PBPK An Old Hat with New Tricks Amin Rostami-Hodjegan, PharmD, PhD, - - PowerPoint PPT Presentation
PBPK An Old Hat with New Tricks Amin Rostami-Hodjegan, PharmD, PhD, FCP Professor of Systems Pharmacology University of Manchester, Manchester, UK & Vice President R&D Simcyp , Sheffield, UK amin.rostami@manchester.ac.uk
Amin Rostami-Hodjegan, PharmD, PhD, FCP
Professor of Systems Pharmacology University of Manchester, Manchester, UK & Vice President R&D Simcyp , Sheffield, UK
amin.rostami@manchester.ac.uk
http://www.natu re.com/clpt/jour nal/v92/n1/cov ers/index.html
PBPK/IVIVE Linked Models
Systems Approach: e.g. Inter-Individual Variability in PK
Americans/Europeans Japanese/Chinese
Age / Genetics / Environment / Disease
Homogenisation HOMOGENATE S9 Nuclear / Mitochondrial pellet Centrifugation @ 9,000g Centrifugation @ 100,000g
Cytosol Microsomes
CYP450 FMO Aldehyde oxidase MAO Aldehyde dehydrogenase Epoxide hydrolase Xanthine oxidase Esterases UGT
HLM HIM HKM rhCYP rhUGT hepatocytes hepatocytes S9 S9 cytosol
Aldehyde oxidase SULT Glutathione S transferase Alcohol dehydrogenase Xanthine oxidase
In In Vitr itro
DMPK K Too
ls: e.g. e.g. Meta Metabo boli lism sm
Dr Drug ug-Foc
used Mode d Modell lling ing
System System-Foc
used d Mode Modell lling ing
Age (PMA)
25 30 35 20 40 60
Relative CYP1A2 Activity (Paediatric:Adult)
1 2 3 4 6
(weeks) (years)
Same Same Type ype of
Init itial ial Data (CL of
affeine eine and and Theo eophyll hylline ine) BUT UT Afte fter Dec econ
to Acc ccou
nt for
Other er Age Rela elated ted Compo mponen ents ts of
learan ance (Siz Size, e, Blood lood Flo low, Pr Prote
in Binding inding, mg mg Micr icrosoma
Prote
in per per Gram am Liv iver er etc etc) and and Sep Separ aration tion of
enal al Pathway thway
CYP2D6 activity was detectable and concordant with genotype by 2 weeks of age, showed no relationship with gestational age, and did not change with post natal age up to 1 year.
In In Vitr itro
vs In In Viv ivo
Ontog
eny y CYP CYP2D6 2D6 an and d 3A4 3A4
Clin Pharmacol Ther 2007 However: we know that: Thus, the development of renal function from birth may change in parallel with the development of the enzyme such that the drug/metabolite ratio may be relatively constant !!!!
Ma Matu turation tion of
enal al Clear Clearan ance ce
y = 87.674x - 14.497 R 2 = 0.9988
50 100 150 0.5 1 1.5 2 BSA (m2) GFR (ml/min) Simcyp vs Rhodin Model
50 100 150 200 250 50 100 150 200 250 GFR (ml/min/1.73m2) Age (months) Schwartz Rowland Rubin data Simcyp
Clin Pharmacol Ther 2008 Figure 1. Changes in CYP2D6 (a) and CYP3A4 (b) activity relative to adult values. The data of Blake et al, corrected for the development of renal function, are indicated by the diamonds. The simulated change in in the activity of each enzyme (solid line) was derived from in vitro data on hepatic enzyme expression and increase in liver weight with age.
0.2 0.4 0.6 0.8 1 4 8 12
Age (Months) CYP2D6 activity (DM/DX ratio relative to adult
0.2 0.4 0.6 0.8 1 4 8 12
Age (Months) CYP3A4 activity (DX/3HM ratio) relative to adult
(A) (B)
Bott Bottom
Up App pproa
h Meet Meets s Top
Down wn
15 30 45 60 75 90 105 120 135 150 165 180 25 50 75 100
Time (minutes)
Mean % remaining in studies
Stomach contents remaining vs time (all literature reports)
No significant effect by postnatal or gestational age, weight or volume of intake but Food Type a significant COVAR: Aqueous < Breast Milk < Formula Milk < Semi-Solid < Solid (44.8 min) < (56.6 min) < (64.1 min) < (87.0 min) < (97.7 min)
Not Not Just ust Cl Clea earan ance ce: Physiolog : Physiology of y of Abso Absorpt ption ion
2i β 2i ij 1i β 1i ij
γ t i γ t i i ij
e PR e ) PR (D y
Blood Lung
Rapidly perfused
Slowly perfused
Kidney Liver Intestines Blood
Elimination Dosing ADME, PK, PD and MOA Metabolism Active transport Passive diffusion Protein binding Drug-drug interactions Receptor binding System component (drug-independent)
PBPK Model Predict, Learn, Confirm
Drug-dependent component
Huang and Temple, 2008 Individual or combined effects
Zhao P, et al Clin Pharmacol Ther 2011
EXTRINSIC INTRINSIC DDI Environment Medical Practice Regulatory Alcohol Smoking Diet
Age Race Disease Gender Genetics Pregnancy Obesity Organ Dysfunction
Well ell Rec ecog
nised by Le by Lead ading ing Regu gula lato tory Agen y Agencies cies
Just ust Made Made It! It! ASC ASCPT PT 20 2012 12 YES NO
DDI DDI in in Neo Neona nate tes s an and d Inf Infan ants ts
0.001 0.010 0.100 1.000 5 10 15 20 Whole liver relative expression Age (y)
Relationship between age and enzyme maturation
CYP1A2 CYP2C9
20 40 60 80 100 120
1 3 5 7 9 11
% fm Age
Fraction
pathway
Pathway 2 Pathway 1
neonate infant child adult
50% 50% 65% 35% 80% 20% 95% 5%
Pr Pregn gnan ancy y as Ano as Anoth ther er E Exa xample mple
Time–varying system parameters (anatomical, physiological and biological; CYPs abundance, etc.)
Clinical Pharmacokinetics 2012 CPT: PSP 2012 Br J Clinical Pharmacol 2012
A PBPK Model to Predict Disposition of CYP3A- metabolized Drugs in Pregnant Women: Verification and Discerning the Site of CYP3A Induction
A.B. Ke, S.C. Nallani, P. Zhao, A. Rostami- Hodjegan, J. D. Unadkat
Blood Enterocyte Lumen PepT1, PepT2, OATP1A2, OATP2B1, OCT3, OCTN1, OCTN2, IBAT, CNT1, CNT2, MCT1, MCT4, MCT5 MDR1 (P-gp) MRP BCRP
Intestine The Blood-CSF Barrier
Cerebrospinal fluid (CSF) apical basolateral Endothelial cells Astrocyte feet Blood Brain parenchyma
The Blood-Brain Barrier
luminal abluminal MRP4 MRP4 BCRP BCRP MDR1 (P-gp) MDR1 (P-gp) OATP1A2 OATP2B1 Choroid epithelium
Duodenum Jejunum I Jejunum II Ileum I Ileum II Ileum III Ileum IV Colon
Segregated Blood Flows Stomach Emptying Luminal Transit Systems Systems App pproa
h: Absorpt ption ion
Enzymes (CYP3A4) vs Transporters (Pgp)
ADAM Model
Seco Second nd Gues Guessing Bioa sing Bioavaila vailabili bility: ty: Baria Bariatric tric Sur Surge gery
RYGB SG BPD-DS JIB
Gastric resection Small intestinal bypass
Invasiveness
(Elder and Wolfe 2007; Padwal et al 2009; Tucker et al 2008)
Mi Mimic micking king Rou
en-Y Y Gas Gastric tric Bypa Bypass ss - Using Using AD ADAM AM
Dissolution / Precipitation / Super-Saturation Pgp
(Darwich et al 2012; JPP)
Cy Cyclospo losporine rine – Post
JI-Bypa Bypass ss
Qbulk QCsink QSsink QSin QSout Qbrain Qbrain
Brain blood Brain mass Cranial CSF Spinal CSF
CLBin CLBout CLCin CLCout PSE PSB PSC
Volume pH Volume pH Volume pH Volume pH CLmet (Eyal et al., 2009)
Systems Systems App pproa
h: Brain ain
Systems Systems App pproa
h : Kidn : Kidney ey Transporters are available in all three proximal tubule cell compartments on the apical and basal membrane. The model can handle:
changes in systemic exposure
efflux and passive permeation
metabolism and transporters
MechKiM: Filtration; Secretion (passive + active) Reabsorption (passive + active), Metabolism
Urinal tubule Cell (renal mass) Renal blood
Assessme Assessment nt of
rhyth ythmic mic Pot
ency y : V : Var aria iabili bility ty
ACTION POTENTIAL (APD90) pseudoECG (QTc) HUMAN HEART VENTRICULAR CELL MODEL MIDMIOCARDIUM HUMAN HEART VENTRICULAR CELL MODEL EPICARDIUM HUMAN HEART VENTRICULAR CELL MODEL ENDOCARDIUM HUMAN HEART VENTRICULAR CELL MODEL ionic channels MEASURED ionic channels ESTIMATED IONIC MODULE CELL/TISSUE MODULE demography POPULATION MODULE physiology
LADME IVIVE
genetics OUTPUT
SYSTEM ATTRIBUTES
covariates for the dynamic effects
ION CHANNELS
hERG necessary – not enough integration step via the apropriate model for cell (extended to the attributes of the whole heart wall)
Toxicology Mechanisms and Methods, 2012
Rema emaining ining Que Question stions P s PBPK BPK - Par art t of
MBDD: : Why? hy? (1) All Models Are Wrong, but Some Models Are Useful ! George EP Box 1987 WE ALL KNOW that:
PWC - Kate Moss June 2008
(1) Moving Away from ‘Drug Focused’ to ‘System Focused’ Modelling (2) Requires Different Type of Data (3) Requires Huge Integration Task (4) Appropriate Tools Are Essential
WE SHOULD ALSO KNOW that: (2) Science is built of facts as a house is built of stones; but an accumulation of facts is no more science than a pile of stones is a house. Henri Poincare, 1902
Chapter 13 – Translation of In Vitro Metabolic Data to Predict In Vivo Drug–Drug Interactions: IVIVE and Modelling and Simulations
Amin Rostami-Hodjegan in ‘Enzyme- and Transporter-Based Drug–Drug Interactions: Progress and Future Challenges’, Pang et al. (Eds); 2010; Springer, New York
Commercial Software/Program In-House Template/Program/Platform
(1) Larger physiology database (ethnic, age, and disease), (2) The opportunity to gather pre- competitive information from multiple (pharmaceutical)
(3) User friendly interfaces for non- modellers. (1) Highest flexibility for real-time changes in models (2) Tailor-made models for specific in-house specific cases which are not available elsewhere, (3) More insight within the organisation into the details of the model
Rema emaining ining Que Question stions P s PBPK BPK - Par art t of
MBDD: : Ho How? w?