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Pediatric & Pregnancy PBPK modelling: Clinical & Drug Development Applications

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Presented by Dr. Trevor Johnson

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Pediatric & Pregnancy PBPK modelling: Clinical & Drug Development Applications

  1. 1. Paediatric and Pregnancy PBPK modelling: Clinical and Drug Development Applications Dr Trevor Johnson Principal Scientist Simcyp Limited trevor.johnson@certara.com
  2. 2. © Copyright 2018 Certara, L.P. All rights reserved. Separating Systems & Drug Information Systems Data Drug Data Trial Design Age Weight Tissue Volumes Tissue Composition Cardiac Output Renal elimination Plasma Protein Enzymes Ontogeny MW LogP pKa Protein binding BP ratio In vitro Metabolism Permeability Transport Solubility Dose Route Frequency Co-administered drugs Populations studied Mechanistic IVIVE approach to predict CL Whole body PBPK model Prediction of drug PK (PD) in population of interest
  3. 3. © Copyright 2018 Certara, L.P. All rights reserved. Model Qualification and Reporting 3
  4. 4. © Copyright 2018 Certara, L.P. All rights reserved. Parameter and model certainty: Paediatric Body Size and Variability Weight based on HeightHeight based on Age 0 50 100 150 200 250 0 5 10 15 20 Height(cm) Age (y) Male plus CV Median 10th Percent 90th Percent 0.4th Percent 99.6 Percent Simulated 0 20 40 60 80 100 120 0 5 10 15 20 Weight(kg) Age (y) Male plus CV Median 10th 90th 0.4th 99.6th Simulated Correlated Monte Carlo modelUncorrelated Monte Carlo model BSA from HT and WT Dubois and Dubois >15kg Haycock et al <15kg
  5. 5. © Copyright 2018 Certara, L.P. All rights reserved. Parameter certainty: Liver Volume changes with Age Liver Volume = 0.722 * BSA1.176 0 0.5 1 1.5 2 2.5 0 5 10 15 20 25 30 Age (y) LiverVolume(L) Simcyp In vivo Adult
  6. 6. © Copyright 2018 Certara, L.P. All rights reserved. Oral Emphasis on performance verification PBPK AUC – blue, Cmax - red Oral
  7. 7. © Copyright 2018 Certara, L.P. All rights reserved. Parameter Uncertainty:CYP3A4 and UGT2B7 Ontogeny
  8. 8. © Copyright 2018 Certara, L.P. All rights reserved. CYP3A4 in vivo ontogeny vs in vitro Salem et al, Midazolam IV data Upreti and Wahlstrom, Sulfentanil IV data 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 0 5 10 15 20 25 Fraction Age (y) In vitro Salem Upreti
  9. 9. © Copyright 2018 Certara, L.P. All rights reserved. CYP3A ontogeny – middle out analysis 9
  10. 10. © Copyright 2018 Certara, L.P. All rights reserved. Latest CYP3A4 ontogeny 10 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 0 5 10 15 20 Fractionofadult Age (y) CYP3A onotgeny Brussee No MPPGL Salem 2018 Similar to Upreti and Wahlstrom 2016 – methodology???? Verification data to follow – Paediatric substrates ?
  11. 11. © Copyright 2018 Certara, L.P. All rights reserved. Effects of underlying disease on CYP3A ontogeny 11
  12. 12. © Copyright 2018 Certara, L.P. All rights reserved. UGT2B7 Ontogeny Strassburg et al 2002 Zaya et al 2006 Pacifici et al 1990 Pacifici et al 1982 Choonara et al 1989 Bhatt et al 2017 Leiden Collaboration – Top down vs bottom up ontogeny for UGT2B7 - Morphine, - Zidovudine 0 0.2 0.4 0.6 0.8 1 1.2 1.4 0 2 4 6 8 10 12 14 16 18 20 Fraction Age (y) UGT2B7
  13. 13. © Copyright 2018 Certara, L.P. All rights reserved. UGT2B7 ontogeny ‘Top down’ vs ‘Bottom up’ Bottom up Top down • Take home message is that pattern of ontogeny appears to be reasonable except for early neonates • But under-prediction of CL across age band with morphine. Bodyweight (kg) Bodyweight (kg) Clearance(L/h) Glucuronidationclearance(L/h)
  14. 14. © Copyright 2018 Certara, L.P. All rights reserved. Ontogeny of OCT1 14 Prasad et al., CPT 2016; 100: 362 OCT1, OATP1B3 & P-gp - significantly lower in neonates & infants than adolescents & adults
  15. 15. © Copyright 2018 Certara, L.P. All rights reserved. Morphine CL and UGT & OCT1 ontogeny UGT2B7 ontogeny UGT2B7 and OCT1 ontogeny Observed data from Bouwmeester et al 2004, Anand et al 2008, Knibb et al 2009, Lynn & Slattery 1987 Based on work by Emoto et al CPT Pharmacometrics Syst Pharmacol 2018; 7: 464-473.
  16. 16. © Copyright 2018 Certara, L.P. All rights reserved. Introducing UDPGA 16 UGT2B7, OCT1 and UDPGA ontogeny Tao Lui, PhD thesis 2017. Learn and confirm paradigm to optimize pharmacotherapy in neonatal abstinence syndrome using pharmacometrics. School of Pharmacy and medicine., University of Maryland.
  17. 17. © Copyright 2018 Certara, L.P. All rights reserved. Case study 1: GBT440 • Used for the treatment of Sickle Cell Disease • Low clearance drug (4-6 L/h) • Half-life of ~75 h in healthy subjects • Half-life of ~ 36 hours in subjects with SCD • Cleared by oxidation (74%), reduction (19%) and UGT- mediated metabolism (8%) • Main oxidative enzyme – CYP3A4 (74% of oxidation) • fu=0.002; B:P ratio =33 17
  18. 18. © Copyright 2018 Certara, L.P. All rights reserved. PBPK modelling strategy: from adult to paediatric Review of in vitro and clinical data to develop PBPK model in healthy adults Verify PBPK model in healthy adults using independent clinical data sets Verify (and refine if necessary) PBPK model in adults with SCD using clinical data sets Verify PBPK model in adolescents with SCD using clinical data sets Integrate physiological changes related to SCD Integrate age-related changes Integrate age-related changes including enzyme and haematocrit ontogenies Predict exposure of GBT440 in children aged 9 months up to 12 years of age
  19. 19. © Copyright 2018 Certara, L.P. All rights reserved. GBT440: simulated blood exposures in healthy adults 19 Cmax AUC (0,24) (µg/mL) (µg/mL.h) Simulated (n=240) 139 3077 Observed (n=24) 160 3472 S/O 0.87 0.89 A loading dose of 900 mg GBT440 on days 1 and 2 and 600 mg QD on days 3 to 7 (linear and log-linear plots are on the left and right). Solid black line is the mean and dashed lines are the 5th and 95th percentiles of the simulated population. Circles are observed data.
  20. 20. © Copyright 2018 Certara, L.P. All rights reserved. Key system parameter changes in patients with SCD • Coagulation, platelet and adhesion markers are increased in patients with SCD. • Changes in protein binding may occur as a result of lower albumin levels. • Moreover, sickled red blood cells are prone to haemolysis. Thus, haematocrits are significantly lower in patients with SCD than in healthy subjects (21% versus 40%; Connes et al., PLOS 2013; 8(11): 1-5. • Integration of the lower haematocrit within the PBPK model for GBT440 led to a reduction in the B:P ratio from 33.16 to 15.5 (consistent with observed data). 20
  21. 21. © Copyright 2018 Certara, L.P. All rights reserved. GBT440: simulated blood exposures in adults with SCD 21 A). single oral dose of 900 mg GBT440. B). Multiple oral doses of GBT440 (500 mg BID) for 28 days Solid black line is the mean and dashed lines are the 5th and 95th percentiles of the simulated population. Circles are observed data. Cmax AUC t1/2 (µg/mL) (µg/mL*h) (h) Simulated (n=60) 34.6 2144 39.4 Observed (n=6) 36 2480 38.8 S/O 0.96 0.86 1.02 A B Cmax AUC (0,24) (µg/mL) (µg/mL.h) Simulated (n=60) 95 2147 Observed (n=6) 116 2430 S/O 0.92 0.83
  22. 22. © Copyright 2018 Certara, L.P. All rights reserved. GBT440: simulated blood exposures in children (6 to < 12 years) with SCD 22 A single oral dose of 600 mg GBT440 (linear and log- linear plots are on the top and bottom). Solid black line is the mean and dashed lines are the 5th and 95th percentiles of the simulated population. Circles are observed data. Cmax AUC Trial (n=6) (µg/mL) (µg/mL.h) 1 2 3 4 5 6 7 8 9 10 51.8 55.9 44.5 61.0 54.5 51.6 59.8 61.9 56.6 59.0 3344 2279 2560 3405 2693 3077 3666 2464 2185 2007 Population (n=60) 55.4 2716 Observed (n=6) 47.3 2785 S/O 1.17 0.98
  23. 23. © Copyright 2018 Certara, L.P. All rights reserved. Predicted whole blood exposures in paediatrics with SCD 23 Predicted mean blood concentrations of GBT440 following administration of multiple oral doses of GBT440 (900 mg QD) in: • infants aged 9 months to 2 years (black) • children aged 2 to 5 years (orange) • children aged 6 to 11 years (red) • adolescents aged 12 to 17 years (blue) • adults (green) with SCD The solid and dashed black lines represent simulations using the CYP3A4 ontogeny profiles based on Simcyp and Upreti and Wahlstrom (2016), respectively. CYP3A4 ontogeny profiles based on Simcyp (black circles) and Upreti and Wahlstrom (J Clin Pharmacol 2016) (grey circles)
  24. 24. © Copyright 2018 Certara, L.P. All rights reserved. Dose projections in paediatrics with SCD 24 Predicted mean blood concentrations of GBT440 following administration of multiple oral doses of GBT440 (dose equivalent to 900 mg QD in adults) in: • infants aged 9 months to 2 years (black) • children aged 2 to 5 years (orange) • children aged 6 to 11 years (red) • adults (green) with SCD The solid and dashed black lines represent simulations using the CYP3A4 ontogeny profiles based on Simcyp and Upreti and Wahlstrom (2016), respectively. Dose equivalent Cmin Cmax AUC(0,24) Cmin Cmax AUC(0,24) Populations (n=70) (900 mg in adults) (ng/mL)(ng/mL) (ng/mL.h) Ratios (relative to adult) 9 months to 2 years - Simcyp ontogeny 200 73.7 118 2330 1.25 1.34 1.31 9 months to 2 years - Upreti ontogeny 200 43.6 87.9 1590 0.74 1.00 0.89 2 to 5 years 300 67.7 112 2190 1.15 1.27 1.23 6 to 11 years 400 55.0 89.5 1754 0.93 1.02 0.99 12 to 17 years 900 70.0 109 2180 1.19 1.24 1.22 adults 900 58.9 87.9 1780 1.00 1.00 1.00
  25. 25. © Copyright 2018 Certara, L.P. All rights reserved. Conclusions • PBPK modelling allows mechanistic investigation of exposure differences in healthy adults versus adults with SCD (disease-related changes) • PBPK modelling allows mechanistic investigation of exposure differences in adults with SCD versus children with SCD (age-related changes) • PBPK modelling can be used to assess dose projections in children 25
  26. 26. © Copyright 2018 Certara, L.P. All rights reserved. Predicting DDI in Paediatrics
  27. 27. © Copyright 2018 Certara, L.P. All rights reserved. Relative Importance of Pathways: “Ratio of Ratios”! Pathway A in Paediatrics Pathway A in Adults Pathway B in Paediatrics Pathway B in Adults Relative Ontogeny = 0.1 1.0 10.0 4 Days 36 Days 1 Year 10 Years RatioX(adult/Paed):CYP1A2(Adults/Paed Age X vs CYP1A2 Renal(male) CYP2D6 CYP3A4 CYP2B6 0.5 2.0 3.0 8.0 20.0 40.0 0.3 1 Day 0.01 0.10 1.00 1 Day 4 Days 36 Days 1 Year 10 Years RatioX(adult/Paed):CYP29(Adults/Paed) Age X vs CYP2C9 CYP1A2 CYP3A4 CYP2B6 CYP2D6 CYP2E1 CYP2C8 Renal CYP2C18/19 0. 04 0. 05 0.20 0.40 0.50 0.60 2.00 3.00
  28. 28. © Copyright 2018 Certara, L.P. All rights reserved. Anticipated Effects Drug metabolised by two enzymes inhibitor of minor enzyme introduced Assuming in adult that fm3A4=0.5 vs fmx = 0.5 when 3A4 is inhibited, …
  29. 29. © Copyright 2018 Certara, L.P. All rights reserved. Regulatory examples 29 Drug Key theme (Impact level) Key question(s) Brief description Internal impact Qualification dataset FDA response EMA response Eribulin (NDA submission) Pediatric (Low – moderate) What is the starting dose of eribulin in children A PBPK model was developed for eribulin and used to perform simulations with the Simcyp pediatric population. Model predicted that the starting dose in 6 – 12 year old patients should be half of the therapeutic doses in adults. CL characteristic CYP3A metabolism, but mainly biliary excretion (which was converted into HLM CLint with the retrograde calculator) PBPK confirmed results from traditional population-based scaling approaches to set the starting dose for the pediatric program Clinical PK data. Results of the first pediatric trial showed that the model predicted the clearance of 12 – 18 year old patients very well. Clearance of 6 – 12 year old was slightly over predicted, but within acceptable range. No comment. Starting dose was accepted. No comment. Starting dose was accepted. Quetiapine (late development) Pediatrics (medium) Bridging formulations. Quetiapine XR and Quetiapine formulations and extrapolating from adult to pediatric Could we set a dose for the XR formulation in children without performing a trial based on existing preclinical and clinical exposure data? Inform dose selection in children Internal compound file Accepted Not submitted Emflaza (late development) Pediatrics (medium) Effect of CYP3A4 perpetrators in pediatric population PBPK model built in adult population with DDIs CYP3A4 verified with clinical data. Pediatric PK data showed no change in PK compared to adults Dose adjustments with CYP3A4 perpetrators in line with adult adjustments DDI CYP3A4 in adult population. A case could be made to support same dose adjustments in pediatrics as in adults. Accepted
  30. 30. © Copyright 2018 Certara, L.P. All rights reserved. Case study 2: Deflazocort (Emflaza) • PBPK model for 21 desDFZ • Model verification • Prediction of concentration-time profiles in adults • Predicted DDI liability clarithromycin and rifampicin in adults • Predicted exposure in children 4 to 11y and adolescents 12 to 16y • Model application • Predicted DDI liability in children (clarithromycin, fluconazole, rifampicin, efavirenz) 30 Deflazocort 21-desacetyl deflazocort (21-desDFZ) Esterases CYP3A4 6β hydroxyl DFZ and other metabolites
  31. 31. © Copyright 2018 Certara, L.P. All rights reserved. Model verification (Adults) 31
  32. 32. © Copyright 2018 Certara, L.P. All rights reserved. Model verification (Paediatrics) 32 Children Adolescents
  33. 33. © Copyright 2018 Certara, L.P. All rights reserved. Model application 33 Adult values Simulations Cmax AUC 2.1 4.2 2.25 3.37 0.22 0.15 0.06 0.08 600mg 500mg Obs Obs
  34. 34. © Copyright 2018 Certara, L.P. All rights reserved. 34 Model application
  35. 35. © Copyright 2018 Certara, L.P. All rights reserved. 35 Application of PBPK and POPPK in pediatric DDI
  36. 36. © Copyright 2018 Certara, L.P. All rights reserved. Acceptance criteria for PBPK models • In vitro data prediction of CL or Vss typically 2 – 5 fold • More fitted model e.g. in vivo CL data to fit Clint via retrograde model; 0.75 to 1.5 or 0.8 to 1.25-fold? • Depends on variability of observed data – link success to the measure of variation in the observed values 36
  37. 37. © Copyright 2018 Certara, L.P. All rights reserved. Feto-Placental-Maternal PBPK model 37 Venous Blood Arterial Blood Lung Adipose Bone Brain Heart Kidney Muscle Skin Liver Spleen Gut Portal Vein IV Dose EHC Generic Pancreas PO Dose Tissue Fetal-placental blood Venous Blood Liver Gut Spleen Pancreas CLmet Heart Muscle Skin Kidneys Lungs Bone Brain Adipose Amniotic Fluid Maternal Placental Blood Arterial Blood CLplacenta Intracellular (Placental tissue) Maternal placental permeability limited placenta model CLPDM CLPDF Fetal placental
  38. 38. © Copyright 2018 Certara, L.P. All rights reserved. Summary • Paediatric PBPK models have the potential to improve drug development and not just in under 2 years • Increasing use of p-PBPK in regulatory submissions – Use p- PBPK where the question justifies its use and where you can verify the model – Model verification what is really needed? – Novel use of p-PBPK in clinical trials • Paediatric PBPK models, more understanding of the system, some parameters are known unknowns.  Some transporter ontogeny  Co-factor ontogeny and effects on drug metabolism  Intestinal UGT and other enzymes  Biologics area: FcRn receptor ontogeny • Collaborative approach between academia, drug industry and regulators in continuing to establish best practice. 38
  39. 39. © Copyright 2018 Certara, L.P. All rights reserved. Acknowledgements • Prof Amin Rostami-Hodjegan • Dr Masoud Jamei • Dr Khaled Abduljalil • Dr Farzaneh Salem • Dr Jennifer Bonner • Dr Xian Pan • Ms Amita Pansari 39

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