Assessing Potential Drug–Drug Interactions Between Dabigatran Etexilate and a P‐Glycoprotein Inhibitor in Renal Impairment Populations Using Physiologically Based Pharmacokinetic Modeling

Plasma concentrations of dabigatran, an active principle of prodrug dabigatran etexilate (DABE), are increased by renal impairment (RI) or coadministration of a P‐glycoprotein inhibitor. Because the combined effects of drug–drug interactions and RI have not been evaluated by means of clinical studies, the decision of DABE dosing for RI patients receiving P‐glycoprotein inhibitors is empirical at its best. We conducted virtual drug–drug interactions studies between DABE and the P‐glycoprotein inhibitor verapamil in RI populations using physiologically based pharmacokinetic modeling. The developed physiologically based pharmacokinetic model for DABE and dabigatran was used to predict trough dabigatran concentrations in the presence and absence of verapamil in virtual RI populations. The population‐based physiologically based pharmacokinetic model provided the most appropriate dosing regimen of DABE for likely clinical scenarios, such as drug–drug interactions in this RI population based on available knowledge of the systems changes and in the absence of actual clinical studies

Refined in vitro Models for Prediction of Intestinal Drug Transport : Role of pH and Extracellular Additives in the Caco-2 Cell Model

Drug transport across the intestinal epithelium is roughly predicted from permeability values obtained from Caco-2 cell monolayers. This thesis examines the important role of pH and extracellular additives for increasing the reliability and predictivity of the in vitro screening system, Caco-2. It was shown that the passive transport of ionizable compounds may be biased by a false efflux or uptake component, when applying a physiological pH-gradient across the membrane. pH also affected the amount of compound available at the transporter-binding site. Therefore, pH dependence should be considered in studies of such compounds and of drug-drug interactions involving efflux transporters. It was also shown that proton-dependent apical uptake or basolateral efflux should be studied both with and without a pH gradient over the whole monolayers. The two extracellular additives, bovine serum albumin (BSA) and the solubilizing agent, Cremophor® EL, also influenced Caco-2 permeabilities. BSA applied to the receiver side increases, and to the donor side decreases drug permeation according to the drug’s protein binding capacity. Thus, the absorptive transport for both passive and active compounds is favoured, giving a physiologically sound improvement of the Caco-2 cell model. Inclusion of BSA increased both the predictivity and quality of permeability studies, particularly of highly lipophilic, BCS class II compounds. Passive and active transport processes could also be distinguished after accounting for unbound concentrations. The overall effect of Cremophor® EL on the permeability to a drug was compound-specific and probably dependent on micellar incorporation. Cremophor® EL can therefore not be recommended. Neither pH nor BSA affect the functionality of transporters such as P-glycoprotein. However, efflux ratios of ionizable or protein bound drugs are altered in the presence of a pH-gradient or BSA, indicating that an experimental system without protein or pH gradient can over- or underestimate active and passive efflux in drug transport

Comparison of Canine and Human Physiological Factors: Understanding Interspecies Differences that Impact Drug Pharmacokinetics

This review is a summary of factors affecting the drug pharmacokinetics (PK) of dogs versus humans. Identifying these interspecies differences can facilitate canine-human PK extrapolations while providing mechanistic insights into species-specific drug in vivo behavior. Such a cross-cutting perspective can be particularly useful when developing therapeutics targeting diseases shared between the two species such as cancer, diabetes, cognitive dysfunction, and inflammatory bowel disease. Furthermore, recognizing these differences also supports a reverse PK extrapolations from humans to dogs. To appreciate the canine-human differences that can affect drug absorption, distribution, metabolism, and elimination, this review provides a comparison of the physiology, drug transporter/enzyme location, abundance, activity, and specificity between dogs and humans. Supplemental material provides an in-depth discussion of certain topics, offering additional critical points to consider. Based upon an assessment of available state-of-the-art information, data gaps were identified. The hope is that this manuscript will encourage the research needed to support an understanding of similarities and differences in human versus canine drug PK.This article is published as Martinez, Marilyn N., Jonathan P. Mochel, Sibylle Neuhoff, and Devendra Pade. "Comparison of Canine and Human Physiological Factors: Understanding Interspecies Differences that Impact Drug Pharmacokinetics." The AAPS Journal 23 (2021): 59. DOI: 10.1208/s12248-021-00590-0.</p

PBPK Model of Morphine Incorporating Developmental Changes in Hepatic OCT1 and UGT2B7 Proteins to Explain the Variability in Clearances in Neonates and Small Infants

Morphine has large pharmacokinetic variability, which is further complicated by developmental changes in neonates and small infants. The impacts of organic cation transporter 1 (OCT1) genotype and changes in blood‐flow on morphine clearance (CL) were previously demonstrated in children, whereas changes in UDP‐glucuronosyltransferase 2B7 (UGT2B7) activity showed a small effect. This study, targeting neonates and small infants, was designed to assess the influence of developmental changes in OCT1 and UGT2B7 protein expression and modified blood‐flow on morphine CL using physiologically based pharmacokinetic (PBPK) modeling. The implementation of these three age‐dependent factors into the pediatric system platform resulted in reasonable prediction for an age‐dependent increase in morphine CL in these populations. Sensitivity of morphine CL to changes in cardiac output increased with age up to 3 years, whereas sensitivity to changes in UGT2B7 activity decreased. This study suggests that morphine exhibits age‐dependent extraction, likely due to the developmental increase in OCT1 and UGT2B7 protein expression/activity and hepatic blood‐flow

Affordability: a step forward: establishing principles for rent setting

Affinity Sutton is a national Housing Association and as a business for social purpose it wants to ensure that Affordable Rents are set in a way that is genuinely affordable to low income households whilst continuing to build new and maintain existing homes. This research was set up to consider what the principles of setting a rent policy should be and what their new Affordable Rent policy might look like. The lessons learned here and the principles of rent setting identified will be equally relevant to other developing Housing Associations although not all will be able to maintain development capacity at the same time as reducing rents to affordable levels. We know that affordability is complex – it depends on incomes, rents, household composition, geography and benefits – as well as on how we define it. As Figure 1 shows, housing affordability has worsened for renters since we last looked at it in 2011 and more working households are dependent on housing benefits to pay their housing costs. Rents have risen faster than incomes so the affordability of any given proportion of market rent has fallen; but Affordable Rents set as a proportion of these higher market rents also raise more revenue. For Housing Associations there is a tension between putting resources towards housebuilding and holding down rents, as shown in Figure 2. The challenge of this trade off will need to be addressed by different organisations in the context of their charitable mission, vision and values