Towards human ex vivo organ perfusion models to elucidate drug pharmacokinetics in health and disease

Abstract

To predict the absorption, distribution, metabolism and excretion (ADME) profile of candidate drugs a variety of preclinical models can be applied. The ADME and toxicological behavior of newly developed drugs are often investigated prior to assessment in humans, which is associated with long time-lines and high costs. Therefore, good predictions of ADME profiles earlier in the drug development process are very valuable. Good prediction of intestinal absorption and renal and biliary excretion remain especially difficult, as there is an interplay of active transport and metabolism involved. To study these processes, including enterohepatic circulation, ex vivo tissue models are highly relevant and can be regarded as the bridge between in vitro and in vivo models. In this review the current in vitro, in vivo and in more detail ex vivo models for studying pharmacokinetics in health and disease are discussed. Additionally, we propose novel models, i.e., perfused whole-organs, which we envision will generate valuable pharmacokinetic information in the future due to improved translation to the in vivo situation. These machine-perfused organ models will be particularly interesting in combination with biomarkers for assessing the functionality of transporter and CYP450 proteins.     

Recombinant Immunomodulating Lentogenic or Mesogenic Oncolytic Newcastle Disease Virus for Treatment of Pancreatic Adenocarcinoma

Oncolytic Newcastle disease virus (NDV) might be a promising new therapeutic agent for the treatment of pancreatic cancer. We evaluated recombinant NDVs (rNDVs) expressing interferon (rNDV-hIFNβ-F₀) or an IFN antagonistic protein (rNDV-NS1-F₀), as well as rNDV with increased virulence (rNDV-F_3aa) for oncolytic efficacy in human pancreatic adenocarcinoma cells. Expression of additional proteins did not hamper virus replication or cytotoxic effects on itself. However, expression of interferon, but not NS1, resulted in loss of multicycle replication. Conversely, increasing the virulence (rNDV-F_3aa) resulted in enhanced replication of the virus. Type I interferon was produced in high amounts by all tumor cells inoculated with rNDV-hIFNβ-F₀, while inoculation with rNDV-NS1-F₀ resulted in a complete block of interferon production in most cells. Inoculation of human pancreatic adenocarcinoma cells with rNDV-F_3aa caused markedly more cytotoxicity compared to rNDV-F₀, while inoculation with rNDV-hIFNβ-F₀ and rNDV-NS1-F₀ induced cytotoxic effects comparable to those induced by the parental rNDV-F₀. Evaluation in vivo using mice bearing subcutaneous pancreatic cancer xenografts revealed that only intratumoral injection with rNDV-F_3aa resulted in regression of tumors. We conclude that although lentogenic rNDVs harboring proteins that modulate the type I interferon pathway proteins do have an oncolytic effect, a more virulent mesogenic rNDV might be needed to improve oncolytic efficacy.     

Effects of Pulmonary Rehabilitation Including Inspiratory Muscle Training in Patients with Chronic Obstructive Pulmonary Disease after Stratification by the Degree of Static Hyperinflation

Background

Inspiratory muscle training (IMT) improves inspiratory muscle strength, exercise capacity and health status in patients with chronic obstructive pulmonary disease (COPD). However, there is no additional effect on top of comprehensive pulmonary rehabilitation (PR). It is unclear whether patients with different baseline degrees of static hyperinflation respond differentially to IMT as part of a PR program. Therefore, the aim was to study the effects of IMT as an add-on on PR after stratification for baseline degrees of static hyperinflation.

Methods

In this single center retrospective study data were extracted between June 2013 and October 2020 of COPD patients who participated in a comprehensive PR program including IMT. IMT was performed twice daily, one session consisted of 3 series of 10 breaths and training intensity was set initially at a load of approximately 50% of patients’ maximal static inspiratory mouth pressure (MIP). The primary outcome measure was MIP. Secondary outcomes were the distance achieved on the 6-min walk test (6MWD), endurance cycling exercise capacity at 75% of the peak work rate (CWRT) and disease-specific health status using the COPD assessment test.

Results

754 patients with COPD were screened for eligibility and 328 were excluded because of repeated PR programs, missing data or baseline residual volume (RV)?>?350%. In total, 426 COPD patients were categorized into RV categories 50–130% (n?=?84), 131–165% (n?=?86), 166–197% (n?=?86), 198–234% (n?=?85) and 235–349% (n?=?85). In the whole sample, MIP, endurance exercise capacity and health status improved significantly. The change in 6MWD was higher in the lowest baseline degree of static hyperinflation [+?39 (9–92) m] compared with the baseline highest degree of static hyperinflation [+?11 (??18–54) m] (p?<?0.05).

Conclusions

IMT as part of a PR program in patients with COPD with different baseline degrees improved MIP irrespective of the degree of static lung hyperinflation. Improvement in functional exercise capacity was significantly higher in the group with the lowest degree of static hyperinflation compared with the patients with the highest degree of static hyperinflation.

     

Inhibition of bone resorption in culture by (+)-catechin

A pretreatment with (+)-catechin renders embryonic mouse calvaria in culture resistant to the action of bone resorbing agents, either parathyroid hormone (PTH), prostaglandin E2 or retinoic acid, and inhibits in a parallel way the enhanced excretion of N-acetyl-beta-glucosaminidase, a reference lysosomal enzyme, induced by these agents; it has, however, no effect on the small spontaneous leakage of lactate dehydrogenase from the explants. Moreover, the resorption induced in calvaria by a pretreatment with PTH or retinoic acid is inhibited by a further culture with catechin. This inhibition of bone resorption is discussed in relation with the collagen-stabilizing properties of (+)-catechin.     

Plasma concentrations of epidural bupivacaine in mother and newborn: 0.125% versus 0.375%

Central venous plasma concentrations of bupivacaine were determined in two groups of 15 parturients each who were given epidural analgesia for labor and vaginal delivery. One group received 10 ml of 0.125% bupivacaine plus epinephrine 1:800,000, the other group received 7 ml of 0.375% bupivacaine plus epinephrine 1:800,000. Plasma concentrations of bupivacaine in the umbilical venous (UV) and the umbilical arterial (UA) blood of their babies were also determined. The mean UA, UV, and maternal central venous (MV) plasma concentrations of bupivacaine differed significantly between the two groups: in patients given 0.375% bupivacaine UA values were 63% higher (P less than 0.01), UV values were 57% higher (P less than 0.01), and the MV values were 34% higher (P less than 0.05) than in patients given 0.125% bupivacaine. The measured plasma concentrations speak in favor of the less concentrated solution of bupivacaine in epidural analgesia for obstetrics. Seven milliliters of bupivacaine 0.375% is suitable for epidural analgesia in obstetrics but a low concentration-low dose technique, using 10 ml of bupivacaine 0.125% plus epinephrine 1:800,000 is safer. It provides good analgesia with minimal or no motor block and is associated with low maternal and neonatal plasma concentrations of bupivacaine, well below toxic levels and, to our knowledge, lower than in any other study.