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CPT: Pharmacometrics & Systems... Oct 2016The aim of this tutorial is to introduce the fundamental concepts of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling with a special focus on...
The aim of this tutorial is to introduce the fundamental concepts of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling with a special focus on their practical implementation in a typical PBPK model building workflow. To illustrate basic steps in PBPK model building, a PBPK model for ciprofloxacin will be constructed and coupled to a pharmacodynamic model to simulate the antibacterial activity of ciprofloxacin treatment.
Topics: Animals; Computer Simulation; Humans; Models, Biological; Pharmacokinetics; Risk Assessment; Tissue Distribution
PubMed: 27653238
DOI: 10.1002/psp4.12134 -
American Journal of Perinatology Jul 2019Neonates are a uniquely vulnerable population, compromised by immature physiology and critical illness if born premature. Furthermore, neonates have frequent exposures... (Review)
Review
Neonates are a uniquely vulnerable population, compromised by immature physiology and critical illness if born premature. Furthermore, neonates have frequent exposures to drugs that lack adequate data on safety, efficacy, and appropriate dosing in this population. Key physiologic differences between neonates and older children and adults affect drug absorption, distribution, metabolism, and elimination. Adequate understanding and consideration of these differences is essential to ensure optimal dosing of therapeutic agents in this vulnerable population. Moreover, direct study of neonates through appropriately designed pharmacokinetic and pharmacodynamic studies can ensure the development of safe and effective therapeutics in our youngest populations of patients.
Topics: Absorption, Physiological; Humans; Infant, Newborn; Pharmaceutical Preparations; Pharmacokinetics; Tissue Distribution
PubMed: 31238353
DOI: 10.1055/s-0039-1691772 -
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 -
Seminars in Perinatology Apr 2020The effects of the many biochemical and physiologic changes of pregnancy on the dose-response relationship of drugs administered to pregnant women are poorly understood.... (Review)
Review
The effects of the many biochemical and physiologic changes of pregnancy on the dose-response relationship of drugs administered to pregnant women are poorly understood. The dose-response relationship is affected by pharmacokinetics, or what the body does to a drug, and pharmacodynamics, or what a drug does to the body. Insights into the potential effects of the changes of pregnancy on one aspect of the dose-response relationship of a drug can be obtained by studying the pharmacokinetics of the drug in the various stages of pregnancy and the postpartum period. There are several available approaches to studying pharmacokinetic changes in pregnancy. Single trough screening studies can provide qualitative estimates of elimination clearance, which with the dosing rate determines the steady-state drug concentration, throughout pregnancy and into the postpartum period. Population pharmacokinetic studies such as two stage pharmacokinetic studies and studies using a nonlinear mixed effects pharmacokinetic modeling approach can characterize pharmacokinetic changes more rigorously.
Topics: Absorption, Physiological; Dose-Response Relationship, Drug; Drug Elimination Routes; Female; Humans; Pharmaceutical Preparations; Pharmacokinetics; Pharmacological Phenomena; Pregnancy; Tissue Distribution
PubMed: 32093881
DOI: 10.1016/j.semperi.2020.151227 -
Future Oncology (London, England) Apr 2019As originator biologic medicines lose patent protection, some biopharmaceutical companies are focusing on developing similar versions of these costly and complex... (Review)
Review
As originator biologic medicines lose patent protection, some biopharmaceutical companies are focusing on developing similar versions of these costly and complex therapies with a goal of providing more affordable treatment options. Many of these molecules, known as biosimilars, are now approved worldwide and several more are expected to be introduced in the near future. As more biosimilars become available, it is important for clinicians to become familiar with this new category of products and understand how biosimilars are developed, how their development differs from that of originator biologics and how they differ from generics. This review aims to provide the practicing clinician with the knowledge needed to understand biosimilars, along with some guidance on their use in treating oncologic diseases.
Topics: Biosimilar Pharmaceuticals; Drug Approval; Humans; Neoplasms; Oncologists; Practice Guidelines as Topic; Therapeutic Equivalency; Tissue Distribution
PubMed: 30793950
DOI: 10.2217/fon-2018-0728 -
Journal of Pharmaceutical Sciences Jan 2019Nanoparticles are frequently designed to improve the pharmacokinetics profiles and tissue distribution of small molecules to prolong their systemic circulation, target... (Review)
Review
Nanoparticles are frequently designed to improve the pharmacokinetics profiles and tissue distribution of small molecules to prolong their systemic circulation, target specific tissue, or widen the therapeutic window. The multifunctionality of nanoparticles is frequently presented as an advantage but also results in distinct and complicated in vivo disposition properties compared with a conventional formulation of the same molecules. Physiologically based pharmacokinetic (PBPK) modeling has been a useful tool in characterizing and predicting the systemic disposition, target exposure, and efficacy and toxicity of various types of drugs when coupled with pharmacodynamic modeling. Here we review the unique disposition characteristics of nanoparticles, assess how PBPK modeling takes into account the unique disposition properties of nanoparticles, and comment on the applications and challenges of PBPK modeling in characterizing and predicting the disposition and biological effects of nanoparticles.
Topics: Animals; Humans; Models, Biological; Nanoparticles; Pharmacokinetics; Tissue Distribution
PubMed: 30385282
DOI: 10.1016/j.xphs.2018.10.037 -
Advanced Drug Delivery Reviews Jun 2015Although significant progress has been made in experimental high throughput screening (HTS) of ADME (absorption, distribution, metabolism, excretion) and pharmacokinetic... (Review)
Review
Although significant progress has been made in experimental high throughput screening (HTS) of ADME (absorption, distribution, metabolism, excretion) and pharmacokinetic properties, the ADME and Toxicity (ADME-Tox) in silico modeling is still indispensable in drug discovery as it can guide us to wisely select drug candidates prior to expensive ADME screenings and clinical trials. Compared to other ADME-Tox properties, human oral bioavailability (HOBA) is particularly important but extremely difficult to predict. In this paper, the advances in human oral bioavailability modeling will be reviewed. Moreover, our deep insight on how to construct more accurate and reliable HOBA QSAR and classification models will also discussed.
Topics: Administration, Oral; Animals; Biological Availability; Computer Simulation; Humans; Models, Biological; Pharmacokinetics
PubMed: 25582307
DOI: 10.1016/j.addr.2015.01.001 -
The AAPS Journal Dec 2012Biotherapeutics are becoming an increasingly common drug class used to treat autoimmune and other inflammatory conditions. Optimization of absorption, distribution,... (Review)
Review
Biotherapeutics are becoming an increasingly common drug class used to treat autoimmune and other inflammatory conditions. Optimization of absorption, distribution, metabolism, and excretion (ADME) profiles of biotherapeutics is crucial for clinical, as well as commercial, success of these drugs. This review focuses on the common questions and challenges in ADME optimization of biotherapeutics for inflammatory conditions. For these immunomodulatory and/or immunosuppressive biotherapeutics, special consideration should be given to the assessment of the interdependency of ADME profiles, pharmacokinetic/pharmacodynamic (PK/PD) relationships, and immunogenicity profiles across various preclinical species and humans, including the interdependencies both in biology and in assay readouts. The context of usage, such as dosing regimens, extent of disease, concomitant medications, and drug product characteristics may have a direct or indirect (via modulation of immunogenicity) impact on ADME profiles of biotherapeutics. Along these lines, emerging topics include assessments of preexisting reactivity to a biotherapeutic agent, impact of immunogenicity on tissue exposure, and analysis of penetration to normal versus inflamed tissues. Because of the above complexities and interdependences, it is essential to interpret PK, PD, and anti-drug antibody results in an integrated manner. In addition, because of the competitive landscape in autoimmune and inflammatory markets, many pioneering ADME-centric protein engineering and subsequent in vivo testing (such as optimization of novel modalities to extend serum and tissue exposures and to improve bioavailability) are being conducted with biotherapeutics in this therapeutic area. However, the ultimate challenge is demonstration of the clinical relevance (or lack thereof) of modified ADME and immunogenicity profiles.
Topics: Animals; Autoimmune Diseases; Biological Availability; Drug Evaluation, Preclinical; Humans; Immunologic Factors; Immunosuppressive Agents; Inflammation; Protein Engineering; Proteins
PubMed: 22798020
DOI: 10.1208/s12248-012-9385-y -
Molecules (Basel, Switzerland) Nov 2018Drug transporters mediate the absorption, tissue distribution, and excretion of drugs. The cDNAs of P-glycoprotein, multidrug resistance proteins (MRPs/ABCC), breast... (Review)
Review
Drug transporters mediate the absorption, tissue distribution, and excretion of drugs. The cDNAs of P-glycoprotein, multidrug resistance proteins (MRPs/ABCC), breast cancer resistance protein (BCRP/ABCG2), peptide transporters (PEPTs/SLC15), proton-coupled folate transporters (PCFT/SLC46A1), organic anion transporting polypeptides (OATPs/SLCO), organic anion transporters (OATs/SLC22), organic cation transporters (OCTs/SLC22), and multidrug and toxin extrusions (MATEs/SLC47) have been isolated, and their functions have been elucidated. Enantioselectivity has been demonstrated in the pharmacokinetics and efficacy of drugs, and is important for elucidating the relationship with recognition of drugs by drug transporters from a chiral aspect. Enantioselectivity in the transport of drugs by drug transporters and the inhibitory effects of drugs on drug transporters has been summarized in this review.
Topics: Animals; Humans; Membrane Transport Proteins; Molecular Structure; Pharmaceutical Preparations; Pharmacokinetics; Stereoisomerism; Structure-Activity Relationship; Tissue Distribution
PubMed: 30467304
DOI: 10.3390/molecules23123062 -
Anti-cancer Agents in Medicinal... Dec 2012Genistein, one of the most active natural flavonoids, exerts various biological effects including chemoprevention, antioxidation, antiproliferation and anticancer. More... (Review)
Review
Genistein, one of the most active natural flavonoids, exerts various biological effects including chemoprevention, antioxidation, antiproliferation and anticancer. More than 30 clinical trials of genistein with various disease indications have been conducted to evaluate its clinical efficacy. Based on many animals and human pharmacokinetic studies, it is well known that the most challenge issue for developing genistein as a chemoprevention agent is the low oral bioavailability, which may be the major reason relating to its ambiguous therapeutic effects and large interindividual variations in clinical trials. In order to better correlate pharmacokinetic to pharmacodynamics results in animals and clinical studies, an in-depth understanding of pharmacokinetic behavior of genistein and its ADME properties are needed. Numerous in vitro/in vivo ADME studies had been conducted to reveal the main factors contributing to the low oral bioavailability of genistein. Therefore, this review focuses on summarizing the most recent progress on mechanistic studies of genistein ADME and provides a systemic view of these processes to explain genistein pharmacokinetic behaviors in vivo. The better understanding of genistein ADME property may lead to development of proper strategy to improve genistein oral bioavailability via mechanism-based approaches.
Topics: Absorption; Administration, Oral; Animals; Anticarcinogenic Agents; Biological Availability; Genistein; Humans; Injections, Intraperitoneal; Injections, Intravenous; Metabolic Clearance Rate; Models, Biological; Molecular Structure; Tissue Distribution
PubMed: 22583407
DOI: 10.2174/187152012803833107