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Journal of Clinical Pharmacology Feb 2022Population pharmacokinetic (PK) modeling is a widely used approach to analyze PK data obtained from groups of individuals, in both industry and academic research. The... (Review)
Review
Population pharmacokinetic (PK) modeling is a widely used approach to analyze PK data obtained from groups of individuals, in both industry and academic research. The approach can also be used to analyze pharmacodynamic (PD) data and pooled PK/PD data. There are 2 main families of population PK methods: parametric and nonparametric. The objectives of this article are to present an overview of nonparametric methods used in population pharmacokinetic modeling and to explain their specific characteristics to inform scientists and clinicians about their potential value for data analysis, simulation, dosage design, and therapeutic drug monitoring (TDM). Nonparametric methods have several interesting characteristics for population PK analysis, including computation of exact likelihoods, the ability to accommodate parameter probability distributions of any shape (eg, non-Gaussian), and to detect subpopulations and outliers. Nonparametric population methods are also highly relevant for model-based TDM and design of individualized drug dosage regimens. Several algorithms have been developed to estimate model parameter values within an individual and compute that individual's dosage to achieve target drug exposure with maximum precision and accuracy. Nonparametric modeling methods for both population and individual PK analysis are available under user-friendly packages.
Topics: Age Factors; Algorithms; Alkynes; Area Under Curve; Benzoxazines; Cyclopropanes; Humans; Metabolic Clearance Rate; Models, Biological; Models, Statistical; Pharmacokinetics; Sex Factors; Software Design
PubMed: 33103785
DOI: 10.1002/jcph.1650 -
Expert Opinion on Drug Metabolism &... Sep 2020A poor pharmacokinetic profile due to inadequate distribution and rapid renal clearance limits site-specific target engagement and drug efficacy. The inherent properties... (Review)
Review
INTRODUCTION
A poor pharmacokinetic profile due to inadequate distribution and rapid renal clearance limits site-specific target engagement and drug efficacy. The inherent properties of human serum albumin for broad tissue distribution, prolonged circulation, and ligand transport have been engineered into albumin-based drug designs to modulate the pharmacokinetics to increase efficacy and reduce the frequency of dose.
AREAS COVERED
This review highlights albumin structural features, ligand binding, and molecular interactions key to albumin-drug designs and an overview of the repertoire of albumin-drugs and approaches, with focus on pharmacokinetics of marketed products and clinical trials.
EXPERT OPINION
Comparison, and advantages as well as disadvantages of the endogenous albumin-binding versus recombinant albumin construct approach, and half-life extension and intracellular drug delivery applications. The section addresses current challenges and solutions to the different drug designs, and considerations needed to progress the field such as conjugation chemistries, drug loading, and animal models. The section highlights the need for a paradigm shift in the field from 'utilizing' to 'controlling' albumin transport with recombinant human albumin variants engineered for tuned affinity to albumin cellular receptors.
Topics: Animals; Drug Delivery Systems; Drug Design; Humans; Pharmaceutical Preparations; Pharmacokinetics; Serum Albumin, Human; Tissue Distribution
PubMed: 32729729
DOI: 10.1080/17425255.2020.1801633 -
International Journal of Molecular... Jan 2023RNA-mediated drugs are a rapidly growing class of therapeutics. Over the last five years, the list of FDA-approved RNA therapeutics has expanded owing to their unique... (Review)
Review
RNA-mediated drugs are a rapidly growing class of therapeutics. Over the last five years, the list of FDA-approved RNA therapeutics has expanded owing to their unique targets and prolonged pharmacological effects. Their absorption, distribution, metabolism, and excretion (ADME) have important clinical im-plications, but their pharmacokinetic properties have not been fully understood. Most RNA therapeutics have structural modifications to prevent rapid elimination from the plasma and are administered intravenously or subcutaneously, with some exceptions, for effective distribution to target organs. Distribution of drugs into tissues depends on the addition of a moiety that can be transported to the target and RNA therapeutics show a low volume of distribution because of their molecular size and negatively-charged backbone. Nucleases metabolize RNA therapeutics to a shortened chain, but their metabolic ratio is relatively low. Therefore, most RNA therapeutics are excreted in their intact form. This review covers not only ADME features but also clinical pharmacology data of the RNA therapeutics such as drug-drug interaction or population pharmacokinetic analyses. As the market of RNA therapeutics is expected to rapidly expand, comprehensive knowledge will contribute to interpreting and evaluating the pharmacological properties.
Topics: Drug Interactions; Chemical Phenomena; Biological Transport; Pharmacokinetics
PubMed: 36614189
DOI: 10.3390/ijms24010746 -
Molecules (Basel, Switzerland) May 2021Enzymes, receptors, and other binding molecules in biological processes can recognize enantiomers as different molecular entities, due to their different dissociation... (Review)
Review
Enzymes, receptors, and other binding molecules in biological processes can recognize enantiomers as different molecular entities, due to their different dissociation constants, leading to diverse responses in biological processes. Enantioselectivity can be observed in drugs pharmacodynamics and in pharmacokinetic (absorption, distribution, metabolism, and excretion), especially in metabolic profile and in toxicity mechanisms. The stereoisomers of a drug can undergo to different metabolic pathways due to different enzyme systems, resulting in different types and/or number of metabolites. The configuration of enantiomers can cause unexpected effects, related to changes as unidirectional or bidirectional inversion that can occur during pharmacokinetic processes. The choice of models for pharmacokinetic studies as well as the subsequent data interpretation must also be aware of genetic factors (such as polymorphic metabolic enzymes), sex, patient age, hepatic diseases, and drug interactions. Therefore, the pharmacokinetics and toxicity of a racemate or an enantiomerically pure drug are not equal and need to be studied. Enantioselective analytical methods are crucial to monitor pharmacokinetic events and for acquisition of accurate data to better understand the role of the stereochemistry in pharmacokinetics and toxicity. The complexity of merging the best enantioseparation conditions with the selected sample matrix and the intended goal of the analysis is a challenge task. The data gathered in this review intend to reinforce the importance of the enantioselectivity in pharmacokinetic processes and reunite innovative enantioselective analytical methods applied in pharmacokinetic studies. An assorted variety of methods are herein briefly discussed.
Topics: Chemical Phenomena; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmaceutical Preparations; Pharmacokinetics; Stereoisomerism
PubMed: 34070985
DOI: 10.3390/molecules26113113 -
Journal of Veterinary Pharmacology and... Nov 2022The aim of this study was to determine the pharmacokinetics and bioavailability of carprofen in sheep following single intravenous (IV), intramuscular (IM), subcutaneous...
The aim of this study was to determine the pharmacokinetics and bioavailability of carprofen in sheep following single intravenous (IV), intramuscular (IM), subcutaneous (SC), and oral (PO) administrations of a parenteral formulation at a dose of 4 mg/kg. A total of eight sheep were used for the investigation. The study comprised four periods, according to a crossover design with a 21-day washout period between treatments. Plasma concentrations of carprofen were measured using HPLC-UV. Pharmacokinetic parameters were estimated by non-compartmental model analysis. Following IV administration, t , Cl , and V were 43.36 h, 1.98 ml/h/kg, and 121.36 ml/kg, respectively. The C was 26.57 mg/ml for the IM, 23.76 mg/ml for the SC, and 15.90 mg/ml for the PO. The bioavailability following IM, SC, and PO administrations was 75.47%, 82.00%, and 62.51%, respectively. Plasma creatine kinase activity increased significantly at 3, 6, and 12 h following IM administration of carprofen. Despite differences in plasma concentrations and bioavailability among administration routes, carprofen at 4 mg/kg dose may provide the plasma concentration (>1.5 μg/ml) needed for analgesic effect during 144 h in all routes. However, because of the slow absorption rate after SC and PO routes, the IV route may be preferred primarily for the rapid onset in the analgesic and anti-inflammatory effect of carprofen in sheep. Despite the favorable kinetics, the muscle damage caused by IM injection limits use of carprofen via IM route.
Topics: Sheep; Animals; Biological Availability; Half-Life; Injections, Intramuscular; Injections, Intravenous; Area Under Curve; Analgesics
PubMed: 35768899
DOI: 10.1111/jvp.13085 -
Obesity Reviews : An Official Journal... May 2020Bariatric surgeries induce structural changes that can alter the absorption of drugs in patients already at risk of polypharmacy. This scoping review aimed to explore... (Review)
Review
Bariatric surgeries induce structural changes that can alter the absorption of drugs in patients already at risk of polypharmacy. This scoping review aimed to explore pharmacokinetic changes of orally administered drugs in patients post-bariatric surgery, and assess the quality and level of bias. Electronic databases were searched for articles relating to bariatric surgery and pharmacokinetics published between 1998 and 2019. Pre-post studies reporting on pharmacokinetic parameters were included, and the Newcastle-Ottawa Scale was used to assess risk-of-bias. A total of 21 studies were included in this review, and changes in absorption were reported in all included studies across 29 drugs. In 11 studies, this change was reported as statistically significant (p<.05), while six reported a nonsignificant change. More drugs exhibited a shorter Tmax and higher Cmax after surgery than otherwise, however changes in AUC were variable. Four studies were assessed as having fair quality while the remainder of the included studies were of good quality and low risk-of-bias. Bariatric surgery alters the absorption of drugs and several mechanisms are implicated to be responsible. Short and long-term monitoring is recommended in patients post-surgery for clinical changes in response to medications. Future research with a higher number of participants and greater control of variables, such as concurrent medications, malabsorptive disorders, and body composition should be considered.
Topics: Absorption, Physiological; Bariatric Surgery; Body Composition; Humans; Obesity; Pharmaceutical Preparations; Pharmacokinetics
PubMed: 32100411
DOI: 10.1111/obr.12988 -
Biostatistics (Oxford, England) Jan 2022The classical approach to analyze pharmacokinetic (PK) data in bioequivalence studies aiming to compare two different formulations is to perform noncompartmental...
The classical approach to analyze pharmacokinetic (PK) data in bioequivalence studies aiming to compare two different formulations is to perform noncompartmental analysis (NCA) followed by two one-sided tests (TOST). In this regard, the PK parameters area under the curve (AUC) and $C_{\max}$ are obtained for both treatment groups and their geometric mean ratios are considered. According to current guidelines by the U.S. Food and Drug Administration and the European Medicines Agency, the formulations are declared to be sufficiently similar if the $90\%$ confidence interval for these ratios falls between $0.8$ and $1.25 $. As NCA is not a reliable approach in case of sparse designs, a model-based alternative has already been proposed for the estimation of $\rm AUC$ and $C_{\max}$ using nonlinear mixed effects models. Here we propose another, more powerful test than the TOST and demonstrate its superiority through a simulation study both for NCA and model-based approaches. For products with high variability on PK parameters, this method appears to have closer type I errors to the conventionally accepted significance level of $0.05$, suggesting its potential use in situations where conventional bioequivalence analysis is not applicable.
Topics: Area Under Curve; Computer Simulation; Cross-Over Studies; Humans; Nonlinear Dynamics; Therapeutic Equivalency
PubMed: 32696053
DOI: 10.1093/biostatistics/kxaa026 -
Drug Metabolism and Disposition: the... Jun 2022Characterization of the pharmacokinetics and biodistribution of therapeutic proteins (TPs) is a hot topic within the pharmaceutical industry, particularly with an... (Review)
Review
Characterization of the pharmacokinetics and biodistribution of therapeutic proteins (TPs) is a hot topic within the pharmaceutical industry, particularly with an ever-increasing catalog of novel modality TPs. Here, we review the current practices, and provide a summary of extensive cross-company discussions as well as a survey completed by International Consortium for Innovation and Quality members on this theme. A wide variety of in vitro, in vivo and in silico techniques are currently used to assess pharmacokinetics and biodistribution of TPs, and we discuss the relevance of these from an industry perspective, focusing on pharmacokinetic/pharmacodynamic understanding at the preclinical stage of development, and translation to human. We consider that the 'traditional in vivo biodistribution study' is becoming insufficient as a standalone tool, and thorough characterization of the interaction of the TP with its target(s), target biology, and off-target interactions at a microscopic scale are key to understand the overall biodistribution on a full-body scale. Our summary of the current challenges and our recommendations to address these issues could provide insight into the implementation of best practices in this area of drug development, and continued cross-company collaboration will be of tremendous value. SIGNIFICANCE STATEMENT: The Innovation and Quality Consortium Translational and ADME Sciences Leadership Group working group for the absorption, distribution, metabolism, and excretion of therapeutic proteins evaluates the current practices and challenges in characterizing the pharmacokinetics and biodistribution of therapeutic proteins during drug development, and proposes recommendations to address these issues. Incorporating the in vitro, in vivo and in silico approaches discussed herein may provide a pragmatic framework to increase early understanding of pharmacokinetic/pharmacodynamic relationships, and aid translational modeling for first-in-human dose predictions.
Topics: Drug Industry; Humans; Pharmaceutical Preparations; Pharmacokinetics; Tissue Distribution
PubMed: 35149542
DOI: 10.1124/dmd.121.000463 -
Pharmacotherapy Jul 2023
Topics: Child; Humans; Pediatrics; Pharmacokinetics
PubMed: 37435987
DOI: 10.1002/phar.2840 -
European Journal of Pharmaceutical... Sep 2022The infinite time of oral drug absorption was conceived from the first day of the birth of pharmacokinetics when H. Dost introduced the term pharmacokinetics in his book... (Review)
Review
The infinite time of oral drug absorption was conceived from the first day of the birth of pharmacokinetics when H. Dost introduced the term pharmacokinetics in his book published in 1953. He adopted the function developed by H. Bateman back in 1908 for the decay of the nuclei isotopes to describe oral drug absorption as a first-order process. We unveiled this false hypothesis relying on common wisdom i.e. drugs are absorbed in finite time. This false assumption had dramatic effects on the evolution of oral pharmacokinetics but most importantly on the bioavailability and bioequivalence concepts and metrics. This work focuses on the finite absorption time (FAT) concept, the relevant Physiologically Based Finite Time (PBFTPK) models developed and their applications in oral pharmacokinetics, bioavailability and bioequivalence. The crux of the matter is that drug absorption from the gastrointestinal tract takes place under sink conditions because of the high blood flow rate in the vena cava. The termination of oral, pulmonary and intranasal drug absorption at a specific time point, calls for regulatory changes in bioavailability and bioequivalence studies in terms of the study design and metrics used for the bioequivalence assessment.
Topics: Administration, Oral; Biological Availability; Gastrointestinal Tract; Humans; Male; Pharmacokinetics; Therapeutic Equivalency
PubMed: 35863551
DOI: 10.1016/j.ejps.2022.106265