until the end of midazolam infusion. A total of 1858 concentrations were equally divided between midazolam and its metabolite, 1’-hydroxymidazolam. A nonlinear mixed-effects population pharmacokinetic model of both compounds was developed using NONMEM®. CYP3A activity modulation was quantified over time, as the relative change of midazolam clearance encountered by the perpetrator drug, compared to the corresponding clearance value in the placebo arm. Results Time course of CYP3A modulation and magnitude of maximum effect were identified for each perpetrator drug. While efavirenz CYP3A activation was relatively fast and short, reaching a maximum after approximately 2–3 h, the induction effect of rifampicin could only be observed after 22 h, with a maximum after approximately 28–30 h followed by a steep drop to almost baseline within 1–2 h. In contrast, the inhibitory impact of both oral and intravenous voriconazole was prolonged with a steady inhibition of CYP3A activity followed by a gradual increase in the inhibitory effect until the end of sampling at 8 h. Relative maximum clearance changes were +59.1%, +46.7%, −70.6%, and −61.1% for efavirenz, rifampicin, oral voriconazole, and intravenous voriconazole, respectively. Conclusions We could distinguish between different mechanisms of CYP3A modulation by the time of onset. Identification of the time at which clearance significantly changes, per perpetrator drug, can guide the design of an optimal sampling schedule for future drug-drug interaction studies. The impact of a short-term combination of different perpetrator drugs on the paradigm CYP3A substrate midazolam was characterized and can define combination intervals in which no relevant interaction is to be expected. Clinical Trial Registration The trial was registered at the European Union Drug Regulating Authorities for Clinical Trials (EudraCT-No. 2013-004869-14).
      PubDate: 2022-10-04
       
  • Role of Genetic Polymorphisms in Drug-Metabolizing Enzyme-Mediated
           Toxicity and Pharmacokinetic Resistance to Anti-Cancer Agents: A Review on
           the Pharmacogenomics Aspect

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      Abstract: Abstract The inter-individual differences in cancer susceptibility are somehow correlated with the genetic differences that are caused by the polymorphisms. These genetic variations in drug-metabolizing enzymes/drug-inactivating enzymes may negatively or positively affect the pharmacokinetic profile of chemotherapeutic agents that eventually lead to pharmacokinetic resistance and toxicity against anti-cancer drugs. For instance, the CYP1B1*3 allele is associated with CYP1B1 overexpression and consequent resistance to a variety of taxanes and platins, while 496T>G is associated with lower levels of dihydropyrimidine dehydrogenase, which results in severe toxicities related to 5-fluorouracil. In this context, a pharmacogenomics approach can be applied to ascertain the role of the genetic make-up in a person’s response to any drug. This approach collectively utilizes pharmacology and genomics to develop effective and safe medications that are devoid of resistance problems. In addition, recently reported genomics studies revealed the impact of many single nucleotide polymorphisms in tumors. These studies emphasized the importance of single nucleotide polymorphisms in drug-metabolizing enzymes on the effect of anti-tumor drugs. In this review, we discuss the pharmacogenomics aspect of polymorphisms in detail to provide an insight into the genetic manipulations in drug-metabolizing enzymes that are responsible for pharmacokinetic resistance or toxicity against well-known anti-cancer drugs. Special emphasis is placed on different deleterious single nucleotide polymorphisms and their effect on pharmacokinetic resistance. The information provided in this report may be beneficial to researchers, especially those who are working in the field of biotechnology and human genetics, in rationally manipulating the genetic information of patients with cancer who are undergoing chemotherapy to avoid the problem of pharmacokinetic resistance/toxicity associated with drug-metabolizing enzymes.
      PubDate: 2022-09-30
       
  • Characterizing Absorption Properties of Dispersible Pretomanid Tablets
           Using Population Pharmacokinetic Modelling

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      Abstract: Background and Introduction The dispersible tablet formulation (DTF) of pretomanid has been developed to facilitate future use in children. This work aimed to assess the pharmacokinetics (PK) and relative bioavailability of the DTF compared to the marketed formulation (MF) and the potential influence of dose. Methods Pretomanid DTF was investigated in a single-dose, randomized, four-period, cross-over study, with 7 days of washout between doses. Forty-eight healthy volunteers were enrolled and randomized into one of two panels to receive doses either in the fasted state or after a high-fat meal. Each volunteer received doses of 10, 50, and 200 mg DTF, and 200 mg MF pretomanid. Blood samples for pharmacokinetic assessment were drawn following a rich schedule up to 96 h after each single dose. The study data from the panel receiving the high-fat meal were analyzed using a nonlinear mixed-effects modeling approach, and all data were characterized with noncompartmental methods. Results A one-compartment model with first-order elimination and absorption through a transit compartment captured the mean and variability of the observed pretomanid concentrations with acceptable precision. No significant difference in bioavailability was found between formulations. The mean absorption time for the DTF was typically 137% (86–171%) of that for the MF. The bioavailability was found to be dose dependent with a small positive and larger negative correlation under fed and fasted conditions, respectively. Conclusion Using data from a relative bioavailability study in healthy adult volunteers, a mathematical model has been developed to inform dose selection for the investigation of pretomanid in children using the new dispersible tablet formulation. Under fed conditions and at the currently marketed adult dose of 200 mg, the formulation type was found to influence the absorption rate, but not the bioavailability. The bioavailability of the DTF was slightly positively correlated with doses when administered with food. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT04309656, first posted on 16 March 2020.
      PubDate: 2022-09-30
       
  • Pharmacokinetic Study of Conjugated Equine Estrogens in Healthy Chinese
           Postmenopausal Women Using a Parallel Two-Column LC–MS/MS Method

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      Abstract: Background and Objective Postmenopausal women often require estrogen supplementation to improve menopausal and postmenopausal vasomotor symptoms and maintain hormonal balance. Conjugated equine estrogens extracted from the urine of pregnant mares are commonly used to provide this estrogen replacement therapy. The complex composition of this mixture of animal sulfated metabolites makes its bioanalysis challenging such that its detailed pharmacokinetics has not been fully characterized. The purpose of this work is to reveal the pharmacokinetic behavior of conjugated equine estrogens in healthy Chinese postmenopausal women by a parallel two-column LC–MS/MS method. Methods An open-label study was carried out in 35 Chinese healthy postmenopausal women who received a single dose of Premarin® 0.625 mg. A high-throughput column-switching liquid chromatography-tandem mass spectrometry method was developed to determine four conjugated estrogens and two unconjugated estrogens formed by hydrolysis in vivo. The method multiplexes two high-performance liquid chromatography systems into one mass spectrometer and incorporates the positive/negative ion switching acquisition mode of mass spectrometry to significantly increase analysis efficiency. Pharmacokinetics was determined using non-compartmental methods. Results Both conjugated and unconjugated estrogens can be analyzed simultaneously in a single run with an analysis time of 13.0 minutes in the column-switching liquid chromatography-tandem mass spectrometry method as opposed to 23.0 minutes in a single-column liquid chromatography-tandem mass spectrometry system. The exposures (maximum concentration and area under the curve) of estrone and equilin in Chinese women were higher than those in the North American women. Conclusions The fully validated assay was successfully applied to a pharmacokinetic study in healthy postmenopausal Chinese women after oral administration of a conjugated equine estrogen tablet. This study suggests that Chinese postmenopausal women achieve the same level of unconjugated estrogens in plasma at a lower dose of conjugated equine estrogens than North American women. Graphical
      PubDate: 2022-09-29
       
 
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