Delineating the Role of Various Factors in Renal Disposition of Digoxin through Application of Physiologically Based Kidney Model to Renal Impairment Populations

Development of sub-models of organs within physiologically-based pharmacokinetic (PBPK) principles and beyond simple perfusion limitations may be challenging because of underdeveloped in vitro-in vivo extrapolation approaches or lack of suitable clinical data for model refinement. However, the advantage of such models in predicting clinical observations in divergent patient groups is now commonly acknowledged. Mechanistic understanding of altered renal secretion in renal impairment is one area that may benefit from such models, despite knowledge gaps in renal pathophysiology (Rowland Yeo et al., 2011; Sayama et al., 2014). In the current study a PBPK kidney model was developed for digoxin, accounting for the roles of organic anion transporting peptide 4C1 (OATP4C1) and P-glycoprotein (P-gp) in its tubular secretion, with the aim to investigate the impact of age and renal impairment (moderate to severe) on renal drug disposition. Initial PBPK simulations based on changes in glomerular filtration rate (GFR) underestimated the observed reduction in digoxin renal excretion clearance (CLR) in subjects with moderately impaired renal function relative to healthy. Reduction in either proximal tubule cell number or the OATP4C1 abundance in the mechanistic kidney model successfully predicted 59% decrease in digoxin CLR, in particular when these changes were proportional to reduction in GFR. In contrast, predicted proximal tubule concentration of digoxin was only sensitive to changes in the transporter expression/ million proximal tubule cells. Based on the mechanistic modelling, reduced proximal tubule cellularity and OATP4C1 abundance, and inhibition of OATP4C1-mediated transport, are proposed as possible causes of reduced digoxin renal secretion in renally impaired patients

Toward systems-informed models for biologics disposition: covariates of the abundance of the neonatal Fc Receptor (FcRn) in human tissues and implications for pharmacokinetic modelling

Biologics are a fast-growing therapeutic class, with intertwined pharmacokinetics and pharmacodynamics, affected by the abundance and function of the FcRn receptor. While many investigators assume adequacy of classical models, such as allometry, for pharmacokinetic characterization of biologics, advocates of physiologically-based pharmacokinetics (PBPK) propose consideration of known systems parameters that affect the fate of biologics to enable a priori predictions, which go beyond allometry. The aim of this study was to deploy a systems-informed modelling approach to predict the disposition of Fc-containing biologics. We used global proteomics to quantify the FcRn receptor [p51 and β2-microglobulin (B2M) subunits] in 167 samples of human tissue (liver, intestine, kidney and skin) and assessed covariates of its expression. FcRn p51 subunit was highest in liver relative to other tissues, and B2M was 1–2 orders of magnitude more abundant than FcRn p51 across all sets. There were no sex-related differences, while higher expression was confirmed in neonate liver compared with adult liver. Trends of expression in liver and kidney indicated a moderate effect of body mass index, which should be confirmed in a larger sample size. Expression of FcRn p51 subunit was approximately 2-fold lower in histologically normal liver tissue adjacent to cancer compared with healthy liver. FcRn mRNA in plasma-derived exosomes correlated moderately with protein abundance in matching liver tissue, opening the possibility of use as a potential clinical tool. Predicted effects of trends in FcRn abundance in healthy and disease (cancer and psoriasis) populations using trastuzumab and efalizumab PBPK models were in line with clinical observations, and global sensitivity analysis revealed endogenous IgG plasma concentration and tissue FcRn abundance as key systems parameters influencing exposure to Fc-conjugated biologics

LEARN: A multi-centre, cross-sectional evaluation of Urology teaching in UK medical schools

OBJECTIVE: To evaluate the status of UK undergraduate urology teaching against the British Association of Urological Surgeons (BAUS) Undergraduate Syllabus for Urology. Secondary objectives included evaluating the type and quantity of teaching provided, the reported performance rate of General Medical Council (GMC)-mandated urological procedures, and the proportion of undergraduates considering urology as a career. MATERIALS AND METHODS: LEARN was a national multicentre cross-sectional study. Year 2 to Year 5 medical students and FY1 doctors were invited to complete a survey between 3rd October and 20th December 2020, retrospectively assessing the urology teaching received to date. Results are reported according to the Checklist for Reporting Results of Internet E-Surveys (CHERRIES). RESULTS: 7,063/8,346 (84.6%) responses from all 39 UK medical schools were included; 1,127/7,063 (16.0%) were from Foundation Year (FY) 1 doctors, who reported that the most frequently taught topics in undergraduate training were on urinary tract infection (96.5%), acute kidney injury (95.9%) and haematuria (94.4%). The most infrequently taught topics were male urinary incontinence (59.4%), male infertility (52.4%) and erectile dysfunction (43.8%). Male and female catheterisation on patients as undergraduates was performed by 92.1% and 73.0% of FY1 doctors respectively, and 16.9% had considered a career in urology. Theory based teaching was mainly prevalent in the early years of medical school, with clinical skills teaching, and clinical placements in the later years of medical school. 20.1% of FY1 doctors reported no undergraduate clinical attachment in urology. CONCLUSION: LEARN is the largest ever evaluation of undergraduate urology teaching. In the UK, teaching seemed satisfactory as evaluated by the BAUS undergraduate syllabus. However, many students report having no clinical attachments in Urology and some newly qualified doctors report never having inserted a catheter, which is a GMC mandated requirement. We recommend a greater emphasis on undergraduate clinical exposure to urology and stricter adherence to GMC mandated procedures

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Delineating the role of various factors in renal disposition of digoxin through application of physiologically-based kidney model to renal impairment populations

Development of submodels of organs within physiologically-based pharmacokinetic (PBPK) principles and beyond simple perfusion limitations may be challenging because of underdeveloped in vitro-in vivo extrapolation approaches or lack of suitable clinical data for model refinement. However, advantage of such models in predicting clinical observations in divergent patient groups is now commonly acknowledged. Mechanistic understanding of altered renal secretion in renal impairment is one area that may benefit from such models, despite knowledge gaps in renal pathophysiology. In the current study, a PBPK kidney model was developed for digoxin, accounting for the roles of organic anion transporting peptide 4C1 (OATP4C1) and P-glycoprotein (P-gp) in its tubular secretion, with the aim to investigate the impact of age and renal impairment (moderate to severe) on renal drug disposition. Initial PBPK simulations based on changes in glomerular filtration rate (GFR) underestimated the observed reduction in digoxin renal excretion clearance (CL(R)) in subjects with moderately impaired renal function relative to healthy. Reduction in either proximal tubule cell number or the OATP4C1 abundance in the mechanistic kidney model successfully predicted 59% decrease in digoxin CL(R), in particular when these changes were proportional to reduction in GFR. In contrast, predicted proximal tubule concentration of digoxin was only sensitive to changes in the transporter expression/ million proximal tubule cells. Based on the mechanistic modeling, reduced proximal tubule cellularity and OATP4C1 abundance, and inhibition of OATP4C1-mediated transport, are proposed as possible causes of reduced digoxin renal secretion in renally impaired patients