-
Pharmaceutical Research Mar 2017Physiologically-based pharmacokinetic (PBPK) models explicitly incorporate tissue-specific blood flows, partition coefficients, and metabolic processes. Since PBPK... (Review)
Review
Physiologically-based pharmacokinetic (PBPK) models explicitly incorporate tissue-specific blood flows, partition coefficients, and metabolic processes. Since PBPK models are derived using physiologic parameters and interactions of the compound with tissue components, these models are considered to be "bottom up" as opposed to "top down". Modeling approaches can be characterized as either a posteriori (observational) or a priori (based solely on theory). Furthermore, approaches can be mechanistic (structure and components based on mechanisms) or empirical (based on observations alone). Both "bottom up" and "top down" approaches can incorporate either empirical or mechanistic components. In this perspective, we discuss some of the methods and assumptions of current PBPK modeling approaches. Specifically, we discuss drug partitioning into phospholipids and neutral lipids, use of blood-plasma ratios to estimate basic drug tissue partitioning, and clearance of neutral and acidic drugs. Based on these discussions, we believe that current PBPK models are mechanistic but a posteriori and semi-empirical.
Topics: Chemistry, Pharmaceutical; Humans; Models, Biological; Molecular Structure; Pharmaceutical Preparations; Pharmacokinetics; Phospholipids; Tissue Distribution
PubMed: 28028770
DOI: 10.1007/s11095-016-2089-8 -
Clinical Pharmacology in Drug... Feb 2023Absolute bioavailability (F) and the impact of gastric pH, tablet formulation, and food on the pharmacokinetics and safety of asundexian, an oral factor XIa inhibitor,...
Absolute bioavailability (F) and the impact of gastric pH, tablet formulation, and food on the pharmacokinetics and safety of asundexian, an oral factor XIa inhibitor, was assessed in healthy White men aged 18-45 years in 4 studies. For F, fasted participants received 50 μg of [ C , N]-labeled asundexian intravenously 2 hours after 25 mg of asundexian orally. Tablet formulation (50-mg immediate release [IR], and different amorphous solid dispersion [ASD] IR 25-mg and 50-mg ASD IR tablets) and food effects were explored in 2 studies. Formulation was compared using 50-mg IR versus 25-mg ASD IR and 25-mg ASD IR versus 50-mg ASD IR (fasted); food effect using 25-mg ASD IR and 50-mg ASD IR. Gastric pH modulation was assessed using omeprazole or antacid coadministration with asundexian in the fasted state. Pharmacokinetic parameters included area under the concentration-time curve (AUC; and AUC/dose [D]) and maximum observed concentration (C and C /D) data were evaluable for 59 participants. F was 103.9%. Relative bioavailability with 25-mg ASD IR and 50-mg ASD IR tablets, respectively, was marginally affected by formulation (AUC/D ratios, 94.3% and 95.1%; C /D ratios, 95.5% and 88.7%), food (AUC[/D] ratios, 91.1% and 96.9%; C [/D] ratios: 78.3% and 95.1%), and gastric pH (omeprazole, no effect; antacid, AUC ratio, 89.9% and C ratio, 83.7%). No serious adverse events or deaths occurred; most adverse events were mild or moderate. In summary, oral asundexian was well tolerated and demonstrated complete bioavailability irrespective of tablet formulation, food, or gastric pH.
Topics: Male; Humans; Biological Availability; Antacids; Therapeutic Equivalency; Tablets; Hydrogen-Ion Concentration
PubMed: 36507617
DOI: 10.1002/cpdd.1207 -
Pharmaceutical Research Sep 2009Drug transporters are recognized as key players in the processes of drug absorption, distribution, metabolism, and elimination. The localization of uptake and efflux... (Review)
Review
Drug transporters are recognized as key players in the processes of drug absorption, distribution, metabolism, and elimination. The localization of uptake and efflux transporters in organs responsible for drug biotransformation and excretion gives transporter proteins a unique gatekeeper function in controlling drug access to metabolizing enzymes and excretory pathways. This review seeks to discuss the influence intestinal and hepatic drug transporters have on pharmacokinetic parameters, including bioavailability, exposure, clearance, volume of distribution, and half-life, for orally dosed drugs. This review also describes in detail the Biopharmaceutics Drug Disposition Classification System (BDDCS) and explains how many of the effects drug transporters exert on oral drug pharmacokinetic parameters can be predicted by this classification scheme.
Topics: Administration, Oral; Animals; Biological Availability; Biotransformation; Carrier Proteins; Half-Life; Humans; Pharmacokinetics
PubMed: 19568696
DOI: 10.1007/s11095-009-9924-0 -
CPT: Pharmacometrics & Systems... Dec 2022The gold-standard approach for modeling pharmacokinetic mediated drug-drug interactions is the use of physiologically-based pharmacokinetic modeling and population... (Review)
Review
The gold-standard approach for modeling pharmacokinetic mediated drug-drug interactions is the use of physiologically-based pharmacokinetic modeling and population pharmacokinetics. However, these models require extensive amounts of drug-specific data generated from a wide variety of in vitro and in vivo models, which are later refined with clinical data and system-specific parameters. Machine learning has the potential to be utilized for the prediction of drug-drug interactions much earlier in the drug discovery cycle, using inputs derived from, among others, chemical structure. This could lead to refined chemical designs in early drug discovery. Machine-learning models have many advantages, such as the capacity to automate learning (increasing the speed and scalability of predictions), improved generalizability by learning from multicase historical data, and highlighting statistical and potentially clinically significant relationships between input variables. In contrast, the routinely used mechanistic models (physiologically-based pharmacokinetic models and population pharmacokinetics) are currently considered more interpretable, reliable, and require a smaller sample size of data, although insights differ on a case-by-case basis. Therefore, they may be appropriate for later stages of drug-drug interaction assessment when more in vivo and clinical data are available. A combined approach of using mechanistic models to highlight features that can be used for training machine-learning models may also be exploitable in the future to improve the performance of machine learning. In this review, we provide concepts, strategic considerations, and compare machine learning to mechanistic modeling for drug-drug interaction risk assessment across the stages of drug discovery and development.
Topics: Humans; Models, Biological; Drug Interactions; Machine Learning; Drug Discovery; Pharmacokinetics
PubMed: 36176050
DOI: 10.1002/psp4.12870 -
Scientific Reports Mar 2021Enteric reabsorption occurs when a drug is secreted into the intestinal lumen and reabsorbed into the systemic circulation. This distribution process is evidenced by...
Enteric reabsorption occurs when a drug is secreted into the intestinal lumen and reabsorbed into the systemic circulation. This distribution process is evidenced by multiple peaks in pharmacokinetic profiles. Commonly, hepatobiliary drug secretion is assumed to be the underlying mechanism (enterohepatic reabsorption, EHR), neglecting other possible mechanisms such as gastric secretion (enterogastric reabsorption, EGR). In addition, the impact of drug reabsorption on systemic clearance, volume of distribution and bioavailability has been a subject of long-standing discussions. In this work, we propose semi-mechanistic pharmacokinetic models to reflect EHR and EGR and compare their respective impact on primary pharmacokinetic parameters. A simulation-based analysis was carried out considering three drug types with the potential for reabsorption, classified according to their primary route of elimination and their hepatic extraction: (A) hepatic metabolism-low extraction; (B) hepatic metabolism-intermediate/high extraction; (C) renal excretion. Results show that an increase in EHR can significantly reduce the clearance of drugs A and B, increase bioavailability of B drugs, and increase the volume of distribution for all drugs. Conversely, EGR had negligible impact in all pharmacokinetic parameters. Findings provide background to explain and forecast the role that this process can play in pharmacokinetic variability, including drug-drug interactions and disease states.
Topics: Administration, Intravenous; Biological Availability; Computer Simulation; Intestinal Absorption; Kinetics; Models, Biological; Pharmaceutical Preparations; Pharmacokinetics
PubMed: 33707635
DOI: 10.1038/s41598-021-85174-w -
BioMed Research International 2016Astragalus polysaccharide (APS) (used for intestinal protection) was added to formulate the Tongshu suppository to improve the pharmacokinetics of Aceclofenac, which...
Astragalus polysaccharide (APS) (used for intestinal protection) was added to formulate the Tongshu suppository to improve the pharmacokinetics of Aceclofenac, which were assessed in New Zealand rabbits using an orthogonal experimental design. The single-agent Aceclofenac was taken as the control formulation. The concentration-time and drug release curves were drawn, and T max (min), C max (μg·mL(-1)), AUC0→∞ , and MRT were compared using a pharmacokinetic systems program. The formulated Tongshu suppository had moderate hardness, a smooth surface with uniform color, and theoretical drug-loading rate of 8%. Its release rate was in accordance with the drug preparation requirements. The concentration-time curves and drug release curves revealed that the maximum concentrations (C max) were 4.18 ± 1.03 μg·mL(-1) and 3.34 ± 0.41 μg·mL(-1) for the Tongshu and Aceclofenac suppositories, respectively, showing statistically insignificant difference, while the peak times were 34.87 ± 4.69 min and 34.76 ± 6.34 min, respectively, also showing statistically insignificant difference. Compared with the Aceclofenac suppository, the relative bioavailability of the Tongshu suppository was 104.4%, and the difference between them was statistically insignificant. In this experiment, the Tongshu suppository was prepared using the hot-melt method. In vivo pharmacokinetic studies confirmed it had higher bioavailability than the Aceclofenac suppository.
Topics: Animals; Area Under Curve; Biological Availability; Chemistry, Pharmaceutical; Color; Diclofenac; Drug Liberation; Hardness; Rabbits; Rats; Suppositories; Technology, Pharmaceutical
PubMed: 27610366
DOI: 10.1155/2016/1691579 -
Advanced Drug Delivery Reviews Jan 2013Drug delivery systems involve technology designed to maximize therapeutic efficacy of drugs by controlling their biodistribution profile. In order to optimize a function... (Review)
Review
Drug delivery systems involve technology designed to maximize therapeutic efficacy of drugs by controlling their biodistribution profile. In order to optimize a function of the delivery systems, their biodistribution characteristics should be systematically understood. Pharmacokinetic analysis based on the clearance concepts provides quantitative information of the biodistribution, which can be related to physicochemical properties of the delivery system. Various delivery systems including macromolecular drug conjugates, chemically or genetically modified proteins, and particulate drug carriers have been designed and developed so far. In this article, we review physiological and pharmacokinetic implications of the delivery systems.
Topics: Drug Carriers; Drug Delivery Systems; Pharmaceutical Preparations; Pharmacokinetics; Tissue Distribution
PubMed: 23280371
DOI: 10.1016/j.addr.2012.11.006 -
British Journal of Clinical Pharmacology Feb 2022This study implements a physiologically-based pharmacokinetic (PBPK) modelling approach to investigate inter-ethnic differences in imatinib pharmacokinetics and dosing...
AIMS
This study implements a physiologically-based pharmacokinetic (PBPK) modelling approach to investigate inter-ethnic differences in imatinib pharmacokinetics and dosing regimens.
METHODS
A PBPK model of imatinib was built in the Simcyp Simulator (version 17) integrating in vitro drug metabolism and clinical pharmacokinetic data. The model accounts for ethnic differences in body size and abundance of drug-metabolising enzymes and proteins involved in imatinib disposition. Utility of this model for prediction of imatinib pharmacokinetics was evaluated across different dosing regimens and ethnic groups. The impact of ethnicity on imatinib dosing was then assessed based on the established range of trough concentrations (C ).
RESULTS
The PBPK model of imatinib demonstrated excellent predictive performance in describing pharmacokinetics and the attained C in patients from different ethnic groups, shown by prediction differences that were within 1.25-fold of the clinically-reported values in published studies. PBPK simulation suggested a similar dose of imatinib (400-600 mg/d) to achieve the desirable range of C (1000-3200 ng/mL) in populations of European, Japanese and Chinese ancestry. The simulation indicated that patients of African ancestry may benefit from a higher initial dose (600-800 mg/d) to achieve imatinib target concentrations, due to a higher apparent clearance (CL/F) of imatinib compared to other ethnic groups; however, the clinical data to support this are currently limited.
CONCLUSION
PBPK simulations highlighted a potential ethnic difference in the recommended initial dose of imatinib between populations of European and African ancestry, but not populations of Chinese and Japanese ancestry.
Topics: Asian People; Computer Simulation; Humans; Imatinib Mesylate; Metabolic Clearance Rate; Models, Biological; Pharmacokinetics
PubMed: 34535920
DOI: 10.1111/bcp.15084 -
Drug Delivery and Translational Research Apr 2021For topical drug products that target sites of action in the viable epidermal and/or upper dermal compartment of the skin, the local concentration profiles have proven...
For topical drug products that target sites of action in the viable epidermal and/or upper dermal compartment of the skin, the local concentration profiles have proven difficult to quantify because drug clearance from the viable cutaneous tissue is not well characterised. Without such knowledge, of course, it is difficult-if not impossible-to predict a priori whether and over what time frame a topical formulation will permit an effective concentration of drug within the skin 'compartment' to be achieved. Here, we test the hypothesis that valuable information about drug disposition, and specifically its clearance, in this experimentally difficult-to-access compartment (at least, in vivo) can be derived from available systemic pharmacokinetic data for drugs administered via transdermal delivery systems. A multiple regression analysis was undertaken to determine the best-fit empirical correlation relating clearance from the skin to known or easily calculable drug properties. It was possible, in this way, to demonstrate a clear relationship between drug clearance from the skin and key physical chemical properties of the drug (molecular weight, log P and topological polar surface area). It was further demonstrated that values predicted by the model correlated well with those derived from in vitro skin experiments.
Topics: Administration, Cutaneous; Drug Delivery Systems; Drug Elimination Routes; Metabolic Clearance Rate; Skin; Skin Absorption
PubMed: 33164164
DOI: 10.1007/s13346-020-00864-8 -
Drug Design, Development and Therapy 2023This study aimed to investigate the effect of food on the pharmacokinetics and safety profiles of SCC244, a novel oral c-Met inhibitor in healthy Chinese male subjects. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
This study aimed to investigate the effect of food on the pharmacokinetics and safety profiles of SCC244, a novel oral c-Met inhibitor in healthy Chinese male subjects.
METHODS
It was a randomized, open-label, and 3-period crossover design, single-dose phase I clinical trial. A total of 18 healthy male subjects were enrolled. These subjects received a single oral 300 mg dose of SCC244 with a 14-day washout between each period. Blood samples were collected at the designated time points and determined using a validated liquid chromatography tandem mass spectrometry method. Pharmacokinetic parameters were calculated by noncompartmental methods. Tolerability was assessed by physical examination, vital sign measurements, 12-lead ECG, clinical laboratory tests, and adverse events (AEs) monitoring throughout the study.
RESULTS
Eighteen eligible subjects were enrolled in the study. The ratios (90% CI) of C values for SCC244 in high-fat and low-fat meal states to that observed in fasted state were 194.8% (174.3-217.7%) and 194.6% (174.1-217.5%), respectively. The ratios of AUC and AUC in the high-fat meal state versus the fasted state were 237.4% (208.7-270.0%) and 235.9% (207.5-268.3%), respectively. The ratios of AUC and AUC in the low-fat meal state versus the fasted state were 219.2% (192.7-249.3%) and 218.3% (192.0-248.3%), respectively. Median T values and mean t were similar in all groups. The most common AEs were headache, blood fibrinogen decreased, head discomfort, dizziness, and protein urine presence. All AEs were Common Terminology Criteria for Adverse Events (CTCAE) grade 1 (except 1 case of grade 2) and have resolved by the end of the study.
CONCLUSION
The bioavailability of the tablet formulation of SCC244 was significantly increased when administered with high- and low-fat meals. However, the meals did not affect the median T and t. Safety under different fed conditions was comparable to fasted conditions in this study.
Topics: Humans; Male; Healthy Volunteers; Area Under Curve; Biological Availability; Therapeutic Equivalency; Fasting; Protein Kinase Inhibitors; Cross-Over Studies; Food-Drug Interactions; Administration, Oral; Tablets
PubMed: 36925997
DOI: 10.2147/DDDT.S388846