https://orcid.org/0000-0002-7708-7699
Abstract
Challenges within peptide and oligonucleotide ADME (absorption, distribution, metabolism and elimination) and scientific ideas on how to solve them were presented and discussed at the DMDG (Drug Metabolism and Discussion Group) Peptide and Oligonucleotide ADME Workshop 2022 (2nd and 3rd of October 2022). This meeting report summarises the presentations and discussions from this workshop.
The following topics were covered:
Overview of the drug modality landscape
Metabolism & modelling
Analytical challenges
Drug-drug interactions reports from industry working groups
Regulatory interactions
Introduction
The aim of the Peptide and Oligonucleotide ADME (absorption, distribution, metabolism and elimination) workshop is to bring scientists together to discuss and exchange ideas and experience of peptide and oligonucleotide ADME related challenges as the current regulatory landscape for the development of peptides and oligonucleotide drugs may lead companies to perform a variety of small molecule-focussed ADME studies in support of Investigational New Drug (IND) filing packages. It was discussed whether the current activities are suitable for these modalities, or should science-driven decisions on development of such molecules be implemented more in the pharmaceutical industry and how to approach regulatory authorities with these modalities.
This meeting report covers the topics of the DMDG (Drug Metabolism and Discussion Group) Peptide and Oligonucleotide ADME Workshop 2022, which was held at the Park Plaza Victoria Hotel, Amsterdam the 2nd and 3rd October 2022 (two ½ days), before the start of the 2022 Joint Meeting between the European DMDG, the French GMP (Groupe de Métabolisme et Pharmacocinétique) & the Swedish SPS (Swedish Pharmaceutical Society) scientific societies. There was great interest in the workshop which was fully booked with 60 participants who with huge enthusiasm enjoyed their first face-to-face meeting after two years of on-line meetings due to the Covid-19 pandemic. The delegates represented both pharma and contract research organisation (CRO) representatives assuring good input from both worlds.
The workshop started with two talks providing an overview of the modality landscapes. Vera D’Aloisio (AmbioPharm, US) shared a talk on the database PepTherDia and Jesper K Christensen (Novo Nordisk, Denmark) presented an overview of oligonucleotide drug development and Novo Nordisk’s ADME strategy for N-acetyl-galactosamine (GalNAc) conjugated small interfering RNAs (siRNAs) (also known as GalNAc-siRNAs). Two talks addressed metabolism & modelling for peptide and oligonucleotide drugs. Ari Tolonen (Admescope, Finland) shared a talk on different in vitro metabolism models for peptides. This was followed by a talk by Farzaneh Salem (GSK, UK) on physiologically based pharmacokinetic (PBPK) modelling of an oligonucleotide drug for hepatitis B patients.
The final two talks of the first day addressed the analytical challenges with these two modalities, Michael Blackburn (Quotient Sciences, UK) gave a talk on strategies for using liquid chromatography and mass spectrometry (LC-MS) for the bioanalysis of peptides and proteins in biofluids with a reference to insulins and Alex Bushby (Labcorp, UK) presented a talk on the challenges and strategies for the development of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for a GalNAc conjugated oligonucleotide to be used in pre-clinical and clinical studies. Topics and ideas, touched and raised upon after the presentations, were further discussed before leaving the meeting venue for the day and the discussions continuing in the following bar session.
The second half-day started with two talks on drug-drug interactions (DDI), which is a hot topic, to debate whether it is sensible to perform such studies for peptide and oligonucleotide drugs. Constanze Hilgendorf (AstraZeneca, Sweden) shared an update from the EFPIA (European Federation of Pharmaceutical Industries and Associations) Cross-industry peptide DDI working group on the outcome of an industry survey of DDI studies performed for peptide modalities and a review of submission packages of peptide drugs from the last decade on which studies had been performed. Jan Snoeys (Janssen, Belgium) shared considerations and recommendations for oligonucleotide plasma protein binding evaluation and DDI risk assessment from an IQ consortium (International Consortium for Innovation and Quality in Pharmaceutical Development) working group. The final presentation was given by Michelle McDonald-Alexis (Parexel, UK) who gave a talk on the regulatory aspects of peptides and oligonucleotides. The workshop was closed after concluding discussions on the topics covered by the presenters. Abstracts of the presentations by the authors follows below.
‘PepTherDia’: Overview of the landscape of marketed Peptides – Vera d’Aloisio (AmbioPharm, US)
Since the approval of the first peptide therapeutic agent, insulin, in 1923, drug discovery has progressively expanded into the chemical space between small molecules and large biologics, with a significant number of peptides being approved in the last 100 years. As of 2022, there are over 110 peptide therapeutics and diagnostics approved in the main pharmaceutical market areas (i.e. EU, US, Japan).
The database PepTherDia (http://peptherdia.herokuapp.com/) was created to address the unmet necessity of a database gathering information on approved peptides. In addition to this, a detailed structural analysis was performed to understand the key compositional trends of these compounds and guide future peptide design (D’Aloisio et al. Citation2021).
To create a database, a clear definition of peptide was given: a peptide is a ‘chemical entity comprising at least two amino acids, linked together by an amide bond, with a maximum of 50 amino acids and molar mass lower than 5000 g/mol’. This definition, together with some additional criteria of inclusion (e.g. only peptides for human use, approved in the main pharmaceutical market areas), drove the creation of the database.
The distribution of peptides by number of constitutional members and molar mass, shows a clear bimodal distribution (a bigger cluster of small-size peptides and a smaller cluster of big-size peptides, with a clear lack of mid-size peptides). Moreover, there is almost a 50–50 distribution between linear and cyclic peptides, with large majority of these macrocycles comprising 5–7 members. Finally, majority of marketed peptides contains 35–75% of polar amino acids, necessary for acceptable pharmacokinetic (PK) profile. The investigation of the origin of the approved peptides, showed that majority (∼84%) are either natural or naturally derived, confirming the influence of nature on their structure.
Overview of the oligonucleotide landscape & ADME strategy for GalNAc-siRNAs – Jesper Kammersgaard Christensen (Novo Nordisk, Denmark)
An overview of the oligonucleotide landscape was provided, by touching upon the historic landmarks of gene silencing, which to date has resulted in 18 approved oligonucleotide drugs (ten antisense oligonucleotides (ASOs), five siRNAs, two messenger RNAs (mRNAs), and one aptamer (single stranded oligonucleotides that are capable of binding to target proteins with high affinity and specificity)). Furthermore, the talk also provided an update on the regulatory landscape and the current industry position of oligonucleotide ADME.
Hereafter, the talk focussed on ADME perspectives of siRNAs delivered to the liver via GalNAc conjugation (GalNAc-siRNA). The ADME packages of the four approved GalNAc-siRNAs was presented and Novo Nordisk’s thoughts on ADME strategy for GalNAc-siRNAs and regulatory feedback was shared. Briefly, Novo Nordisk considers there is a low need for generating metabolism data at an early stage in development, and hence postpone this activity to prior to phase 2, leaving only the in vitro plasma protein binding study to be conducted prior to phase 1.
This represents our current thinking for the GalNAc-siRNA platform (meaning strategies for extrahepatic delivered siRNAs will likely differ). The strategy is based on a balance between scientific rationale and expected regulatory requirements. Keeping in mind that this is a rapidly evolving field, and the strategy will be adapted along the way.
Finally, the necessity for radiolabelled tissue distribution and mass balance studies, are still being considered, due to uncertainty about the regulatory requirements. However, from a scientific perspective limited new ADME information from radiolabelled studies is expected for GalNAc-siRNAs as ADME properties of different compounds within the same platform with similar chemistry appear to have similar ADME properties.
Hepatic and extrahepatic in vitro systems to investigate peptide metabolism – Ari Tolonen (Admescope Ltd, Finland)
The number of peptide-like compounds in drug discovery and developmental programs has been strongly increasing over the years, and even though companies have their preferred methods for investigating peptide metabolism, limited experimental results comparing the performance, and in vivo predictability, of in vitro assays have been published. To evaluate in vitro assay differences in metabolite profile, human liver, kidney and intestinal S9 fraction (± reduced nicotinamide adenine dinucleotide phosphate (NADPH)), suspended human hepatocytes, plated human proximal tubule cells and fresh human plasma for studies with cyclosporin, cetrorelix and leuprorelin (also known as leuprolide) as model substrates were employed. As expected, the cyclosporin metabolism proceeded solely through established cytochrome P450 (CYP)-mediated oxidative reactions, and metabolites were observed mainly with hepatocytes and NADPH-supplemented hepatic S9, although the main hepatic metabolite was also detected at low concentration in proximal tubules. Cetrorelix metabolism proceeded mainly via hydrolysis reactions, and the same most abundant metabolites were observed in all employed tissue models (but not in plasma, where the compound was stable), all models producing the two reported in vivo metabolites, although with some quantitative differences. Yet, two low abundance oxidative metabolites were detected in NADPH-supplemented hepatic S9. Metabolism of leuprorelin did proceed only via hydrolysis-based reactions, so that a large number of metabolites were observed in liver and kidney models, and a lower number in the intestinal and plasma models. The same most abundant metabolite was observed in hepatocytes and all S9 models in the absence of NADPH (but not in plasma, where the compound was stable), being however formed via a reaction that has not been reported from in vivo studies with human or animals. On the contrary, NADPH supplemented liver and kidney S9 fractions and proximal tubule cells did show different metabolites, the metabolite profiles highlighting better the in vivo metabolites reported in literature. The NADPH dependency of leuprorelin metabolism was further investigated with human kidney microsomes and cytosol, of which the experiments with cytosolic fraction, but not with microsomes, closely resembled the results with kidney S9, suggesting that NADPH-dependent hydrolysis reactions of peptides may occur in the cytosolic fraction. Altogether, this limited data set suggests that selection of the in vitro model and cofactors may highly impact the results from peptide metabolite profiling studies, depending on the chemical moieties present in the peptide, and that cell permeability/uptake is likely play a role in the results. Yet, more research on the mechanism of the observed results and in vivo predictability is needed to better understand the differences (Jyrkäs and Tolonen Citation2021; Jyrkäs et al. Citation2023).
Physiologically based pharmacokinetic modelling of oligonucleotide, Bepirovirsen – Farzaneh Salem (GSK, UK)
A physiologically based pharmacokinetic (PBPK) model for bepirovirsen, a 20-mer antisense oligonucleotide, was developed and verified. Single and multiple dose subcutaneous (SC) data from preclinical species and human healthy volunteers were used to develop and verify the PBPK model using large molecule module in Simcyp v21.0. For subcutaneous absorption a first order model was used. Complete absorption (fa = 1) and estimated ka to capture the 75 mg dose in healthy volunteers was used. A full PBPK model was applied to account for partitioning into tissues including liver and kidney. To estimate volume of distribution at steady state (Vss) all the tissues were considered perfusion limited. A minimum in vivo reported clearance value 2.13 L/h from the low dose study of 75 mg in human was used. Renal clearance is not measured in healthy volunteers, and the model predicted renal clearance from physicochemical parameters. Ten trials were simulated using a trial design matched as closely as possible to the clinical study for age, number of individuals, sex, dose, dosing intervals and duration of study.
The model predicted plasma concentration-time profile and PK in monkey and human. Dose normalised comparison of plasma concentration-time profile showed a linear PK but absorption and distribution phases are different between human and monkey leading to higher Cmax and Tmax values in monkey. Therefore, the monkey PBPK model is not directly applicable to humans. Observed plasma profile and PK parameters are within 5th and 95th centile and two-folds of predictions, respectively. Renal excretion is predicted to be a minor pathway of elimination.
Perspectives on the past and future of peptides bioanalysis: with reference to Insulins – Michael Blackburn (Quotient Sciences, UK)
Mass spectrometry has become an important tool for the bioanalysis of peptides and small proteins (up to around 10 kDa) in biofluid samples derived from all stages of drug development. A case study was presented of a LC-MS suite of assays for insulins, initially developed using a ‘hybrid’ (that is combined immuno-affinity with MS) top-down approach, and then switched to a physicochemical technique (solid phase extraction) due to the loss of antibody supply. Assay performance was similar, in-house data suggesting the physicochemical assay may be more precise, but sensitivity was not quite as good, as the background noise could be higher.
LC-MS data usually correlated well with immunoassay data, but scientists should expect some variation as the different assay modes are orthogonal, one measuring a concentration, the other essentially an interaction. Development scientists should consider which type of interaction they require, in addition to considerations around the free and total peptide. Anti-drug antibody effects can affect LC-MS assays, as for ligand binding assays (LBAs), usually identified by a reduction in internal standard response. These can be minimised by diluting the subject plasma with a control matrix, or acidification, but such data should be treated with caution and may be atypical.
The advantages of MS are enhanced specificity and ease of multiplexing. In the case of physicochemical assays, there is no need for an antibody, which means development can be rapid, and there is now a basic toolkit of solid phase extraction methods, using both ion exchange and reverse phase interactions, which can be effective for most types of peptides. However, ligand binding approaches may be preferred if antibodies or specific kits are readily available or very low detection levels are required.
High resolution MS (HRMS) or ion mobility MS can help with difficult to fragment peptides and it is anticipated that more examples of these assays will be encountered in the future.
Development of an LC-MS/MS method for GSK3389404, a GalNAc conjugated oligonucleotide and its non-conjugated metabolite in pre-clinical and clinical studies – challenges and strategies – Alex Bushby (Labcorp, UK)
Previous LabCorp LC-MS/MS experience for oligonucleotides used a phosphoric acid addition followed by solid phase extraction (SPE) to extract a DNA oligonucleotide (Hemsley et al. Citation2012) and phenol-chloroform liquid-liquid extraction (LLE) then SPE to extract a phosphorothioate oligonucleotide (Ewles et al. Citation2014); however neither method was validated. The Tandem labs method transfer for GSK3389404 and GSK3228836 (also known as bepirovirsen) was the first introduction of the use of a phenol-chloroform LLE followed by dichloromethane LLE to extract oligonucleotides. In our hands the LC-MS/MS methods for monkey, rat, rabbit, and mouse resulted in high carryover, due to instrumentation differences. This was addressed by utilising a second mobile phase B with higher acetonitrile percentage. Linearity and variability, especially at the lower end, were also an issue due to adsorption. This was overcome by the addition of human plasma after aliquoting the sample.
Fatty acid conjugated oligonucleotides do not extract well using the regular phenol-chloroform LLE. They exhibit poor recovery despite extensive method development. Instead, a denaturing solution, such as 8 M guanidine or urea, should be added to disrupt protein binding prior to extraction with reverse phase SPE. Optimisation between the denaturing agent and SPE pre-treatment is required to ensure optimal recovery. Deaminated metabolites of oligonucleotides cause a 1 Da mass shift which cannot be separated by reverse phase chromatography and cause an interfering peak in front of the peak of interest. This can be resolved by using high resolution mass spectrometry but as this metabolite is primarily seen in later time-points, it may be possible to calculate area under the curve by omitting later time-point data.
DDI Strategies for peptide therapeutics – update from the EFPIA peptide DDI working Group – Constanze Hilgendorf (Astra Zeneca, Sweden)
Starting from the DMDG-meeting 2020, experts from ten companies formed a cross-industry peptide DDI working group under the sponsorship of the EFPIA (European Federation of Pharmaceutical Industries and Associations), to summarise current practice and propose areas of harmonisation for the assessment of DDI risks during the development of peptide therapeutics (Säll et al. Citation2023). Strategies for DDI assessments are informed through the highly specified DDI-guidelines for small drug molecules, and the guidances for development of therapeutic proteins and biologicals, where only minimal DDI-assessment is required. Therapeutic peptides are a heterogeneous class of molecules, and general strict adherence to either guidance appears not to be meaningful. The working group presented results from their survey to understand the currently pursued DDI study types and strategies across industry, and analysis of the in vitro/clinical DDI data included in submission packages for recently approved peptide drugs. A large variation in timing of in vitro peptide DDI studies, from early phase to documentation during phase 3, or no in vitro studies unless requested by regulators may be rationalised as only few in vitro inhibition studies reported positive hits. However, lack of clinical follow-up studies questions the clinical relevance of these tests and findings. Similarly, available submission packages reveal DDI likelihood is low for therapeutic peptides >2 kDa, whilst for highly chemically modified smaller peptides in vitro substrate and inhibition assays can flag clinical interactions. This suggests that it may be reasonable to adopt a risk-based approach during drug development for larger peptides, and the benchmarking of peptide DDI activities across the industry should set the stage for future discussions with health authorities on harmonising peptide DDI approaches. We encourage the community to actively publish all DDI data (both positive and/or negative results) to add to the collective knowledge pool and better inform guidelines moving forward.
Considerations & recommendations for therapeutic siRNA plasma protein binding evaluation & drug-drug interaction risk assessment – Jan Snoeys (Janssen, Belgium) on behalf of the IQ siRNA PPB and DDI Working Group
From a thorough review of data publicly available in regulatory filing documents and literature, along with experience from industry representatives, recommendations and decision trees intended to guide industry on IND workflows were established and published in a position paper (Humphreys et al. Citation2022).
Plasma protein binding (PPB) evaluation is not advised when it does not aid in therapeutic index estimation, as in the case of GalNAc-siRNA. For other siRNA-containing therapeutic platforms including but not limited to, lipid nano particles (LNPs), peptide-siRNA conjugates, antibody-siRNA conjugates, lipid-siRNA conjugates, it is recommend generating PPB data to establish regulatory precedence for a given class.
DDI risk assessment is not advised for GalNAc-siRNA except when the target RNA transcript or the protein it encodes is known or anticipated to play a role in the regulation or expression of a drug metabolising enzyme, transporter, or siRNA-related protein. In addition, a risk assessment may be warranted when the disease state of the targeted patient population has an altered expression or activity profile of a drug metabolising enzyme, transporter, or siRNA-related protein, and treatment of the disease is anticipated to normalise or otherwise modulate these profiles.
It is cautiously recommend that, if in doubt, PPB evaluations and DDI risk assessments should be conducted for siRNA-containing novel ligands, linkers and/or formulation excipients. In the future, once data accumulates and these moieties are no longer considered novel, as in the case of GalNAc- siRNA today, and if the aggregate data indicate that PPB and DDI studies would not aid in therapeutic index estimation or uncover DDI liabilities, respectively, then it is similarly recommended that these studies are not be performed.
Development of peptides and oligonucleotides: a regulatory perspective – Michelle McDonald-Alexis (Parexel, UK)
The nonclinical development of peptides is covered by ICH S6(R1) (ICH 2011) and the timing of the studies to support the various stages of development is documented in ICH M3(R2) (ICH 2009). While the principles of ICH S6 may also be applied to ASOs, apart from the Committee for Medicinal Products for Human Use (CHMP) reflection paper on the assessment of genotoxic potential of oligonucleotides (CHMP 2005), or the recommendations made by the oligonucleotide safety working group (Berman et al. Citation2016), there was no single regulatory guideline (or publication) to advise on the precise nature of the nonclinical package required to initiate a clinical trial or marketing authorisation for ASOs.
However, in 2021, the US Food and Drug Administration (FDA) issued a draft guideline (FDA Citation2021) applicable to the non-clinical development of ASOs aimed to treat severely debilitating or life-threatening disease. Of note, is the encouragement to submit study plans in advance, to determine suitability and the suggestion that toxicology reports/studies may not need to be absolutely complete for indications where the disease progression is rapid. More recently, in the EU, a Concept Paper on the Establishment of a Guideline on the Development and Manufacture of Synthetic Oligonucleotides was published in September 2022 (EMA 2022). This is an exciting time for a group of molecules that are viewed as a hybrid between biotechnology products and small molecular products. At present, nonclinical development plans to support ASO products typically adopt principles from all aforementioned guidelines/publications and as a result can take on many different shapes and sizes. Consistency and a scientific rationale for studies to be performed is needed and thus, the long-awaited advances in the regulatory landscape for ASOs are welcomed.
Concluding remarks
The DMDG Peptide and Oligonucleotide ADME Workshop 2022, and previous workshops (Sonesson et al. Citation2021a, Citation2021b, Citation2021c; Hood et al. Citation2022) stands out from other fora by focussing on the discussion of peptide and/or oligonucleotide ADME-related topics in relation to drug development of these modalities. The feedback from the delegates attending this workshop was positive and the presentations stimulated fruitful discussions around the different ADME topics addressed.
Acknowledgements
The organisers thank all speakers for their contributions, and to all participants for fruitful discussions. The authors acknowledge also the DMDG organising and technical team, in particular Stuart Hex and Chris Barron (AssociAction Enterprises), for support with organizing the workshop.
Disclosure statement
No potential conflict of interest was reported by the author(s).
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References
- Berman CL, Barros SA, Galloway SM, Kasper P, Oleson FB, Catherine Priestley CC, Sweder KS, Schlosser MJ, Sobol Z. 2016. OSWG recommendations for genotoxicity testing of Novel oligonucleotide-based therapeutics. Nucleic Acid Ther. 26(2):73–85. doi: 10.1089/nat.2015.0534.
- [CHMP]. 2005. CHMP SWP reflection paper on the assessment of the genotoxic potential of antisense oligodeoxynucleotides; [accessed 2023 May 17]. https://www.ema.europa.eu/en/assessment-genotoxic-potential-antisense-oligodeoxynucleotides-scientific-guideline.
- D’Aloisio V, Dognini P, Hutcheon GA, Coxon CR. 2021. PepTherDia: database and structural composition analysis of approved peptide therapeutics and diagnostics. Drug Discov Today. 26(6):1409–1419. doi: 10.1016/j.drudis.2021.02.019.
- [EMA]. 2022. Concept paper on the establishment of a guideline on the development and manufacture of synthetic oligonucleotides; [accessed 2023 May 17]. https://www.ema.europa.eu/en/establishment-guideline-development-manufacture-synthetic-oligonucleotides-scientific-guideline.
- Ewles M, Goodwin L, Schneider A, Rothhammer-Hampl T. 2014. Quantification of oligonucleotides by LC-MS/MS: the challenges of quantifying a phosphorothioate oligonucleotide and multiple metabolites. Bioanalysis. 6(4):447–464. doi: 10.4155/bio.13.319.
- [FDA]. 2021. Guideline on nonclinical testing of individualized antisense oligonucleotide drug products for severely debilitating or life-threatening diseases; [accessed 2023 May 17]. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/nonclinical-testing-individualized-antisense-oligonucleotide-drug-products-severely-debilitating-or.
- Hemsley M, Ewles M, Goodwin L. 2012. Development of a bioanalytical method for quantification of a 15-mer oligonucleotide at sub-ng/ml concentrations using LC-MS/MS. Bioanalysis. 4(12):1457–1469. doi: 10.4155/bio.12.117.
- Hood S, Kenworthy D, Christensen JK. 2022. Meeting report: oligonucleotide ADME Workshop. Xenobiotica. 52(8):957–961. doi: 10.1080/00498254.2022.2115428.
- Humphreys S, Davis JA, Iqbal S, Kamel A, Kulmatycki K, Lao Y, Liu X, Rodgers J, Snoeys J, Vigil A, et al. 2022. Considerations and recommendations for assessment of plasma protein binding and drug-drug interactions for siRNA therapeutics. Nucleic Acids Res. 50(11):6020–6037. doi: 10.1093/nar/gkac456.
- [ICH]. 2009. Guideline on non-clinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals M3(R2); [accessed 2023 May 17]. https://www.ich.org/page/multidisciplinary-guidelines.
- [ICH]. 2011. Guideline on preclinical safety evaluation of biotechnology-derived pharmaceuticals S6(R1); [accessed 2023 May 17]. https://www.ich.org/page/safety-guidelines.
- Jyrkäs J, Tolonen A. 2021. Hepatic in vitro metabolism of peptides; Comparison of human liver S9, hepatocytes and Upcyte hepatocytes with cyclosporine A, leuprorelin, desmopressin and cetrorelix as model compounds. J Pharm Biomed Anal. 196:113921. doi: 10.1016/j.jpba.2021.113921.
- Jyrkäs J, Lassila T, Tolonen A. 2023. Extrahepatic in vitro metabolism of peptides; comparison of human kidney and intestinal S9 fraction, human plasma and proximal tubule cells, using cyclosporine A, leuprorelin, and cetrorelix as model compounds. J Pharm Biomed Anal. 225:115219. doi: 10.1016/j.jpba.2022.115219.
- Säll C, Argikar U, Fonseca K, Hilgendorf C, Lopes F, Riedel J, Schiller H, Sonesson A, Umehara K, Wang K. 2023. Industry perspective on therapeutic peptide drug–drug interaction assessments during drug development: a European Federation of pharmaceutical industries and associations White Paper. Clin Pharmacol Ther. 113(6):1199–1216. doi: 10.1002/cpt.2847.
- Sonesson A, Brady K, Bjørnsdottir I, Christensen JK. 2021a. Meeting report: 1st workshop of the peptide ADME discussion group. Xenobiotica. 51(1):122–125. doi: 10.1080/00498254.2020.1729447.
- Sonesson A, Bjørnsdottir I, Christensen JK. 2021b. Meeting report: 2nd workshop of the Peptide ADME discussion group. Xenobiotica. 51(1):1–4. doi: 10.1080/00498254.2020.1784496.
- Sonesson A, Bjørnsdottir I, Christensen JK. 2021c. Meeting report: 3rd Workshop of the Peptide ADME Discussion Group. Xenobiotica. 51(12):1470–1474. doi: 10.1080/00498254.2021.2020377.