August 17, 2022
To support our extensive contract research portfolio in transporter services and to be able to offer a full in vitro DDI study package, we have created a dedicated metabolism team to develop and execute these new in-house assays. A brand-new metabolism lab was built and equipped over the past year to meet all technical requirements and ensure capacity for this additional work. Prior to the official service announcement in June, we have already performed a number of these studies for select clients to their full satisfaction. In fact, our in vitro CYP450 inhibition data has already supported a drug approval in 2021! With this new launch, we are glad to become your trusted partner not only for transporter studies, but for metabolism studies as well. Currently in our portfolio, CYP450 inhibition and induction is available, both of which can be done for regulatory compliance and in tailored setups as well.
For discovery phase clients we also offer metabolic stability assays, available in commonly studied species, using various models including microsomes and hepatocytes – where, for low-turnover compounds, we can provide a follow-up step of assessing metabolic stability in micropatterned co-cultured hepatocytes (HepatoPac). Additional metabolism services are also in development, keep an eye on our newsletter to stay up to date with our offers!
SOLVO’s screening laboratory has increased its capacity for transporter assay automation over the past year. We have expanded the dedicated laboratory space and hired additional automation and transporter scientists to develop and deliver and array of high throughput, large scale, early phase screening services. Set up as standardized workflows, our automated setups provide outstanding consistency and reliability with fast turnaround times. We have also invested in additional liquid handlers and dispenser robots as well as software solutions to increase the capacity and throughput of our Automated Screening laboratory.
Earlier this year, we launched the DILIScreen service package, the first in line of our new service portfolio of more early-phase discovery type assays. This package includes key transporters involved in drug-induced liver injury (DILI): BSEP, MRP2, MRP3 and MRP4 efflux pumps and the NTCP uptake carrier to investigate potential transporter-mediated hepatotoxic properties at an early stage of drug discovery. Since the launch of the screening package several clients were provided with high-quality data in very short turnaround-times.
Current developments are focusing on the generation of additional screening packages utilizing our portfolio of stable cell lines expressing selected non-regulatory uptake transporters as well as our transporter transfected monolayer cells lines to support early phase drug development.
For our RnD team, ‘new normal’ at SOLVO looks very much like the old, with the development of multiple cell lines and assays approaching or reaching the launch phase. Among them are preclinical-species MDR1 monolayer assays built upon the Abcb1-knockout MDCKII cell line, devoid of endogenous canine MDR1 activity. Mouse and rat Mdr1a as well as cynomolgus MDR1, all expressed in the Abcb1KO-MDCKII background, have been validated with digoxin as the probe substrate and valspodar as well as verapamil as reference inhibitors. Similar to the human MDR1 assay developed using this Abcb1KO background, now routinely used in our regulatory assay packages as well, performance of the preclinical species assays has also significantly improved. Comparison of efflux activity between the Abcb1KO cell line and wild type MDCKII also allows addressing interactions with canine MDR1.
Still focusing on the same preclinical species, uptake assays with mouse, rat, dog and cynomolgus hepatocytes have been developed and systematically compared with the human assay. Similar to the human, animal hepatocyte uptake assays utilize an inhibitor cocktail or 4°C incubation as passive control condition and are available both in plated (preferred) and suspension format. Hepatocyte uptake assays are routinely used to address potential liver accumulation and related toxicity for new compounds. Hepatocyte uptake assays will be officially launched in Q3 2022.
In 2022, 4 webinars have already been hosted as part of SOLVO’s ongoing webinar series focusing on topics related to in vitro ADME-T assessment for any stage of drug development. In addition to our in-house presenters, we had the pleasure again to welcome two invited speakers, both renowned experts in the field whom we thank again for sharing their latest results and insight with our audience!
The year was kicked off by a presentation by Zsuzsanna Gáborik, PhD, our head of RnD who shared some of our experience with setting up and calibrating efflux transporter assays, including some “behind the scenes” trick, challenges and success stories.
David Rodrigues, PhD, fAAPS of Pfizer followed with an overview of potential biomarkers to be used for assessing interaction with solute carriers (SLCs) and shared some notes as well on the efforts that go into identifying and validating potentially useful biomarkers.
Endogenous markers were also highlighted in the presentation given by Pieter Annaert, PhD, representing KU Leuven, who gave an overview on the most recent advances in in vitro modeling of drug-induced cholestatic liver injury, with a focus on bile acid profiling as a useful and specific marker.
The first half of the year was rounded up by an overview of the freshly released ICH M12 Draft Guidelines on drug interaction studies, focusing on the in vitro study elements. Differences to the guidelines currently in force, such as the FDA, EMA and PMDA DDI guidance documents have been highlighted. The presentation, given by Noémi Szili, PhD from our team, was followed by a panel discussion with SOLVO experts.
The webinar series will continue this fall with new speakers soon to be announced!
Next entry: Meet the SOLVO team at ISSX/MDO Meeting!