Evaluation of the estimation and classification performance of NONMEM when applying mixture model for drug clearance.

Maximum likelihood estimation of parameters involving mixture model is known to have significant and specific patterns of errors. Population pharmacokinetic (PopPK) modeling using NONMEM is no exception. A few relevant studies on estimation and classification performance were done, but a comprehensive study was not yet available.

Population Pharmacokinetic Study and Individual Dose Adjustments of High-Dose Methotrexate in Chinese Pediatric Patients With Acute Lymphoblastic Leukemia or Osteosarcoma.

High-dose methotrexate (>0.5 g/m ) is among the first-line chemotherapeutic agents used in treating acute lymphoblastic leukemia (ALL) and osteosarcoma in children. Despite rapid hydration, leucovorin rescue, and routine therapeutic drug monitoring, severe toxicity is not uncommon.

In silico drug absorption tract: An agent-based biomimetic model for human oral drug absorption.

Background: An agent-based modeling approach has been suggested as an alternative to traditional, equation-based modeling methods for describing oral drug absorption. It enables researchers to gain a better understanding of the pharmacokinetic (PK) mechanisms of a drug. This project demonstrates that a biomimetic agent-based model can adequately describe the absorption and disposition kinetics both of midazolam and clonazepam.

Orally-dissolving film for sublingual and buccal delivery of ropinirole.

Ropinirole is a very important treatment option for Parkinson's disease (PD), a major threat to the aging population. However, this drug undergoes extensive first-pass metabolism, resulting in a low oral bioavailability. Moreover, the necessity of frequent administration due to the short half-life of ropinirole may jeopardize patient compliance.

A Review of Food-Drug Interactions on Oral Drug Absorption.

Food effect, also known as food-drug interactions, is a common phenomenon associated with orally administered medications and can be defined as changes in absorption rate or absorption extent. The mechanisms of food effect and their consequences can involve multiple factors, including human post-prandial physiology, properties of the drug, and how the drug is administered. Therefore, it is essential to have a thorough understanding of these mechanisms when recommending whether a specific drug should be taken with or without food.

An Agent-Based Approach to Dynamically Represent the Pharmacokinetic Properties of Baicalein.

Baicalein, a typical flavonoid presented in Scutellariae radix, exhibits a unique metabolic profile during first-pass metabolism: parallel glucuronidation and sulfation pathways, with possible substrate inhibition in both pathways. In this project, we aimed to construct an agent-based model to dynamically represent baicalein pharmacokinetics and to verify the substrate inhibition hypothesis. The model consisted of three 3D spaces and two membranes: apical space (S1), intracellular space (S2), basolateral space (S3), apical membrane (M1), and basolateral membrane (M2).

Induction of liver cytochrome P450s by Danshen-Gegen formula is the leading cause for its pharmacokinetic interactions with warfarin.

Ethnopharmacological Relevance: Although the increased usage of herbal medicine leading to herb-drug interactions is well reported, the mechanism of such interactions between herbal medicines with conventionally prescribed drugs such as warfarin is not yet fully understood. Our previous rat in vivo study demonstrated that co-administration of Danshen-Gegen Formula (DGF), a Radix Salvia miltiorrhiza (Danshen) and Radix Puerariae lobatae (Gegen) containing Chinese medicine formula recently developed for the treatment of cardiovascular disease, with warfarin could cause significant herb-drug interactions. The current study aims to explore the pharmacokinetics-based mechanism of the DGF-warfarin interactions during absorption, distribution and metabolism processes.

Radix Puerariae: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use.

Radix Puerariae has been traditionally used for the treatment of diarrhea, acute dysentery, deafness and cardiovascular diseases. Yege (Gegen or Radix Puerariae lobatae), the dried root of Pueraria lobata (Wild.) Ohwi, has been widely used in China and, to a lesser extent, in Japan, Korea, and the United States.

Relational grounding facilitates development of scientifically useful multiscale models.

We review grounding issues that influence the scientific usefulness of any biomedical multiscale model (MSM). Groundings are the collection of units, dimensions, and/or objects to which a variable or model constituent refers. To date, models that primarily use continuous mathematics rely heavily on absolute grounding, whereas those that primarily use discrete software paradigms (e.

Mechanistic insight from in silico pharmacokinetic experiments: roles of P-glycoprotein, Cyp3A4 enzymes, and microenvironments.

Saquinavir exhibits paradoxical transport across modified Caco-2 cell monolayers (doi: 10.1124/jpet.103.

At the biological modeling and simulation frontier.

We provide a rationale for and describe examples of synthetic modeling and simulation (M&S) of biological systems. We explain how synthetic methods are distinct from familiar inductive methods. Synthetic M&S is a means to better understand the mechanisms that generate normal and disease-related phenomena observed in research, and how compounds of interest interact with them to alter phenomena.

Mechanistic simulations explain paradoxical saquinavir metabolism during in vitro vectorial transport study.

We were confronted by an unexpected observation: in a Transwell study of confluent, Cyp3A4 and P-gp-expressing Caco-2 cells, higher intracellular saquinavir levels, yet less first metabolite (M7) formation were observed following apical dosing, compared to basal dosing. To test two seemingly plausible hypothesized explanations, we constructed an in silico working analogue using the synthetic method. Neither mechanism alone was sufficient, but when combined and tuned within the analogue, the results generated were a semi-quantitative match to the experimental data.

Discovering plausible mechanistic details of hepatic drug interactions.

We sought a single set of mechanisms that could provide a quantitative explanation of three pairs of published time series data: perfusate concentration of digoxin and its metabolite in perfusates of isolated perfused rat livers 1) in the absence of any predose and with a predose of either 2) the uptake inhibitor rifampicin or 3) the efflux inhibitor quinidine. We used the synthetic modeling and simulation method because it provides a means of developing a scientific, experimental approach to unraveling and understanding some of the complexities of drug-drug interactions. We plugged together validated, quasi-autonomous software components to form abstract but mechanistically realistic analogs of livers undergoing perfusion [recirculating in silico livers (RISLs)], into which we could add objects representing each of the above three drugs, alone or in combination.

Applying models of targeted drug delivery to gene delivery.

Gene delivery requires targeted delivery systems. Exploratory simulations using models of targeted drug delivery helps one assess the worthiness of such systems, and helps quantify the expected therapeutic benefits of the systems. The drug targeting index (DTI), a ratio of availabilities, is a measure of pharmacokinetic benefit of the delivery device, based on a combination of a physiologically-based pharmacokinetic model and a single pharmacodynamic Emaxmodel.