Population Pharmacokinetic and Pharmacogenetic Analysis of Mitotane in Patients with Adrenocortical Carcinoma: Towards Individualized Dosing
ConclusionsA two-compartment PopPK model well-characterized mitotane PK profiles in patients with ACC. The CYP2C19 enzyme and SLCO1B1 and SLCO1B3 transporters may play roles in mitotane disposition. The developed model is beneficial in terms of optimizing mitotane treatment schedules and individualizing the initial dose for patients with ACC. Further validation of these findings is still required. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - June 30, 2020 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetics and Generic Drug Switching: A Regulator ’s View
AbstractThere appears to be a mismatch between the assumed therapeutic equivalence of generic drugs, their interchangeability, and reported clinical discomfort following generic drug use and drug switches. In this article, we describe why we are of the opinion that the current regulatory approach to the evaluation of generic drugs based on average bioequivalence is sufficient to expect therapeutic equivalence in the clinical setting. This has often been debated, specifically as adverse drug reactions related to generic drug switches are regularly reported. We agree that clinical discomfort during a bioequivalent drug switc...
Source: Clinical Pharmacokinetics - June 17, 2020 Category: Drugs & Pharmacology Source Type: research

Influence of Cow ’s Milk and Esomeprazole on the Absorption of Erlotinib: A Randomized, Crossover Pharmacokinetic Study in Lung Cancer Patients
AbstractIntroductionErlotinib ’s gastrointestinal solubility and absorption are decreased by proton pump inhibitors (PPIs). Since erlotinib is a lipophilic drug, we hypothesized that concomitant intake with the fatty beverage milk may be a feasible way to increase erlotinib uptake. We performed a two-period, randomized, crosso ver study to investigate the influence of cow’s milk with 3.9% fat on the exposure of erlotinib with and without the PPI esomeprazole in patients with non-small cell lung cancer (NSCLC). The effect of esomeprazole was studied in an additional intrapatient comparison.MethodPharmacokinetic ...
Source: Clinical Pharmacokinetics - June 17, 2020 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetics of ASP4345 from Single Ascending-Dose and Multiple Ascending-Dose Phase I Studies
ConclusionsThe pharmacokinetics of ASP4345 suggest that single daily dosing is appropriate for ASP4345. Furthermore, the concentration of ASP4345 in cerebrospinal fluid compared to free drug concentrations in plasma provides evidence of penetration of ASP4345 into the brain. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - June 12, 2020 Category: Drugs & Pharmacology Source Type: research

Validation of a Drug Transporter Probe Cocktail Using the Prototypical Inhibitors Rifampin, Probenecid, Verapamil, and Cimetidine
ConclusionsTaking all the interaction results together, the transporter cocktail is considered to be validated as a sensitive and specific tool for evaluating transporter-mediated drug –drug interactions in drug development.Clinical Trial RegistrationEudraCT number 2017-001549-29. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - June 5, 2020 Category: Drugs & Pharmacology Source Type: research

Population Pharmacokinetic Analysis and Exploratory Exposure –Bleeding Rate Relationship of Emicizumab in Adult and Pediatric Persons with Hemophilia A
ConclusionsEmicizumab pharmacokinetics in PwHA was described with dose-independent parameters. Body weight was an important predictor of emicizumab pharmacokinetics. All three dosing regimens are predicted to achieve similar exposure associated with clinically meaningful prevention of bleeding. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - June 5, 2020 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetics and Glucodynamics of Ultra  Rapid Lispro (URLi) versus Humalog ® (Lispro) in Younger Adults and Elderly Patients with Type 1 Diabetes Mellitus: A Randomised Controlled Trial
ConclusionIn patients with T1DM, URLi showed ultra-rapid pharmacokinetics and glucodynamics, with the differences between URLi and Humalog in elderly patients mirroring those in younger adults.ClinicalTrials.gov identifier: NCT03166124. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - May 29, 2020 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetics and Glucodynamics of Ultra Rapid Lispro (URLi) versus Humalog ® (Lispro) in Patients with Type 2 Diabetes Mellitus: A Phase I Randomised, Crossover Study
This study compared the insulin lispro pharmacokinetics and glucodynamics, safety and tolerability of URLi and Humalog® after a single subcutaneous dose in patients with type 2 diabetes mellitus (T2DM).MethodsThis was a phase I, randomised, two-period, two-treatment, double-blind, crossover study in 38 patients with T2DM. At each dosing visit, patients received either 15 units of URLi or Humalog, followed by a 10  h automated euglycaemic clamp procedure. Serum insulin lispro and blood glucose were measured.ResultsInsulin lispro appeared in the serum 5  min faster (p 
Source: Clinical Pharmacokinetics - May 29, 2020 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetic Assessment of Pre- and Post-Oxygenator Vancomycin Concentrations in Extracorporeal Membrane Oxygenation: A Prospective Observational Study
ConclusionsExtracorporeal membrane oxygenation flow rates did not influence vancomycin clearance between flow rates of 3500 and 5000  mL/min and vancomycin was not sequestered in ECMO. Common vancomycin regimens resulted in suboptimal efficacy and/or excessive toxicity. Individual therapeutic drug monitoring is recommended for patients on ECMO. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - May 28, 2020 Category: Drugs & Pharmacology Source Type: research

Comparative Clinical Pharmacokinetics and Pharmacodynamics of HIV-1 Integrase Strand Transfer Inhibitors: An Updated Review
AbstractBictegravir, cabotegravir, dolutegravir, elvitegravir, and raltegravir are members of the latest class of antiretrovirals available to treat human immunodeficiency virus (HIV) infection, the integrase strand transfer inhibitors. Integrase strand transfer inhibitors are potent inhibitors of the HIV integrase enzyme with IC90/95 values in the low nanogram per milliliter range and they retain antiviral activity against strains of HIV with acquired resistance to other classes of antiretrovirals. Each of the integrase strand transfer inhibitors have unique pharmacokinetic/pharmacodynamic properties, influencing their ro...
Source: Clinical Pharmacokinetics - May 27, 2020 Category: Drugs & Pharmacology Source Type: research

Population Modelling of Dexmedetomidine Pharmacokinetics and Haemodynamic Effects After Intravenous and Subcutaneous Administration
ConclusionsOur final model precisely describes dexmedetomidine pharmacokinetics and accurately predicts dexmedetomidine-induced sympatholysis and other pharmacodynamic effects. After subcutaneous dosing, dexmedetomidine is taken up into subcutaneous fat tissue, but our simulations indicate that accumulation of dexmedetomidine in this compartment is insignificant.ClinicalTrials.orgNCT02724098 and EudraCT 2015-004698-34 (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - May 27, 2020 Category: Drugs & Pharmacology Source Type: research

Comparative Clinical Pharmacokinetics a1 nd Pharmacodynamics of HIV-1 Integrase Strand Transfer Inhibitors: An Updated Review
AbstractBictegravir, cabotegravir, dolutegravir, elvitegravir, and raltegravir are members of the latest class of antiretrovirals available to treat human immunodeficiency virus (HIV) infection, the integrase strand transfer inhibitors. Integrase strand transfer inhibitors are potent inhibitors of the HIV integrase enzyme with IC90/95 values in the low nanogram per milliliter range and they retain antiviral activity against strains of HIV with acquired resistance to other classes of antiretrovirals. Each of the integrase strand transfer inhibitors have unique pharmacokinetic/pharmacodynamic properties, influencing their ro...
Source: Clinical Pharmacokinetics - May 27, 2020 Category: Drugs & Pharmacology Source Type: research

Metabolism and Pharmacokinetic Drug –Drug Interaction Profile of Vericiguat, A Soluble Guanylate Cyclase Stimulator: Results From Preclinical and Phase I Healthy Volunteer Studies
ConclusionsA low pharmacokinetic interaction potential of vericiguat was estimated from in vitro data and confirmed in vivo. Thus, vericiguat is suitable for a patient population with multiple comorbidities requiring polypharmacy. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - May 26, 2020 Category: Drugs & Pharmacology Source Type: research

Population Pharmacokinetic –Pharmacodynamic Relationships of Sarilumab Using Disease Activity Score 28-Joint C-Reactive Protein and Absolute Neutrophil Counts in Patients with Rheumatoid Arthritis
ConclusionThe PopPK/PD models showed numerically greater reductions in DAS28-CRP and ANC with sarilumab 200  mg every 2 weeks than with 150 mg every 2 weeks. There was no clinically meaningful influence of investigated covariates. These data contribute to the totality of evidence that supports a sarilumab subcutaneous starting dose of 200 mg every 2 weeks, with a subsequent reduction to 150 mg ever y 2 weeks in the event of laboratory abnormalities such as neutropenia. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - May 26, 2020 Category: Drugs & Pharmacology Source Type: research

Prediction of Maternal and Fetal Pharmacokinetics of Dolutegravir and Raltegravir Using Physiologically Based Pharmacokinetic Modeling
This study aimed to develop and evaluate maternal –fetal physiologically based pharmacokinetic models for two antiretroviral drugs, dolutegravir and raltegravir. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - May 25, 2020 Category: Drugs & Pharmacology Source Type: research

A Comprehensive Whole-Body Physiologically Based Pharmacokinetic Drug –Drug–Gene Interaction Model of Metformin and Cimetidine in Healthy Adults and Renally Impaired Individuals
ConclusionsWhole-body physiologically based pharmacokinetic models of metformin and cimetidine were built and qualified for the prediction of metformin pharmacokinetics during drug –gene interaction, drug–drug interaction, and different stages of renal disease. The model files will be freely available in the Open Systems Pharmacology model repository. Current guidelines for metformin treatment of renally impaired patients should be reviewed to avoid overdosing in CKD3 and to allow metformin therapy of CKD4 patients. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - May 25, 2020 Category: Drugs & Pharmacology Source Type: research

Comment on: “An Extension of Janmahasatian’s Fat-Free Mass Model for Universal Application Across Populations of Different Ethnicities”
(Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - May 22, 2020 Category: Drugs & Pharmacology Source Type: research

Authors ’ Reply to Friesen: “An Extension of Janmahasatian’s Fat-Free Mass Model for Universal Application Across Populations of Different Ethnicities”
(Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - May 22, 2020 Category: Drugs & Pharmacology Source Type: research

Pipamperone Population Pharmacokinetics Related to Effectiveness and Side Effects in Children and Adolescents
ConclusionsOur findings suggest that pipamperone therapeutic reference ranges may be lower for children with behavioral problems than recommended for adults with psychotic symptoms (100 –400 µg/L). When dosing pipamperone in children and adolescents, bodyweight should be taken into account. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - May 11, 2020 Category: Drugs & Pharmacology Source Type: research

Early Estimation of Renal Function After Transplantation to Enable Appropriate Dosing of Critical Drugs: Retrospective Analysis of 103 Patients in a Single Center
ConclusionsThe newly developed D3C enables reliable assessment of renal function immediately after RTX, provides crucial information for drug dosing, and might also advance the detection of functional decline, potentially improving treatment and renal outcome. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - May 8, 2020 Category: Drugs & Pharmacology Source Type: research

Preclinical Pharmacokinetic/Pharmacodynamic Studies and Clinical Trials in the Drug Development Process of EMA-Approved Antibacterial Agents: A Review
AbstractDevelopment of new antibacterial agents is necessary as drug-resistant bacteria are a threat to global health. In Europe, the European Medicines Agency has been guiding this development process for more than two decades. We investigated preclinical and clinical pre-approval studies to illuminate the current authorization process with emphasis on pharmacokinetic/pharmacodynamic approaches and clinical phases. All centrally authorized systemic antibacterial and antimycobacterial drugs within the European Union were included without any time restriction. Additionally, US Food and Drug Administration-approved antibioti...
Source: Clinical Pharmacokinetics - April 30, 2020 Category: Drugs & Pharmacology Source Type: research

Overview of the Clinical Pharmacology of Ertugliflozin, a Novel Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor
AbstractErtugliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), is approved in the US, EU, and other regions for the treatment of adults with type 2 diabetes mellitus (T2DM). This review summarizes the ertugliflozin pharmacokinetic (PK) and pharmacodynamic data obtained during phase I clinical development, which supported the registration and labeling of this drug. The PK of ertugliflozin was similar in healthy subjects and patients with T2DM. Oral absorption was rapid, with time to peak plasma concentrations (Tmax) occurring at 1  h (fasted) and 2 h (fed) postdose. The terminal phase half...
Source: Clinical Pharmacokinetics - April 27, 2020 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetic Drug –Drug Interaction of Apalutamide, Part 2: Investigating Interaction Potential Using a Physiologically Based Pharmacokinetic Model
ConclusionsBased on our simulations, no major changes in the pharmacokinetics of apalutamide or pharmacologically active moieties are expected with strong CYP3A4/CYP2C8 inhibitors/inducers. This observation supports the existing recommendations that no dose adjustments are needed during coadministration of apalutamide and the known inhibitors or inducers of CYP2C8 or CYP3A4. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - April 27, 2020 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetic Drug –Drug Interaction of Apalutamide, Part 1: Clinical Studies in Healthy Men and Patients with Castration-Resistant Prostate Cancer
ConclusionsCo-administration of apalutamide with CYP3A4, CYP2C19, CYP2C9, P-gp, BCRP or OATP1B1 substrates may cause loss of activity for these medications. Therefore, appropriate mitigation strategies are recommended. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - April 27, 2020 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetics, Safety, and Tolerability of Selonsertib, an Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitor, Following First-in-Human Single and Multiple Ascending Doses in Healthy Subjects
ConclusionsSelonsertib exhibited a favorable PK profile amenable to once-daily dosing without regard to food. PD data suggest pharmacologically relevant exposures were achieved in the dose range evaluated. Study results support further clinical development of selonsertib. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - April 25, 2020 Category: Drugs & Pharmacology Source Type: research

Evaluation of Therapeutic Equivalence for the Follow-On Version of Intravenously Administered Non-Biological Complex Drugs
AbstractThe interchangeability evaluation for generic drugs formulated as intravenous injections normally only requires assessments of pharmaceutical equivalence (PE) when the medicinal products are simple small-molecule drugs. However, intravenously administered non-biological complex drugs (NBCDs), such as liposomes, microsphere suspension, or fat emulsion, have inherent passive disposition selectivity due to their special formulations, thereby the in vivo drug performances are improved. Because of the complexity in formulation, the in vitro pharmaceutical investigations of follow-on NBCDs are more complicated than those...
Source: Clinical Pharmacokinetics - April 24, 2020 Category: Drugs & Pharmacology Source Type: research

Population Pharmacokinetics of Ibrutinib and Its Dihydrodiol Metabolite in Patients with Lymphoid Malignancies
ConclusionsWe present the first population pharmacokinetic model describing ibrutinib and dihydrodiol-ibrutinib concentrations simultaneously. Large inter-individual variability and substantial intra-individual variability were estimated and could not be explained by any covariate. Higher plasma exposure to ibrutinib is associated with cessation of therapy due to the occurrence of adverse events within the first year of treatment. The association between disease progression and ibrutinib exposure in patients with mantle cell lymphoma should be further investigated.Trial RegistrationClinicalTrials.gov no. NCT02824159. (Sour...
Source: Clinical Pharmacokinetics - April 24, 2020 Category: Drugs & Pharmacology Source Type: research

The Predictive Value of Glomerular Filtration Rate-Based Scaling of Pediatric Clearance and Doses for Drugs Eliminated by Glomerular Filtration with Varying Protein-Binding Properties
ConclusionWhen scaling CL and dose by GFR function, maturational changes in plasma protein concentrations impact GF minimally, making this method a superior alternative to empiric bodyweight-based scaling. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - April 21, 2020 Category: Drugs & Pharmacology Source Type: research

Chloroquine for SARS-CoV-2: Implications of Its Unique Pharmacokinetic and Safety Properties
AbstractSince in vitro studies and a preliminary clinical report suggested the efficacy of chloroquine for COVID-19-associated pneumonia, there is increasing interest in this old antimalarial drug. In this article, we discuss the pharmacokinetics and safety of chloroquine that should be considered in light of use in SARS-CoV-2 infections. Chloroquine is well absorbed and distributes extensively resulting in a large volume of distribution with an apparent and terminal half-life of 1.6  days and 2 weeks, respectively. Chloroquine is metabolized by cytochrome P450 and renal clearance is responsible for one third of ...
Source: Clinical Pharmacokinetics - April 18, 2020 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetic Profile of Gilteritinib: A Novel FLT-3 Tyrosine Kinase Inhibitor
ConclusionsGilteritinib exhibits a dose-proportional pharmacokinetic profile in healthy subjects and in patients with relapsed/refractory acute myeloid leukemia. Gilteritinib exposure is not significantly affected by food. Moderate-to-strong CYP3A inhibitors demonstrated a significant effect on gilteritinib exposure. Coadministration of gilteritinib with CYP3A4 or multidrug and toxin extrusion 1 substrates did not impact substrate concentrations. Unbound gilteritinib was comparable between subjects with hepatic impairment and normal hepatic function; dose adjustment is not warranted for patients with hepatic impairment.Cli...
Source: Clinical Pharmacokinetics - April 18, 2020 Category: Drugs & Pharmacology Source Type: research

Influence of Drug –Drug Interactions on the Pharmacokinetics of Atorvastatin and Its Major Active Metabolite ortho -OH-Atorvastatin in Aging People Living with HIV
ConclusionThis study showed an important interindividual variability in atorvastatin pharmacokinetics that remains largely unexplained after the inclusion of covariates. Since boosted ARVs double atorvastatin exposure, the initial dosage might be reduced by half, and titrated based on individual clinical targets. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - April 12, 2020 Category: Drugs & Pharmacology Source Type: research

Imeglimin Does Not Induce Clinically Relevant Pharmacokinetic Interactions When Combined with Either Metformin or Sitagliptin in Healthy Subjects
ConclusionsCo-administration of IMEG with MET or SITA did not result in clinically relevant changes in systemic exposure to MET or SITA, although minor reductions in exposure (AUC0 –τ and maximum concentration) and renal elimination were noted when MET was given with IMEG vs placebo.Clinical Trial RegistrationEudraCT2009-014520-40 (MET-IMEG DDI) and EudraCT2010-022926-34 (SITA-IMEG DDI) (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - April 9, 2020 Category: Drugs & Pharmacology Source Type: research

Comment on “Levothyrox ® New and Old Formulations: Are They Switchable for Millions of Patients?”
(Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - March 31, 2020 Category: Drugs & Pharmacology Source Type: research

An  Extension of Janmahasatian’s Fat-Free Mass Model for Universal Application Across Populations of Different Ethnicities
ConclusionsAn FFMExt model has been achieved by extending the original FFMJan model assumptions to account for inter-ethnic differences in body composition. The extended model can be applied to any ethnic population by estimating a set of body composition-related parameters\(\varPsi\). This can be performed using bioimpedance data without the need for formal FFM measurements. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - March 22, 2020 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetic/Pharmacodynamic Properties and Clinical Use of SGLT2 Inhibitors in Non-Asian and Asian Patients with Type 2 Diabetes and Chronic Kidney Disease
AbstractChronic kidney disease is a prevalent complication of type 2 diabetes mellitus (T2DM). Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) have a unique mode of action targeting the kidney. As their glucose-lowering potency declines with the reduction in estimated glomerular filtration rate, their clinical use in patients with T2DM with chronic kidney disease has been submitted to restriction. However, recent observations demonstrated that SGLT2is reduce the progression of renal impairment in patients with mild-to-moderate chronic kidney disease, with or without albuminuria. Furthermore, SGLT2is reduce the inc...
Source: Clinical Pharmacokinetics - March 22, 2020 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetic Variability of Therapeutic Antibodies in Humans: A Comprehensive Review of Population Pharmacokinetic Modeling Publications
AbstractThe pharmacokinetics of monoclonal antibodies is highly variable among patients. Several factors of variability, referred to as covariates in pharmacokinetic modeling, are known to influence this variability, such as body size, sex, antigen mass, serum albumin levels, or the presence of anti-drug antibodies. We propose a quantitative overview of the occurrence of assessment and detection of the main covariates associated with monoclonal antibody pharmacokinetics by comprehensively examining all population pharmacokinetic studies of monoclonal antibodies in humans. If some covariates are often assessed and detected ...
Source: Clinical Pharmacokinetics - March 13, 2020 Category: Drugs & Pharmacology Source Type: research

Comprehensive Parent –Metabolite PBPK/PD Modeling Insights into Nicotine Replacement Therapy Strategies
ConclusionsOur PBPK/PD model may be helpful in further investigations of nicotine dependence and smoking cessation strategies. As the model represents the first nicotine PBPK/PD  model predicting nicotine concentration and heart rate profiles after the use of e-cigarettes, it could also contribute to a better understanding of the recent increase in youth e-cigarette use. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - March 12, 2020 Category: Drugs & Pharmacology Source Type: research

Intra-individual Pharmacokinetic Variability of Intravenous Busulfan in Hematopoietic Stem Cell-Transplanted Children
ConclusionsSignificant busulfan intra-individual variability may occur in children who receive a HSCT and is hardly predictable. The main risk is busulfan overexposure. Performing TDM repeatedly over therapy appears to be the best way to accurately estimate busulfan exposure and perform precision dosing. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - March 11, 2020 Category: Drugs & Pharmacology Source Type: research

Drug –Drug Interactions with Direct Oral Anticoagulants
AbstractA large body of evidence suggests that not only direct anticoagulant effects but also major bleeding events and stroke prevention depend on plasma concentrations of direct oral anticoagulants (DOACs). Concomitant drugs that cause drug –drug interactions (DDIs) alter DOAC exposure by increasing or decreasing DOAC bioavailability and/or clearance; hence, they might affect the efficacy and safety of DOAC therapy. Patients with renal impairment already receive smaller DOAC maintenance doses because avoidance of elevated DOAC exposu re might prevent serious bleeding events. For other causes of increased exposure s...
Source: Clinical Pharmacokinetics - March 11, 2020 Category: Drugs & Pharmacology Source Type: research

Development of Population and Bayesian Models for Applied Use in Patients Receiving Cefepime
ConclusionThe identified model serves well for population dosing and as a Bayesian prior for precision dosing. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - March 5, 2020 Category: Drugs & Pharmacology Source Type: research

Clinical Pharmacokinetics and Pharmacodynamics of Dasatinib
AbstractDasatinib is an oral, once-daily tyrosine kinase inhibitor used in the treatment of chronic myeloid leukaemia and Philadelphia chromosome-positive acute lymphoblastic leukaemia. Dasatinib is rapidly absorbed, with the time for maximal serum concentration varying between 0.25 and 1.5  h. Oral absorption is not affected by food. The absolute bioavailability of dasatinib in humans is unknown due to the lack of an intravenous formulation preventing calculation of the reference exposure. Dasatinib is eliminated through cytochrome P450 (CYP) 3A4-mediated metabolism, with a terminal half-life of 3–4 h. Bas...
Source: Clinical Pharmacokinetics - February 29, 2020 Category: Drugs & Pharmacology Source Type: research

Systemic and Target-Site Pharmacokinetics of Antiparasitic Agents
AbstractAbout one-sixth of the world ’s population is affected by a neglected tropical disease as defined by the World Health Organization and Center for Disease Control. Parasitic diseases comprise most of the neglected tropical disease list and they are causing enormous amounts of disability, morbidity, mortality, and healthcare co sts worldwide. The burden of disease of the top five parasitic diseases has been estimated to amount to a total 23 million disability-adjusted life-years. Despite the massive health and economic impact, most drugs currently used for the treatment of parasitic diseases have been developed...
Source: Clinical Pharmacokinetics - February 26, 2020 Category: Drugs & Pharmacology Source Type: research

Oral Yohimbine as a New Probe Drug to Predict CYP2D6 Activity: Results of a Fixed-Sequence Phase I Trial
ConclusionsThe pharmacokinetics of yohimbine were highly correlated with CYP2D6, which was further supported by the clearance inhibition caused by the CYP2D6 inhibitor paroxetine. With these data, yohimbine is proposed to be a suitable probe drug to predict CYP2D6 activity. In addition, the microdose can be used in combination with microdosed midazolam to simultaneously evaluate CYP2D6 and CYP3A activity without any interaction between the probe drugs and because the microdoses exert no pharmacological effects.Clinical Trial RegistrationEudraCT2017-001801-34. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - February 15, 2020 Category: Drugs & Pharmacology Source Type: research

Effect of P-glycoprotein (P-gp) Inducers on Exposure of P-gp Substrates: Review of Clinical Drug –Drug Interaction Studies
AbstractUnderstanding transporter-mediated drug –drug interactions (DDIs) for investigational agents is important during drug development to assess DDI liability, its clinical relevance, and to determine appropriate DDI management strategies. P-glycoprotein (P-gp) is an efflux transporter that influences the pharmacokinetics (PK) of various com pounds. Assessing transporter induction in vitro is challenging and is not always predictive of in vivo effects, and hence there is a need to consider clinical DDI studies; however, there is no clear guidance on when clinical evaluation of transporter induction is required. Fu...
Source: Clinical Pharmacokinetics - February 13, 2020 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetics and Pharmacodynamics of Approved and Investigational P2Y12 Receptor Antagonists
AbstractCoronary artery disease remains the major cause of mortality worldwide. Antiplatelet drugs such as acetylsalicylic acid and P2Y12 receptor antagonists are cornerstone treatments for the prevention of thrombotic events in patients with coronary artery disease. Clopidogrel has long been the gold standard but has major pharmacological limitations such as a slow onset and long duration of effect, as well as weak platelet inhibition with high inter-individual pharmacokinetic and pharmacodynamic variability. There has been a strong need to develop potent P2Y12 receptor antagonists with more favorable pharmacological prop...
Source: Clinical Pharmacokinetics - February 13, 2020 Category: Drugs & Pharmacology Source Type: research

Disposition of Oral Cannabidiol-Rich Cannabis Extracts in Children with Epilepsy
The objective of this study was to determine the disposition of oral cannabidiol cannabis extracts and drug interactions in children with pediatric epilepsy.MethodsWe conducted a prospective observational study evaluating the disposition of oral cannabidiol in children (
Source: Clinical Pharmacokinetics - February 12, 2020 Category: Drugs & Pharmacology Source Type: research

Integration of Placental Transfer in a Fetal –Maternal Physiologically Based Pharmacokinetic Model to Characterize Acetaminophen Exposure and Metabolic Clearance in the Fetus
ConclusionThe median dose fraction of acetaminophen converted to its metabolites in the term fetus was predicted. The various placental transfer approaches supported the development of a generic f-m PBPK model incorporating in vivo placental drug transfer. The predicted arterial umbilical cord acetaminophen concentration was far below the suggested postnatal threshold (24.47  mg/L) for ductal closure. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - February 12, 2020 Category: Drugs & Pharmacology Source Type: research

Clinical Pharmacokinetics and Pharmacodynamics of Levobupivacaine
AbstractLevobupivacaine is a long-acting amide local anaesthetic used in analgesia and anaesthesia. Like other local anaesthetic drugs, levobupivacaine exhibits effects on motor and sensory nerves by inhibiting the opening of voltage-gated sodium channels, and hence propagation of neuronal action potentials. Levobupivacaine is the S( −) stereoisomer of dextrobupivacaine, although both are used commercially in the racemic form bupivacaine. A favourable safety and drug effect profile for levobupivacaine has led to widespread use. Levobupivacaine is generally well tolerated but dose adjustment is important in population...
Source: Clinical Pharmacokinetics - February 8, 2020 Category: Drugs & Pharmacology Source Type: research

Inability of Current Dosing to Achieve Carboplatin Therapeutic Targets in People with Advanced Non-Small Cell Lung Cancer: Impact of Systemic Inflammation on Carboplatin Exposure and Clinical Outcomes
This study investigated whether novel factors, such as systemic inflammation [platelet –lymphocyte ratio (PLR) and neutrophil–lymphocyte ratio (NLR)], impact carboplatin pharmacokinetics and drug utilisation. The study also examined the ability of current and alternate dosing regimens to meet therapeutic targets.MethodsSeventy-two people with advanced NSCLC treated with carboplatin-based (460 –1050 mg) doublet chemotherapy were recruited and pharmacokinetic data (n  = 61) were analysed using non-linear mixed modelling. Covariate analysis was performed to investigate the impact of standard an...
Source: Clinical Pharmacokinetics - February 7, 2020 Category: Drugs & Pharmacology Source Type: research

Effective Removal of Dabigatran by Idarucizumab or Hemodialysis: A Physiologically Based Pharmacokinetic Modeling Analysis
ConclusionsA comprehensive and mechanistic PBPK/PD model to study dabigatran reversal has been established, which includes whole-body PBPK modeling of idarucizumab, the idarucizumab-dabigatran interaction, dabigatran hemodialysis, the pharmacodynamic effect of dabigatran on blood coagulation, and the impact of renal function in these different scenarios. The model was applied to explore different reversal scenarios for dabigatran therapy. (Source: Clinical Pharmacokinetics)
Source: Clinical Pharmacokinetics - February 4, 2020 Category: Drugs & Pharmacology Source Type: research