PharmacometEffective Pr

D lDevelopmA Ch d l PhDAyyappa Chaturvedula, PhD

General Manager,GVK Biosciences Pvt. Ltd.

trics For roduct

tmentDD

isclosure

These are my personal views and do npolicies or views.policies or views.

not represent official GVK Bio

genda

DefinitionBasics and TerminologiesBasics and TerminologiesCase Studies

• Long acting formulation of Risperidoneg g p• Fixed dose combination of SC Trastuzuma

Conclusionsab

harmacometrics: Definitiharmacometrics: DefinitiMultidisciplinary Influence

Pharmacometrics is an emerging science defined as he science that quantifies drug, disease and trial nformation to aid efficient drug development and/or regulatory decisions- The US FDA regulatory decisions The US FDA

Exploratory analyses of data pertaining to pharmacokinetic, pharmacodynamic, and disease progression are often referred to as the pharmacometrics (PM) analyses- Battaram et alpharmacometrics (PM) analyses Battaram et al

The science of developing and applying mathematical and statistical methods to characterize, understand and predict a drug’s pharmacokinetic, pharmacodynamic and biomarker-outcomes pharmacodynamic, and biomarker-outcomes behavior- Ette and Williams

Pharmacometrics can be defined as that branch of cience concerned with mathematical models of

biology pharmacology disease and physiology used biology, pharmacology, disease, and physiology used o describe and quantify interactions between

xenobiotics and patients, including beneficial effects and side effects resultant from such interfaces-Barrett et al

on and on and e

Barrett, J. S., Fossler, M. J., Cadieu, K. D. and Gastonguay, M(2008), Journal of Clinical Pharma, 48: 632–649.

harmacokinetic Models

dels are mathematical presentation of a system and processes processesarmacokinetic models assume e body as a series of mpartmentsmpartmentste constants define the nsfer of drug between gmpartments models describe the time urse of plasma concentrations urse of plasma concentrations a function of dose

Ct = Ae-αt+Be-βt

Modeling and Simulation

PK Model is a mathematical representation of biological process p g peg. Absorption, distribution, metabolism, excretion

Modeling is the process of estimating Modeling is the process of estimating the parameters of the most appropriate model that describes the observed data well

Simulation is predicting the data from the estimated parameter in modeling

All Models Are Wrong But So

PK/PD data(Observed)

Modeling

Parameters(Clearance etc)

Predicted Data(Pl )

Simulation

(Plasma conc)

ome Are Useful-George Box

l i l Ph ki ilassical Pharmacokineticsharmacokinetics

P l i s vs Population

lassical Pharmacokinetics

Clinical S

tion

Conc

entr

a

NCA Analy

Plas

ma

C

TIME

s

Study

Stage I

y

Stage IPK Parameters:

AUC, Cmax, Tmax, Half-lifeStage II:

ysis

gDescriptive Statistics:

Mean, SD, %CV

opulation Pharmacokinet

rati

on PharmacokinetiStatistical M

a Co

ncen

tr One Stag

Plas

ma

TIME

M d l b d h b d Model based approach based on soun

tics

ic ModelModel

Fixed Effect Parametersge Random Effect Parameters

Hypothesis testing

d PK d S i i l id ind PK and Statistical considerations

LME/NONMEM: Definitionn

tures of Pop PK Analysis

Pharmacokinetic Model

rati

on

Pharmacokinetic ModelStatistical Model

a Co

ncen

trPl

asm

a

TIME

• Estimates fixed (eg. Cl) and randoeffect (variability) parameters( y) p

• Can handle sparse sampling• No uniform sampling schedules ar

required• Several factors studied in one stu

R l ti f th d t i t• Real time use of the product in tapopulation can be studied

Model Based Drug DevelopModel Based Drug Developulture of Drug Developme

Milligan, P. A., Brown, M. J., Marchant, B., MartN., Nucci, G., Nichols, D. J., Boyd, R. A., MandeS., Gruben, D., Anziano, R. J., Stock, T. C. and Pharmacology & Therapeutics, 93: 502–514.

pment (MBDD): The pment (MBDD): The ent

tin, S. W., van der Graaf, P. H., Benson, ema, J. W., Krishnaswami, S., Zwillich, Lalonde, R. L. (2013) Clinical

pplications of Pharmacom

CPT: Pharmacometrics & Systems PharmacologyVolume 1, Issue 9, pages 1-14, 26 SEP 2012 DOI: 10.1038http://onlinelibrary.wiley.com/doi/10.1038/psp.2012.4

metrics

• NONMEM (ICON)• Monolix (Lixoft)

Ph i (C t• Phoenix (Certara• Trial Simulator

(Certara)• Gastroplus p

(Certara)• SimCyp (Certara)• Matlab

(Mathworks)(Mathworks)• R (Freeware)• SAS

/psp.2012.4/full#psp420124-fig-0001

BP 7000 A N L g A ti gBP-7000, A New, Long-Actingormulation of Risperidone: M

RBP-7000 is a sustained-release (onceResperidone using ATRIGEL® technoloResperidone using ATRIGEL® technoloAdministered as SC injection of a viscforms an implant upon contact with tt is intended for the patients with sccompliance issues associated with oraObjective of this analysis was to deveObjective of this analysis was to deveto define the clinical development pl

eni, R., Heidbreder, C., Fudala, P.J. and Nasser, A.F. (2013), A model-based approaionship between the pharmacokinetic and safety profiles of RBP-7000, a new, long-anal of Clinical Pharma, 53: 1010–1019.

g S t i d R l d g, Sustained-Released MBDD Approach

e monthly) formulation of ogyogycous, liquid formulation that tissue fluidschizophrenia to address the al treatmentelop a model based approach elop a model based approach an for RBP-7000

ch to characterize the population pharmacokinetics and the acting, sustained-released formulation of risperidone.

BP 7000 A N L g A ti gBP-7000, A New, Long-Actingormulation of Risperidone: M

Population PK and PK/PD models werdata from a Phase I study (60,90 and data from a Phase I study (60,90 and Three models were developed for linkconcentrations to safety and efficacy

• PK-D2 receptor occupancy (65-80% for opliterature data)

• PK-Adverse eventsPK l ti l l ( t i f d• PK-prolactin levels (antagonism of dopam

eni, R., Heidbreder, C., Fudala, P.J. and Nasser, A.F. (2013), A model-based approaionship between the pharmacokinetic and safety profiles of RBP-7000, a new, long-anal of Clinical Pharma, 53: 1010–1019.

g S t i d R l d g, Sustained-Released MBDD Approach Contd.

e developed using clinical 120 mg doses, 45 subjects)120 mg doses, 45 subjects)king active moiety

y markersptimal antipsychotic effect,

i i ti it ) l ti l lminergic activity) prolactin levels

ch to characterize the population pharmacokinetics and the acting, sustained-released formulation of risperidone.

BP 7000 A N L g A ti gBP-7000, A New, Long-Actingormulation of Risperidone: M

PK model

eni, R., Heidbreder, C., Fudala, P.J. and Nasser, A.F. (2013), A model-based approaionship between the pharmacokinetic and safety profiles of RBP-7000, a new, long-anal of Clinical Pharma, 53: 1010–1019.

g S t i d R l d g, Sustained-Released MBDD Approach contd.

Receptor occupancy

PK-Adverse event PK Adverse event

PK-Prolactin

ch to characterize the population pharmacokinetics and the acting, sustained-released formulation of risperidone.

BP 7000 A N L g A ti gBP-7000, A New, Long-Actingormulation of Risperidone: M

Predicted D2 receptor occupancy together with incidence of AEs suggest that the clinical dose should lie between 90-120 mg

The model can be applied for the ppclinical development questions:

• Selection of efficacious dose• Dosing strategy in repeated doses• Dose adjustments in

subpopulations

eni, R., Heidbreder, C., Fudala, P.J. and Nasser, A.F. (2013), A model-based approaionship between the pharmacokinetic and safety profiles of RBP-7000, a new, long-anal of Clinical Pharma, 53: 1010–1019.

g S t i d R l d g, Sustained-Released MBDD Approach contd.

PK d lPK model PD model

ch to characterize the population pharmacokinetics and the acting, sustained-released formulation of risperidone.

l ti PK h f lopulation PK approach for clixed Dose SC formulation of

Trastuzumab (Herceptin®) is used in acancercancerV infusion as Q3W or QW as body wei(maintenance dose, 90 min) with a loSC formulation was developed with th

• Provides substantial time savings in clinic• Preferred by healthcare providers and paPreferred by healthcare providers and pa• Expected to improve patient compliance

cade-Potelleret, F., Lemenuel-Diot, A., McIntyre, C., Brewster, M., Lum, Boach for the Clinical Development of a Fixed-Dose Subcutaneous Formulatimacology, 3: 1–9. doi: 10.1038/psp.2013.63

li i l d l t f linical development of Trastuzumab

all stages of HER2+ breast

ight adjusted dose oading dose (30 min)he following benefitsc atientsatients and reduce administration costs

. and Bittner, B. (2014), Use of a Population Pharmacokinetic ion of Trastuzumab. CPT: Pharmacometrics & Systems

l ti PK h f lopulation PK approach for clixed Dose SC formulation of

An integrated population PK model was developed with IV and SC d t f Ph I d Ph IB SC data from Phase I and Phase IB studiesSimulations were conducted using the population pharmacokinetic the population pharmacokinetic model to establish the non-nferiority of Ctrough and other PK correlates of efficacyyModel simulations were retrospectively compared to Phase III study data

cade-Potelleret, F., Lemenuel-Diot, A., McIntyre, C., Brewster, M., Lum, Boach for the Clinical Development of a Fixed-Dose Subcutaneous Formulatimacology, 3: 1–9. doi: 10.1038/psp.2013.63

li i l d l t f linical development of Trastuzumab Contd.

SC SC Dose

IV d KaF

CentralComp (V1)

PeripheralComp (V2)

IV dose KaF

Q

(V1)

CL VmaxKm

. and Bittner, B. (2014), Use of a Population Pharmacokinetic ion of Trastuzumab. CPT: Pharmacometrics & Systems

l ti PK h f lopulation PK approach for clixed Dose SC formulation of

IV data described by the model

cade-Potelleret, F., Lemenuel-Diot, A., McIntyre, C., Brewster, M., Lum, Boach for the Clinical Development of a Fixed-Dose Subcutaneous Formulatimacology, 3: 1–9. doi: 10.1038/psp.2013.63

y

li i l d l t f linical development of Trastuzumab contd.

SC data described by the model

. and Bittner, B. (2014), Use of a Population Pharmacokinetic ion of Trastuzumab. CPT: Pharmacometrics & Systems

y

l ti PK h f lopulation PK approach for clixed Dose SC formulation of

simulations predict that a fixed 600-mg dose ofas high as that obtained with the registered IV both Cycle 1 and Cycle 7, thus ensuring that pawith this novel SC regimen.

cade-Potelleret, F., Lemenuel-Diot, A., McIntyre, C., Brewster, M., Lum, Boach for the Clinical Development of a Fixed-Dose Subcutaneous Formulatimacology, 3: 1–9. doi: 10.1038/psp.2013.63

with this novel SC regimen.

li i l d l t f linical development of Trastuzumab contd.

f SC trastuzumab would provide Ctrough at least regimen, in addition to similar AUC0–21 days, in tients on average would not be underdosed

. and Bittner, B. (2014), Use of a Population Pharmacokinetic ion of Trastuzumab. CPT: Pharmacometrics & Systems

l ti PK h f lopulation PK approach for clixed Dose SC formulation of

Pharmacometrics approach was used predict the right fixed dose of SC (nopredict the right fixed dose of SC (nobody weight adjusted) trastuzumabThe model predictions match Phase IId t l l t ti l lid ti gdata closely retrospectively validatingthe modelSimulations show that higher body g yweight subjects will not be underdosewith fixed SC dose

cade-Potelleret, F., Lemenuel-Diot, A., McIntyre, C., Brewster, M., Lum, Boach for the Clinical Development of a Fixed-Dose Subcutaneous Formulatimacology, 3: 1–9. doi: 10.1038/psp.2013.63

li i l d l t f linical development of Trastuzumab contd.

to n-n

II g g

ed Retrospective validation of mod

comparing to Phase III study

. and Bittner, B. (2014), Use of a Population Pharmacokinetic ion of Trastuzumab. CPT: Pharmacometrics & Systems

p g y

mpact of Pharmacometricmpact of Pharmacometricecisions (Sequel of Public

cometric analyses were cometric analyses were in regulatory decision in more than half of the

s. Of the 14 reviews that

A total of 31 NDAreview componenNDAs involved indquantitative eval

votal to approval related ns, 5 identified the need tional trials, whereas 6

d the burden of

quantitative evalpharmacometriciawere ranked as imregulatory decisio

85% f th 3d the burden of ting additional trials.

over 85% of the 3

ram VA et al, 2005 Oct 7;7(3):E503-12

BhattaramClin Pharmaco

Feb;81(2)

cs on the Regulatory cs on the Regulatory cations)

s included a PM nt. Review of dependent uation by FDA

Pharmacometric analyses selection of pediatric dosiregimens, approval of regithat had not been directlyuation by FDA

ans. PM analyses mportant in on making in 1 NDA

that had not been directlystudied in clinical trials anprovision of evidence of effectiveness to support ai t l t i l1 NDAs. pivotal trial

VA et al, ol Ther. 2007 :213-21.

Lee JA et al, Clin Pharmacokinet. 2

Oct;50(10):627-35.

eturn on Investment and

e selections (phase Ib, II, and III)y designsno-Go decisionsence on clinical development plansfolio prioritizations at milestonesp

mulationatric studies

ulatory interactions and filingsulatory interactions and filingssion making, cost-savings, cost-dance, and cycle-time improvements

G., de Alwis, D. P., Kerbusch, T., Stone, J. A. and n, S. R. B. (2014), Implementation of Quantitative and armacology in Large Pharma. CPT: Pharmacometrics & Systems gy, 3: 1–10. doi: 10.1038/psp.2014.40

Future

onclusions

MBDD is the rational approach to drugtangible benefitstangible benefitsPharmacometrics provide tools for imModeling and simulation is currently wg ydecision making in pharmaceutical ininteractionsQuantitative and Systems PharmacoloQuantitative and Systems Pharmacoloapproach to drug development that inmathematical modeling methods

g development and provided

mplementing MBDDwidely used in internal ydustry and regulatory

ogy is the bottoms up ogy is the bottoms-up nvolves higher order

cknowledgements

Mr. Shiva Subramanyam, SVP, InformaM academic and Professional Ad isorMy academic and Professional AdvisorGVK Bio Sciences Pvt. Ltd.PAPA

atics, GVK Bio Sciencesrsrs