Slide 1: Application of PBPK Modeling in Pediatric Drug Development (GastroPlus)
Application of PBPK Modeling in Pediatric Drug Development (GastroPlus®) Viera Lukacova Simulations Plus, Inc. August 31, 2022 1 | NASDAQ: SLP
Slide 2: Outline
Outline Why? – Role of PBPK in pediatric drug development How? – Pediatric physiology: • Tissue growth • Tissue and blood composition • Intestinal physiology – Clearance and disposition scaling: • Metabolic clearance • Glomerular filtration • Transporters What? – Applications 2 | NASDAQ: SLP
Slide 3: Why PBPK Model
Why PBPK Model Structure → In vitro ADMET Pred. Experiments Formulation - Dose, dosage System/Physiology: Compound: form, particle size, • logP/logD release profile • Body height, weight, BMI • pKa(s) • Tissue sizes & blood • Solubility flows • Permeability • Tissue compositions (water, lipid, prote
Slide 4: U.S. FDA
General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products Guidance for Industry DRAFT GUIDANCE This guidance document is being distributed for comment purposes only. ‘Comments and suggestions regarding this draft docuneat should be submited within 60 days o
Slide 5: EMA
EMA fe) EUROPEAN MEDICINES AGENCY 1. Introduction SCIENCE MEDICINES HEALTH For the purpose of this guideline, a PBPK model is defined as a mathematical model that simulates the concentration of a drug over time in tissue(s) and blood, by taking into account the rate of the drug’s 13 December 2018 bn
Slide 6: PMDA
PMDA The following English translation of Japanese Guideline is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and the translation, the former shall prevail. Provisional Translation PSEHB/PED Notification No. 1221-1 D
Slide 7: CFDA
CFDA BRAS ee aAmmhePy O mune © BRM CD ESE CENTER FOR DRUG EVALUATION, NMPA ( ex ] O SIE: F> > Lreas> >A > KFATMPR (CREST AREER REESE (GERDA) ) TES ‘#40 ERE: 20220817 SESS Re Be) ABSA TAM 2, ATARMCERKEE, SARTPOERERT (FESS RLE LAA RSVR PN ERAS (ERS) >. PPR SS PRS E RSME, AGEs. iPKSWNRABRDZAEITA. BRENR
Slide 8: Why PBPK Model
Why PBPK Model Structure → In vitro ADMET Pred. Experiments Formulation - Dose, dosage System/Physiology: Compound: form, particle size, • logP/logD release profile • Body height, weight, BMI • pKa(s) • Tissue sizes & blood • Solubility flows • Permeability • Tissue compositions (water, lipid, prote
Slide 9: Physiology
Physiology @B8 SimulationsPlus 9 | NASDAQ: SLP- . . be ! Cognigen DiLisym Services | Lixoft
Slide 10: Physiologically Based Pharmacokinetics (PBPK)
Physiologically Based Pharmacokinetics (PBPK) Each compartment represents a tissue: – Specific volume(s) – Blood perfusion rate – Enzyme/transporter expression levels – Volume fractions of lipids & proteins – ….. Each compartment represents intestinal section: – Length, radius and volume(s) – Transi
Slide 11: NHANES Average Body Weight & Height (NHANES 2003-2004)
NHANES Average Body Weight & Height (NHANES 2003-2004) Similar information available from surveys in other countries or regions 11 | NASDAQ: SLP
Slide 12: Virtual Subject Populations
Virtual Subject Populations (NHANES 2003-2004 and other sources) Girls, Ages 0-1 Women, Ages 1-20 Men, Ages 1-20 Boys, Ages 0-1 Population information is used to generate realistic virtual populations or algorithms 12 | NASDAQ: SLP
Slide 13: Individual Tissue Sizes
Individual Tissue Sizes Houtkooper, LB, J. Appl. Physiol. 72:366 (1992) ICRP23 Segal, KR, Am. J. Clin. Nutrition 47(1):7 (1988) NHANES 2003-2004 Price, P.S. Crit. Rev. Toxicol. 33(5):469 (2003) 13 | NASDAQ: SLP
Slide 14: Organ Flow (mL/s/mL tissue) Data
Organ Flow (mL/s/mL tissue) Data Price, P.S. Crit. Rev. Toxicol. 33(5):469 (2003), Table 16 14 | NASDAQ: SLP
Slide 15: Infant Physiologies - Tissue Sizes
Infant Physiologies - Tissue Sizes For some parameters, the total age (gestational age + postnatal age) is the determining factor. Total body weight, height and tissue sizes for most of the tissues (except adipose) belong to this category. Example plots for two of the tissues, Liver and Kidneys, are
Slide 16: Infant Physiologies - Tissue Sizes
Infant Physiologies - Tissue Sizes Gestational age is more important factor for % fat mass in infants born at full term pre-term Black lines – representative of term-born infants blue – males; red – females; yellow – gender not defined PMA – postmenstrual age (gestational + postnatal age) 16 | NASDA
Slide 17: Tissue Composition
Tissue Composition Effect of age on tissue compositions needs to be considered for correct prediction of distribution. Example plots for two of the tissues, Adipose and Brain, as well as total body water are shown below PMA – postmenstrual age (gestational + postnatal age) 17 | NASDAQ: SLP
Slide 18: Plasma Protein and Hematocrit
Plasma Protein and Hematocrit Automatic scaling of Fup and Rbp to account for different hematocrit and plasma protein levels in children than in adults 18 | NASDAQ: SLP
Slide 19: Scaling Pediatric Fup
Scaling Pediatric Fup Fup scaling is based on changes in total plasma protein (albumin and α1-acid glycoprotein) using previously published equation (McNamara, AAPS PharmSci, 2002, E4) Pediatric fup observed and predicted from published equation using pediatric plasma protein level as implemented in
Slide 20: PEAR-Physiology Method
PEAR-Physiology Method 1. Select Species 2. For Human physiologies, specify Population, Gender, Health Status and Age – For Health Status: – Healthy – Hepatic Impairment – NEW: NASH, NAFLD – Renal Impairment – Obesity – Pregnancy For infants specify born at term or premature (up to 16 weeks) (this o
Slide 21: Child Growth During Study
Child Growth During Study Account for growth of a child in multi-day study through .mdd file 21 | NASDAQ: SLP
Slide 22: Intestinal Physiology
Intestinal Physiology • Limited information available for some parameters, i.e. gastric emptying or small intestine transit time (dependent on measurement method) • For some parameters the information is only qualitative (i.e. underdeveloped villi structure in infants < 3 years old or differences in
Slide 23: Estimating PBPK Parameters in GastroPlus
Estimating PBPK Parameters in GastroPlus Tissue weights, tissue perfusion rates, tissue densities, and partition coefficients for each tissue for the drug are required for PBPK. The Population Estimates for Age-Related Physiology™ (PEAR Physiology™) module inside of PBPKPlus™ generates such values.
Slide 24: Metabolic clearance
Metabolic clearance 24 | NASDAQ: SLP
Slide 25: CYP Enzyme Ontogeny
CYP Enzyme Ontogeny Johnson T., Clin Pharmacokinet 45(9):931 (2006) 25 | NASDAQ: SLP
Slide 26: CYP Enzyme Ontogeny
CYP Enzyme Ontogeny 2 days old 6 months old 1 year old 26 | NASDAQ: SLP
Slide 27: CYP Enzyme Ontogeny
CYP Enzyme Ontogeny 5 years old adult Intestinal 3A4 27 | NASDAQ: SLP
Slide 28: Midazolam
Midazolam Lukacova – Workshop on Modeling in Pediatric Medicines, 2008 28 | NASDAQ: SLP
Slide 29: Pediatric CL – metabolism by CYPs
Pediatric CL – metabolism by CYPs Samant et al. – Poster Presentation (Poster # 111) - ASCPT 2015 also Quantitative Systems Pharmacology pre-conference Poster # QP-16 29 | NASDAQ: SLP
Slide 30: Pediatric CL – metabolism by CYPs
Pediatric CL – metabolism by CYPs Samant et al. – Poster Presentation (Poster # 111) - ASCPT 2015 30 | NASDAQ: SLP also Quantitative Systems Pharmacology pre-conference Poster # QP-16
Slide 31: Pediatric CL – Acetaminophen
Pediatric CL – Acetaminophen Adult (5mg/kg) Adolescents (15 mg/kg) Infants (12.5 mg/kg) Neonates (20mg/kg) Samant et al. – Poster Presentation (Poster # 111) - ASCPT 2015 31 | NASDAQ: SLP also Quantitative Systems Pharmacology pre-conference Poster # QP-16
Slide 32: Non-CYP Mediated CL
Non-CYP Mediated CL Pediatric PO oseltamivir Oseltamivir carboxylate Adult PO Oseltamivir oseltamivir carboxylate Adult IV Pediatric physiologies are automatically generated by GastroPlus 32 | NASDAQ: SLP
Slide 33: UGT Enzyme Ontogeny
UGT Enzyme Ontogeny Badee J Clin Pharmacol 2019 33 | NASDAQ: SLP
Slide 34: Renal secretion – glomerular filtration
Renal secretion – glomerular filtration 34 | NASDAQ: SLP
Slide 35: Glomerular Filtration
Glomerular Filtration Prediction of pediatric population based on fitted adult model and known differences in adult and pediatric physiology Kearns – New Engl J Med 2003, 349:1157 Lukacova – Workshop on Modeling in Pediatric Medicines, 2008 35 | NASDAQ: SLP
Slide 36: Glomerular Filtration – Neonates
Glomerular Filtration – Neonates Predicted vancomycin CL in premature infants Kearns – New Engl J Med 2003, 349:1157 Lukacova – AAPS 2015 Predicted vancomycin PK in premature infants 36 | NASDAQ: SLP
Slide 37: Transporters
Transporters 37 | NASDAQ: SLP
Slide 38: Tissue Disposition
Tissue Disposition Scaling from in vitro and pre-clinical data? Scaling to different populations? 38 | NASDAQ: SLP
Slide 39: Transporter Ontogeny
Transporter Ontogeny Alcorn Clin Pharmacokinet 2002; Fakhoury et al. DMD 2005; De Woskin et al. Reg Toxicol Pharmacol 2008 39 | NASDAQ: SLP
Slide 40: Transporter Ontogeny
Transporter Ontogeny 2014 - mRNA • Number of research groups is focused on measuring transporter expression levels • These few publications show a journey of just one of those groups 2016 - mRNA 2016 - Protein 2021 - Protein 2018 - Protein 40 | NASDAQ: SLP
Slide 41: Example: Valsartan
Example: Valsartan • Eliminated by biliary secretion • Substrate for: • OATP1B1 and OATP1B3 • MRP2 • in vitro data available from rat and human suspended hepatocytes and human sandwich-cultured hepatocytes • in vivo data available in rat and human (adult and pediatric for 1- to 16-year-old) 41 | NAS
Slide 42: IVIVE with PStc Scaling for ALL Tissues
IVIVE with PStc Scaling for ALL Tissues 1. Predicted rat IV using in vitro data (Poirier – J Pharmacokinet Pharmacodyn 2009, 36:585) measured in rat hepatocytes 2. Predicted human IV using in vitro data measured in human hepatocytes 42 | NASDAQ: SLP Lukacova – 17th North American ISSX meeting 2011,
Slide 43: Refine Adult Model
Refine Adult Model Passive diffusion through tissue membranes in all tissues scaled from liver PStc predicted from in vitro Liver uptake predicted from in vitro Secretion into bile, urine, and gut lumen via MRP2 - MRP2 expression in different tissues estimated from reported relative mRNA levels in l
Slide 44: Refine Adult Model
Refine Adult Model Refine adult model: - fitted passive diffusion through tissue membranes and intestinal permeability Predict pediatric populations 44 | NASDAQ: SLP
Slide 45: Predict Pediatric Disposition
Predict Pediatric Disposition Dosing 2 mg/kg, experimental profiles are averages of 6-7 individuals (initial assumption – the same transporter density as in adults) Need to account for lower villi density in very young children? 45 | NASDAQ: SLP
Slide 46: Predict Pediatric Disposition
Predict Pediatric Disposition Dosing 2 mg/kg, experimental profiles are averages of 6-7 individuals (initial assumption – the same transporter density as in adults) Decreased absorptive surface area 46 | NASDAQ: SLP
Slide 47: Example: Amoxicillin
Example: Amoxicillin • Eliminated by renal secretion (glomerular filtration and active secretion) • Substrate for: • PepT1/PepT2 • MRP4 • in vivo data available in human (adult and pediatric for infants up to 3 years) Akanuma et al. DMD 2011 47 | NASDAQ: SLP
Slide 48: Fit Adult Model
Fit Adult Model 1000 10000 Cumulative Amount in Urine [mg] Plasma Concentration [ug/mL] 100 10 1000 1 0.1 0.01 100 0 5 10 15 0 2 4 6 8 10 12 Time [hrs] Time [hrs] 30.1 200 Plasma Concentration [ug/mL] 25.1 150 20.1 AUC [ug-h/mL] 15.1 100 10.1 50 5.1 0.1 0 0 2 4 6 8 10 0 500 1000 1500 2000 2500 3000
Slide 49: Validate Adult Model
Validate Adult Model Lukacova – AAPS Annual Meeting 2012, Chicago, IL 49 | NASDAQ: SLP
Slide 50: Predict Pediatric Disposition
Predict Pediatric Disposition Assumed similar transporter density as in adults 50 | NASDAQ: SLP
Slide 51: Scaling Renal Transporters from Maximal Tubular Excretory Capacity
Scaling Renal Transporters from Maximal Tubular Excretory Capacity adult ~ 66% ~ 50% Rubin et al. J Clin Invest 1949 51 | NASDAQ: SLP
Slide 52: Predict Pediatric Disposition
Predict Pediatric Disposition Assuming similar transporter density as in adults Estimating kidney transporter expression from PAH data 52 | NASDAQ: SLP
Slide 53: Predict Pediatric Disposition
Predict Pediatric Disposition 3 days old, 29 weeks gestation, 1-3 days old, 29 weeks gestation, 25 mg/kg 50 mg/kg Transporter density set to 2% of adult values Rubin et al. J Clin Invest 1949 Fawer et al. Helv Paed Acta 1979 53 | NASDAQ: SLP
Slide 54: Applications
Applications 54 | NASDAQ: SLP
Slide 55: Dosing Recommendations
Dosing Recommendations 1-16 yo kidney transplant recipients Neonates with congenital CMV • Animal data was used to determine model structure • Human adult PK data was used to refine parameters • Model included prodrug and parent drug • Permeability-limited tissues • Transporters involved in disposit
Slide 56: Development of Pediatric Formulation I
Development of Pediatric Formulation I • Model refinement for relevant conditions (pediatric formulation, infant formula) in adults was important for accurate pediatric predictions. • Formulation itself (excipients) might be the reason for longer gastric emptying in fasted state in both adults and c
Slide 57: Development of Pediatric Formulation I
Development of Pediatric Formulation I • Adult dasatinib (SPRYCEL®) formulation is an immediate release tablet • Powder for oral suspension formulation was developed for use in pediatric patients • BE study showed differences in PK between these two formulations in adults • GastroPlus® modeling was
Slide 58: Dissolution Safe Space in Pediatric Population
Dissolution Safe Space in Pediatric Population 58 | NASDAQ: SLP
Slide 59: Summary
Summary • PBPK models are important tool in pediatric drug development: pediatric dose selection, trial design, but also evaluation of pediatric formulations - this has been recognized also by regulatory agencies around the world. • GastroPlus makes application of PBPK models in pediatric drug devel
Slide 60: Thank you for your kind attention! Questions?
Thank you for your kind attention! Questions? 60 | NASDAQ: SLP