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Aims RO5459072, a cathepsin‐S inhibitor, Biopharmaceutics Classification System class 2 and P‐glycoprotein substrate, exhibited complex, nonlinear pharmacokinetics (PK) while fasted that seemed to impact both the absorption and the disposition phases. When given with food, all nonlinearities disappeared. Physiologically based PK (PBPK) modelling attributed those nonlinearities to dose‐dependent solubilisation and colonic absorption. The objective of this population PK analysis was to complement the PBPK analysis. Methods PK profiles in 39 healthy volunteers after first oral dosing (1–600 mg) while fasted or fed in single and multiple ascending dose studies were analysed using population compartmental modelling. Results The PK of RO5459072 while fed was characterized by a 1‐compartmental PK model with linear absorption and elimination. The nonlinearities while fasted were captured using dose dependent bioavailability and 2 sequential first‐order absorption phases: one following drug administration and one occurring 11 hours later and only for doses >10 mg. The bioavailability in the first absorption phase increased between 1 and 10 mg and then decreased with dose, in agreement with in vitro dissolution and solubility studies. The remaining fraction of doses to be absorbed by the second absorption phase was found to have a bioavailability similar to that in the first absorption phase. Conclusion The population PK model supported that dissolution‐ and solubility‐limited absorption from the proximal and distal intestine alone explains the nonlinear PK of RO5459072 in fasted state and the linear PK in fed state. This work, together with the PBPK analysis, raised our confidence in the understanding of this complex PK.

Prediction of the pharmacokinetics of orally administered drugs in children is of importance to optimize the efficacy and safety of pediatric medicines. Physiologically based pharmacokinetic (PBPK) models can be helpful for this purpose. However, application of these tools is limited by significant knowledge gaps regarding the physiological and anatomical changes which occur with age. This study aimed at investigating the age-dependent differences in oral absorption of a poorly soluble model compound, carbamazepine (CBZ) in children, infants, and neonates. We developed an oral absorption model in GastroPlus® and, after evaluation of the PBPK model for adults, extrapolation to younger ages was verified with clinical data and sensitivity analyses were applied for uncertain model parameters. We found that age-based scaling of physiological parameters, with clearance in particular, was important to obtain adequate simulation results. The sensitivity analysis revealed that CBZ absorption was influenced by solubility, particle radius, and small intestinal transit time depending on the pediatric age group and CBZ dose. However, in vitro dissolution testing using proposed pediatric biorelevant media suggested no major age dependency of dissolution kinetics. Such better understanding of oral absorption in pediatric patients is required to improve the prediction of exposure in children and the confidence in oral biopharmaceutical tools.

Drug load plays an important role in the development of solid dosage forms, since it can significantly influence both processability and final product properties. The percolation threshold of the active pharmaceutical ingredient (API) corresponds to a critical concentration, above which an abrupt change in drug product characteristics can occur. The objective of this study was to identify the percolation threshold of a poorly water-soluble drug with regard to the dissolution behavior from immediate release tablets. The influence of the API particle size on the percolation threshold was also studied. Formulations with increasing drug loads were manufactured via roll compaction using constant process parameters and subsequent tableting. Drug dissolution was investigated in biorelevant medium. The percolation threshold was estimated via a model dependent and a model independent method based on the dissolution data. The intragranular concentration of mefenamic acid had a significant effect on granules and tablet characteristics, such as particle size distribution, compactibility and tablet disintegration. Increasing the intragranular drug concentration of the tablets resulted in lower dissolution rates. A percolation threshold of approximately 20% v/v could be determined for both particle sizes of the API above which an abrupt decrease of the dissolution rate occurred. However, the increasing drug load had a more pronounced effect on dissolution rate of tablets containing the micronized API, which can be attributed to the high agglomeration tendency of micronized substances during manufacturing steps, such as roll compaction and tableting. Both methods that were applied for the estimation of percolation threshold provided comparable values.

The release and absorption profile of an oral medication is influenced by the physicochemical properties of the drug and its formulation, as well as by the anatomy and physiology of the gastrointestinal (GI) tract. During drug development the bioavailability of a new drug is typically assessed in early clinical studies in a healthy adult population. However, many disease conditions are associated with an alteration of the anatomy and/or physiology of the GI tract. The same holds true for some subpopulations, such as paediatric or elderly patients, or populations with different ethnicity. The variation in GI tract conditions compared to healthy adults can directly affect the kinetics of drug absorption, and thus, safety and efficacy of an oral medication. This review provides an overview of GI tract properties in special populations compared to healthy adults and discusses how drug absorption is affected by these conditions. Particular focus is directed towards non-disease dependent conditions (age, sex, ethnicity, genetic factors, obesity, pregnancy), GI diseases (ulcerative colitis and Crohn's disease, celiac disease, cancer in the GI tract, Roux-en-Y gastric bypass, lactose intolerance, Helicobacter pylori infection, and infectious diseases of the GI tract), as well as systemic diseases that change the GI tract conditions (cystic fibrosis, diabetes, Parkinson's disease, HIV enteropathy, and critical illness). The current knowledge about GI conditions in special populations and their impact on drug absorption is still limited. Further research is required to improve confidence in pharmacokinetic predictions and dosing recommendations in the targeted patient population, and thus to ensure safe and effective drug therapies. ispartof: EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES vol:147 ispartof: location:Netherlands status: published

Amorphous solid dispersions (ASD) are increasingly used to improve the oral bioavailability of poorly water-soluble compounds. However, hydrophilic polymers in ASD have high water-binding properties and, upon water contact, they often form a gel on the surface of the tablet, impacting the rate and extent of drug release. Most inorganic salts decrease water solubility of organic solutes, changing the gel properties of hydrophilic polymers. In this study, the effect of inorganic salts on drug release from a tablet formulation containing an itraconazole (ITZ)-hydroxypropyl methyl cellulose (HPMC) extrudate was investigated. The cloud point of a 1% HPMC solution with and without inorganic salts (KCl, KH2PO4, KHCO3, and potassium iodate (KI)) was determined to classify the salts according to their salting-out or salting-in effect. A kosmotropic effect on HPMC was observed for KCl, KH2PO4, and KHCO3, whereas KI exhibited a chaotropic effect. To prove the effect of these salts on drug release, tablets containing 66% of ITZ-HPMC extrudate (20:80 w/w %), 4% croscarmellose sodium, 30% microcrystalline cellulose, and different types and amounts of KHCO3, KH2PO4, KCl, and KI were compressed (same solid fraction of 0.83-0.85). Tablets without salts showed a slow release and low peak concentrations during dissolution in simulated gastric fluids. By adding the kosmotropic salts to the tablets, the rate and extent of drug release were increased, whereas the chaotropic anion iodide had no effect. The effect was pronounced even with the addition of as little as 2% of inorganic salts and tended to increase with the increasing amount of salt in the formulation. Tablets without salt stored under either dry or humid conditions exhibited a large difference in dissolution profiles, whereas little variation was observed for tablets with kosmotropic salts. In conclusion, the effect of inorganic salts was mechanistically clarified on ASD containing commonly used HPMC. This approach can be beneficial to successfully develop robust formulations containing ASD.

The generation of drug supersaturation close to the absorptive site is an important mechanism of how several formulation technologies enhance oral absorption and bioavailability. Lipid-based formulations belong to the supersaturating drug delivery systems although this is not the only mechanism of how drug absorption is promoted in vivo. Different methods to determine drug supersaturation and precipitation from lipid-based formulations are described in the literature. Experimental in vitro setups vary according to their complexity and proximity to the in vivo conditions and, therefore, some tests are used for early formulation screening, while others better qualify for a later stage of development. The present commentary discusses this rapidly evolving field of in vitro testing with a special focus on the advancements in analytical techniques and new approaches of mechanistic modeling. The importance of considering a drug absorption sink is particularly emphasized. This commentary should help formulators in the pharmaceutical industry as well as in academia to make informed decisions on how to conduct in vitro tests for lipid-based delivery systems and to decide on the implications of experimental results.

Paediatric pharmaceutics has become an important topic, but currently, there is an incomplete knowledge of paediatric gastrointestinal physiology and adequate biopharmaceutical tools still have to be developed. The present study aimed to increase the understanding of oral drug absorption in paediatric populations by using physiologically based pharmacokinetic (PBPK) modelling and in vitro dissolution testing. The oral absorption of two model compounds, sotalol and paracetamol, was studied by collection of reported pharmacokinetic profiles from adult and paediatric subjects. A PBPK model based on input parameters collected from the literature was first developed and validated in adults before being extrapolated to paediatric age groups. The accuracy of the model simulations was assessed by comparison to the observed pharmacokinetic profiles, and in the case of discrepancy, further investigations were made via parameter sensitivity analysis and in vitro dissolution testing. The PBPK models accurately predicted sotalol and paracetamol exposure in adult populations. An accurate simulation was also obtained after model extrapolation to children older than 2 years of age. However, the simulation in infants and newborns resulted in a discrepancy, which was further analysed. Dissolution testing suggested no significant difference in the drug release rate between paediatric and adult age groups. In contrast, mean gastric emptying time seemed to be underestimated in infants and newborns, and optimisation of this input parameter improved the prediction of the model. Considering age-specific differences in gastrointestinal tract physiology should improve prediction of drug absorption in paediatric patients.

The establishment of an in vitro–in vivo correlation (IVIVC) is considered the gold standard to establish in vivo relevance of a dissolution method and to utilize dissolution data in the context of regulatory bioequivalence questions, including the development of dissolution specifications. However, several recent publications, including industry surveys and reviews from regulatory agencies, have indicated a low success rate for IVIVCs, especially for immediate-release formulations. In recent years, the use of physiologically based pharmacokinetics (PBPK) and absorption modeling, as a tool to facilitate formulation development, has been attracting increased attention. This manuscript provides an industry perspective on the current challenges with establishing IVIVCs and the potential PBPK and absorption modeling offer to increase their impact. Case studies across both immediate-release and extended-release formulations from five pharmaceutical companies are utilized to demonstrate how physiologically based IVIVC (PB-IVIVC) may facilitate drug product understanding and to inform bioequivalence assessment and clinically relevant specifications. Finally, PB-IVIVC best practices and a strategy for model development and application are proposed.

Hot-melt extrusion is an option to fabricate amorphous solid dispersions and to enhance oral bioavailability of poorly soluble compounds. The selection of suitable polymer carriers and processing aids determines the dissolution, homogeneity and stability performance of this solid dosage form. A miniaturized extrusion device (MinEx) was developed and Hypromellose acetate succinate type L (HPMCAS-L) based extrudates containing the model drugs neurokinin-1 (NK1) and cholesterylester transfer protein (CETP) were manufactured, plasticizers were added and their impact on dissolution and solid-state properties were assessed. Similar mixtures were manufactured with a lab-scale extruder, for face to face comparison. The properties of MinEx extrudates widely translated to those manufactured with a lab-scale extruder. Plasticizers, Polyethyleneglycol 4000 (PEG4000) and Poloxamer 188, were homogenously distributed but decreased the storage stability of the extrudates. Stearic acid was found condensed in ultrathin nanoplatelets which did not impact the storage stability of the system. Depending on their distribution and physicochemical properties, plasticizers can modulate storage stability and dissolution performance of extrudates. MinEx is a valuable prototyping-screening method and enables rational selection of plasticizers in a time and material sparing manner. In eight out of eight cases the properties of the extrudates translated to products manufactured in lab-scale extrusion trials.