IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 4: Prediction accuracy and software comparisons with improved data and modelling strategies.

Oral drug absorption is a complex process depending on many factors, including the physicochemical properties of the drug, formulation characteristics and their interplay with gastrointestinal physiology and biology. Physiological-based pharmacokinetic (PBPK) models integrate all available information on gastro-intestinal system with drug and formulation data to predict oral drug absorption. The latter together with in vitro-in vivo extrapolation and other preclinical data on drug disposition can be used to predict plasma concentration-time profiles in silico.

Simultaneous Assessment of Transporter-Mediated Drug-Drug Interactions Using a Probe Drug Cocktail in Cynomolgus Monkey.

We aim to establish an in vivo preclinical model to enable simultaneous assessment of inhibition potential of an investigational drug on clinically relevant drug transporters, organic anion-transporting polypeptide (OATP)1B, breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), and organic anion transporter (OAT)3. Pharmacokinetics of substrate cocktail consisting of pitavastatin (OATP1B substrate), rosuvastatin (OATP1B/BCRP/OAT3), sulfasalazine (BCRP), and talinolol (P-gp) were obtained in cynomolgus monkey-alone or in combination with transporter inhibitors. Single-dose rifampicin (30 mg/kg) significantly ( < 0.

Predicting Human Clearance of Organic Anion Transporting Polypeptide Substrates Using Cynomolgus Monkey: In Vitro-In Vivo Scaling of Hepatic Uptake Clearance.

This work explores the utility of the cynomolgus monkey as a preclinical model to predict hepatic uptake clearance mediated by organic anion transporting polypeptide (OATP) transporters. Nine OATP substrates (rosuvastatin, pravastatin, repaglinide, fexofenadine, cerivastatin, telmisartan, pitavastatin, bosentan, and valsartan) were investigated in plated cynomolgus monkey and human hepatocytes. Total uptake clearance and passive diffusion were measured in vitro from initial rates in the absence and presence of the OATP inhibitor rifamycin SV , respectively.

In Vitro-In Vivo Extrapolation of OATP1B-Mediated Drug-Drug Interactions in Cynomolgus Monkey.

Hepatic organic anion-transporting polypeptides (OATP) 1B1 and 1B3 are clinically relevant transporters associated with significant drug-drug interactions (DDIs) and safety concerns. Given that OATP1Bs in cynomolgus monkey share >90% degree of gene and amino acid sequence homology with human orthologs, we evaluated the in vitro-in vivo translation of OATP1B-mediated DDI risk using this preclinical model. In vitro studies using plated cynomolgus monkey hepatocytes showed active uptake K values of 2.

IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 2: An introduction to the simulation exercise and overview of results.

Orally administered drugs are subject to a number of barriers impacting bioavailability (F), causing challenges during drug and formulation development. Physiologically-based pharmacokinetic (PBPK) modelling can help during drug and formulation development by providing quantitative predictions through a systems approach. The performance of three available PBPK software packages (GI-Sim, Simcyp®, and GastroPlus™) were evaluated by comparing simulated and observed pharmacokinetic (PK) parameters.

Bilayer composition, temperature, speciation effects and the role of bilayer chain ordering on partitioning of dexamethasone and its 21-phosphate.

Purpose: Models to predict membrane-water partition coefficients (Kp) as a function of drug structure, membrane composition, and solution properties would be useful. This study explores the partitioning of dexamethasone (Dex) and its ionizable 21-phosphate (Dex-P) in liposomes varying in acyl chain length, physical state, and pH.

Methods: DMPC:mPEG DMPE, DPPC:mPEG DPPE, and DSPC:mPEG DSPE (95:5 mol%) liposomes were prepared by thin film hydration.

Determination of drug release kinetics from nanoparticles: overcoming pitfalls of the dynamic dialysis method.

Dynamic dialysis is one of the most common methods for the determination of release kinetics from nanoparticle drug delivery systems. Drug appearance in the "sink" receiver compartment is a consequence of release from the nanoparticles into the dialysis chamber followed by diffusion across the dialysis membrane. This dual barrier nature inherent in the method complicates data interpretation and may lead to incorrect conclusions regarding nanoparticle release half-lives.

Enhanced active liposomal loading of a poorly soluble ionizable drug using supersaturated drug solutions.

Nanoparticulate drug carriers such as liposomal drug delivery systems are of considerable interest in cancer therapy because of their ability to passively accumulate in solid tumors. For liposomes to have practical utility for antitumor therapy in patients, however, optimization of drug loading, retention, and release kinetics are necessary. Active loading is the preferred method for optimizing loading of ionizable drugs in liposomes as measured by drug-to-lipid ratios, but the extremely low aqueous solubilities of many anticancer drug candidates may limit the external driving force, thus slowing liposomal uptake during active loading.

Hydroxy fatty acid based polyanhydride as drug delivery system: synthesis, characterization, in vitro degradation, drug release, and biocompatibility.

Low molecular weight hydroxy fatty acid based polyanhydrides were synthesized by one pot method, a variable of typical melt-condensation and characterized by FTIR, NMR, DSC, and GPC. Polymer degrades by both surface and bulk erosion as trailed by weight loss, anhydride loss and surface morphology. Control over drug release was accessed with drugs featuring different aqueous solubility, that is, methotrexate (hydrophobic) and 5-fluorouracil (hydrophilic).

Exploiting EPR in polymer drug conjugate delivery for tumor targeting.

Treatment of tumor tissue without affecting normal cells has always been formidable task for drug delivery scientists and this task is effectively executed by polymer drug conjugate (PDC) delivery. The novelty of this concept lies in the utilization of a physical mechanism called enhanced permeability and retention (EPR) for targeting tumors. EPR is a physiological phenomenon that is customary for fast growing tumor and solves the problem of targeting the miscreant tissue.

Copolymers of pharmaceutical grade lactic acid and sebacic acid: drug release behavior and biocompatibility.

Pharmaceutical grade D,L-lactic acid, which is rather an economic source in comparison to lactide monomer, was utilized for synthesis of a series of copolymers with sebacic acid. Polymers were characterized by GPC, FTIR, NMR and DSC techniques, and formulated into blank and methotrexate (MTX) loaded microspheres by emulsion-solvent evaporation method. In vitro degradation of blank microspheres was studied by FTIR, GPC and SEM analysis.

Role of polyanhydrides as localized drug carriers.

Many drugs that are administered in an unmodified form by conventional systemic routes fail to reach target organs in an effective concentration, or are not effective over a length of time due to a facile metabolism. Various types of targeting delivery systems and devices have been tried over a long period of time to overcome these problems. Targeted delivery or localized drug delivery offers an advantage of reduced body burden and systemic toxicity of the drugs, especially useful for highly toxic drugs like anticancer agents.