Development and Qualification of Physiologically Based Pharmacokinetic Models for Drugs With Atypical Distribution Behavior: A Desipramine Case Study.

Desipramine is a secondary tricyclic amine, which is primarily metabolized by cytochrome 2D6. It shows a high volume of distribution (Vss) (10-50 L/kg) due to its high lipophilicity, unspecific phospholipid binding, and lysosomal trapping. The objective of this study was to develop and qualify a physiologically based pharmacokinetic (PBPK) model for desipramine, which accounts for the high Vss of the drug following intravenous and oral administration of doses up to 100 mg. The model also accounts for the extended time to reach maximum concentration after oral dosing due to enterocyte trapping. Once developed and qualified in adults, we characterized the dynamic changes in metabolism and pharmacokinetics of desipramine after birth by scaling the system-specific parameters of the model from adults to pediatrics. The developed modeling strategy provides a prototypical workflow that can also be applied to other drugs with similar properties and a high volume of distribution.

Exploring Canine-Human Differences in Product Performance. Part II: Use of Modeling and Simulation to Explore the Impact of Formulation on Ciprofloxacin In Vivo Absorption and Dissolution in Dogs.

This study explored the in vivo performance of three oral ciprofloxacin formulations (oral solution, fast, or slow dissolving tablets) in beagle dogs. The in vivo absorption and dissolution behaviors, estimated with in silico mechanistic models, were compared to the results previously published in human volunteers. Six normal healthy male beagle dogs (five to completion) received three oral formulations and an intravenous infusion in a randomized crossover design. Plasma ciprofloxacin concentrations were estimated by tandem mass spectrometry detection. A mechanistic absorption model was used to predict the in vivo dissolution and absorption characteristics of the oral formulations. Canine ciprofloxacin absorption was constrained to the duodenum/jejunum. This absorption window was far narrower than that seen in humans. Furthermore, while substantial within-individual variability in drug absorption was seen in human subjects, a greater magnitude of variability was observed in dogs. For three sets of data, a lag time in gastric emptying was necessary to improve the accuracy of model-generated in vivo blood level profile predictions. In addition to species-associated dissimilarities in drug solubilization due to human versus canine differences in gastrointestinal fluid compositions, the far more rapid intestinal transit time and potential segmental differences in drug absorption needed to be considered during human-canine extrapolation of oral drug and drug product performance. Through the use of mechanistic models, the data generated in the human and canine studies contributed insights into some aspects of the interspecies differences to be considered when extrapolating oral bioavailability/formulation effect data between dogs and humans.

Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation: Report of an FDA Public Workshop.

On May 19, 2016, the US Food and Drug Administration (FDA) hosted a public workshop, entitled "Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation." The topic of mechanistic oral absorption modeling, which is one of the major applications of physiologically based pharmacokinetic (PBPK) modeling and simulation, focuses on predicting oral absorption by mechanistically integrating gastrointestinal transit, dissolution, and permeation processes, incorporating systems, active pharmaceutical ingredient (API), and the drug product information, into a systemic mathematical whole-body framework.

A Physiologically Based Pharmacokinetic Model for Ganciclovir and Its Prodrug Valganciclovir in Adults and Children.

A physiologically based pharmacokinetic (PBPK) model has been developed for ganciclovir and its prodrug valganciclovir. Initial bottom-up modeling based on physicochemical drug properties and measured in vitro inputs was verified in preclinical animal species, and then, a clinical model was verified in a stepwise fashion with pharmacokinetic data in adult, children, and neonatal patients. The final model incorporated conversion of valganciclovir to ganciclovir through esterases and permeability-limited tissue distribution of both drugs with active transport processes added in gut, liver, and kidney. A PBPK model which accounted for known age-related tissue volumes, composition and blood flows, and renal filtration clearance was able to simulate well the measured plasma exposures in adults and pediatric patients. Overall, this work illustrates the stepwise development of PBPK models which could be used to predict pharmacokinetics in infants and neonates, thereby assisting drug development in a vulnerable patient population where clinical data are challenging to obtain.

Bottom-up Meets Top-down: Complementary Physiologically Based Pharmacokinetic and Population Pharmacokinetic Modeling for Regulatory Approval of a Dosing Algorithm of Valganciclovir in Very Young Children.

Population pharmacokinetic (PopPK) and physiologically based pharmacokinetic (PBPK) models are frequently used to support pediatric drug development. Both methods have strengths and limitations and we used them complementarily to support the regulatory approval of a dosing algorithm for valganciclovir (VGCV) in children <4 months old. An existing pediatric PBPK model was extended to neonates and showed that potential physiological differences compared with older children are minor. The PopPK model was used to simulate ganciclovir (GCV) exposures in children with population typical combinations of body size and renal function and to assess the effectiveness of an alternative dosing algorithm suggested by the US Food and Drug Administration. PBPK and PopPK confirmed that the proposed VGCV dosing algorithm achieves similar GCV exposures in children of all ages and that the alternative dosing algorithm leads to underexposure in a substantial fraction of patients. Our approach raised the confidence in the VGCV dosing algorithm for children <4 months old and supported the regulatory approval.

Human Ontogeny of Drug Transporters: Review and Recommendations of the Pediatric Transporter Working Group.

The critical importance of membrane-bound transporters in pharmacotherapy is widely recognized, but little is known about drug transporter activity in children. In this white paper, the Pediatric Transporter Working Group presents a systematic review of the ontogeny of clinically relevant membrane transporters (e.g., SLC, ABC superfamilies) in intestine, liver, and kidney. Different developmental patterns for individual transporters emerge, but much remains unknown. Recommendations to increase our understanding of membrane transporters in pediatric pharmacotherapy are presented.

Relationships between the structure, cytotoxicity and hydrophobicity of quinazoline derivatives by quantitative structure-activity relationship.

Cytotoxicities of 93 quinazoline derivatives against HeLa cells have been determined as the isoeffective concentrations inhibiting, after a single dose, the protein synthesis to 50% of the control amount after 48 h incubation. The dependence of cytotoxicity on hydrophobicity of the studied derivatives has been described using a previously published model-based approach. The studied derivatives are classified into nine classes each forming a smooth hydrophobicity-cytotoxicity curve. Owing to the acceptable agreement between the model and the data it can be inferred that: (1) the compounds except two derivatives bind to the receptors with approximately the same affinity; (2) the criterion for the classification is the different rate of metabolism. The results represent a basis for a rational development of more potent quinazoline derivatives.

Predicting pharmacokinetics of drugs using physiologically based modeling--application to food effects.

Our knowledge of the major mechanisms underlying the effect of food on drug absorption allows reliable qualitative prediction based on biopharmaceutical properties, which can be assessed during the pre-clinical phase of drug discovery. Furthermore, several recent examples have shown that physiologically based absorption models incorporating biorelevant drug solubility measurements can provide quite accurate quantitative prediction of food effect. However, many molecules currently in development have distinctly sub-optimal biopharmaceutical properties, making the quantitative prediction of food effect for different formulations from in vitro data very challenging. If such drugs reach clinical development and show undesirable variability when dosed with food, improved formulation can help to reduce the food effect and carefully designed in vivo studies in dogs can be a useful guide to clinical formulation development. Even so, such in vivo studies provide limited throughput for screening, and food effects seen in dog cannot always be directly translated to human. This paper describes how physiologically based absorption modeling can play a role in the prediction of food effect by integrating the data generated during pre-clinical and clinical research and development. Such data include physicochemical and in vitro drug properties, biorelevant solubility and dissolution, and in vivo pre-clinical and clinical pharmacokinetic data. Some background to current physiological absorption models of human and dog is given, and refinements to models of in vivo drug solubility and dissolution are described. These are illustrated with examples using GastroPlus to simulate the food effect in dog and human for different formulations of two marketed drugs.

[Screening of antitumor antibiotics, formed by molds]. / K voprosu o skrininge protivoopukholevykh antibiotikov, obrazuemykh plesnevymi gribami

A system for screening fungal metabolites with cytotoxic activity against tumor cells is described and the results obtained using this system are discussed. It was found that 35.2 per cent of the strains isolated from uranium mines had a cytotoxic effect on the EAC cells in vitro. As for the strains isolated from other sources only 6.85 and 9.87 per cent of them inhibited the EAC cells in vitro. Five substances, i. e. vermiculline, PSX-I, Frequentine, bikaverin and duclauxin isolated from 227 evaluated cultures showed a strong inhibitory effect on the EAC cells and other tumors in vitro.