biopharmaceutical aspects of exploratory microdose … stevens.pdf · exploratory microdose and...

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Biopharmaceutical aspects of exploratory microdose

and microtracer

clinical studies

Lloyd Stevens PhD

Senior Research Fellow

Quotient Clinical

Nottingham, UK

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Scope

• What is a microdose

and....what is a microtracer

• Walk through “fit-for-purpose”

IV product manufacture

• Microdose

and microtracer

study designs

• Examine the biopharmaceutical outcomes from various microdose

and microtracer

study designs

• Utility and caveats

• Summary and take home messages

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Microdosing...... Phase 0 Generation of human pharmacokinetic and ADME profile data to support candidate selection

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What is a microdose?

Exploratory PK and ADME profiling study ........ Regulatory guidance given in ICH M3 (R2) Issued in June 2009 for implementation Jan 2010http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002720.pdf

• Reduced toxicology package to support microdoses

in healthy

male subjects•

A microdose

defined as a total dose ≤

100 μg

AND •

Total dose ≤

1/100th NOAEL and ≤1/100th pharmacologically

active dose (scaled on mg/kg) •

IV/PO 2-way crossover = 50μg IV and 50μg PO... Usually 14C-API

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002720.pdf

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Bioanalysis to support microdosing

High sensitivity permits low doses...

Microdosing instigated by biomedical application of Accelerator

Mass Spectrometry (AMS)•

Quantifies individual carbon atoms by mass (12C, 13C and 14C)

• Enabled detection down to <femtog/mL

(10-15g/mL)•

Specificity provided via LC fractionation with AMS detection

• Able to produce radiochromatographic

profile for 14C vs

LC fraction

622 June 2011

Bringing it all together...... Established practices

14C-API &Product

ManufacturingUnder GMP

Regulatoryframework

LC-AMS and

LC-MS/MS

Clinical and logistics

know-howICH M3

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Utility and perspectives....

• ~25-30 NCE studies/programs undertaken to date•

First study undertaken in 2004/5

• Significant initial scientific scepticism•

Linearity (transporters, clearance, solubility) and extrapolation to therapeutic doses

• Additive cost (time and money)

• Now starting to see changes in the marketplace•

Design is dictated by the questions to be answered

• Back-up programs may be the most useful application

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Scientific and commercial drivers for exploratory microdose

studies

• Bioavailability for investor confidence IV/PO

• Oral bioavailability IV/PO

• Half-life determination and oral bioavailability IV/PO

• Human metabolite hunt IV/PO

• Lead candidate selection from 3 IV/PO

• PK characterisation of lead compound IV/PO

• Back-up candidate selection from 4 + lead IV/PO (LC-MS/MS)

• Clearance and Abs Bio single compound IV/PO (LC-MS/MS)

• Exposure to potential carcinogenic metabolite PO

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Do / will we always need AMS?•

LC-MS/MS approaching low pg/mL;10-12g/mL)

• 2 recent Phase 0 studies achieved decisions on cold data

•

Despite being dosed with 14C compound•

AMS data runs cancelled

• Triggered thoughts of sequential sampling strategy:

•

Dose with 14C compound•

Initial sample analysis by cold LCMSMS assay

•

Progress to AMS analysis only if required•

Currently evaluating operational and scientific impacts

NB: this is only relevant for Phase 0, microdosing, not ivMicrotracerTM

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‘Phase 0’ Microdose

case study

Selection of lead candidate from three

Poster: AAPS Conference 2009, Los Angeles, CA

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Three compound comparison at microdose

0.01

0.1

1

10

0 2 4 6 8 10 12Time (hours post-dose)

Con

cent

ratio

ns o

f rad

ioac

tivity

(ng

equi

vale

nts/

mL)

Mean [14C]-ZPQ-AFN-1492 (IV)Mean [14C]-AFN-1492 (Oral)

0.01

0.1

1

10


Con

cent

ratio

ns o

f rad

ioac

tivity

(ng

equi

vale

nts/

mL)


0.01

0.1

1

10


Con

cent

ratio

ns o

f rad

ioac

tivity

(ng

equi

vale

nts/

mL)


Route tmax(h)

Cmax(ng/mL)

AUCinf(ng/mL*h)

Cl(L/h)

Vd(l)

t½(h)

Fabs(%)

AFN 1492 IV 9.0 11.5 23.7 1.4Oral 0.9 1.3 2.8 0.9 31.5

AFN 1534 IV 23.6 4.3 1850 29.9Oral 6.3 0.5 19.1 30.0 81.0

AFN 1672 IV 8.0 12.5 3.3 1.8Oral 0.7 2.2 5.5 1.6 67.9

AFN 1672AFN 1534AFN 1492

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Example 1: “Develop-ability” issues arising

from a microdose study (100µg)

1.00

10.00

100.00

1000.00

10000.00

0 4 8 12 16 20 24

Time (hours post-dose)

Con

cent

ratio

n (p

g/m

L)

total 14C (oral)ONO-8539 (oral)total 14C (IV)ONO-8539 (IV)

Total radioactivityIV and oral doses

Parent drug IV and oral

“Developability” issuesRapid absorption

High clearance

Low oral Fabs

Dose number/solubility

Short half-life (<2h)

High metabolic burden

Q…

Metabolism p’kinetics/activity

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Biopharmaceutical outcomes from intravenous and oral microdose

studies in compound selection (Phase 0)

Utility and caveats

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Study designs and PK/ADME deliverables

Design: IV/PO crossover with 14C-API microdose:

Plasma & urine/faeces LC-AMS assayDeliverables for a microdose

• Absolute bioavailability of oral solution

• Total and renal clearance

• Distribution volumes

• IV pharmacokinetics for modelling and simulation

• Half-life

•

14C-PK profiles•

Mass balance recovery

• Metabolite burden

• Metabolite profiles (IV & PO)

Design: IV/PO crossover with cold API

Plasma & urine LC-MS/MS assayDeliverables for a microdose

• Absolute bioavailability

• Total and renal clearance

• Distribution volumes

• IV pharmacokinetics for modelling and simulation

• Half-life

•No guarantee of adequate sensitivity

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Biopharmaceutic outcomes from microdosing

• BCS classification:

High absolute bioavailability is directly indicative of high permeability

• First pass metabolism & F

IV data + ClT

= ClR

+ ClH

If Cl is hepatic and approximates to liver blood flow (1500ml/min) the drug will undergo extensive first pass loss on oral dosing

ClH

= QH

x ERX

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Microdosing: Biopharmaceutical outcomes

Microdose to therapeutic dose extrapolation

•

Pharmacokinetic derived non-linearities: •

capacity limited clearance

• transporter

capacity (P-gP, OAT, OATP)

• Physicochemical non-linearities•

Solubility

• Biopharmaceutical challenges identified•

Absolute bioavailability ... Inferences regarding permeability

• Clearance.... Implications regarding first pass metabolism

• PK characteristics will not support QD dosing

• Modified delivery required to alter PK profile

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ivMicrotracer

Generating IV pharmacokinetic data for oral drugs in early development

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ivMicrotracer

Imagine having IV PK data for every molecule coming through into clinical development

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ivMicrotracer study design

A rapid and cost effective approach to generate iv PK data

Time (hr)

Dru

g C

once

ntra

tion

• Oral therapeutic dose•

Measured by LC-MS/MS

• ivMicrotracer

14C-dose administered when oral dose is at Cmax•

IV dose ≤1/200th

of PO dose•

Measured by LC-AMS

• ivMicrotracer

can be “piggy-

backed” onto any standard

clinical development study

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Why is IV data only accessible now and not in the past?

Historical barriers for access to IV data•

Cost and time for IV toxicity testing and human safety, tolerability assessments

ICH M3 (R2) •

“In some situations it could be appropriate to carry out a clinical microdose

study using the i.v. route on a product intended for oral administration and for which an oral nonclinical

toxicology package already exists. In this case the i.v. microdose can be qualified by the existing oral toxicity studies as described in Table 1 or Table 3, Approach 3, where adequate exposure margins have been achieved. It is not recommended to investigate i.v. local tolerance of the drug substance in this situation because the administered dose is very low (100 μg

maximum). If a novel i.v. vehicle is being employed then local tolerance of the vehicle should be assessed.”

........ together with GMP product manufacture

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Rapid development and manufacture of iv drug products: “Fit-for-clinic”

drug product

“Cold”API

“Hot”API

IMPD

< 10 weeks

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“Piggy-back” IVmicrotracers

• IV Microtracers

are incorporated into any other bioavailability or

PK study•

Food interaction

• Drug-drug interaction (victim drug before and after perpetrator)

• Bioavailability or bioequivalence for formulation change

• Effect of age and gender

• Dose proportionality; particularly in cases of non-linear PK

• SAD and MAD (1st

and at steady state)

• Regional absorption study

• Human ADME (14C oral with piggy-back 13C IV microtracer)

• Pro-drug PO plus “piggyback”

IV parent pro-drug and/or active moeity

• Not just “piggy-back”

on oral dosing

• Non-oral routes: inhaled, nasal, rectal, dermal plus ANOther

routes

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Biopharmaceutical outcomes from exploratory IV microtracer

studies

Utility and caveats

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Study designs and deliverables

Design: 14C-API IV microtracer on top of

a cold therapeutic dose (AbsBio)Biopharmaceutic

Deliverables:

• Absolute bioavailability of a therapeutic dose

• Evaluation of permeability (high Fabs

)•

IV PK for modelling and simulation in formulation design (GastroPlus

etc)•

Total clearance and distribution volumes, half-life

• Mass balance recovery (IV only)

•

14C-PK profiles•

Systemic metabolite burden

• Metabolite profile (IV only)

• Metabolite identification (PO only)

Blo

od L

evel

of D

rug

IV 14C-tracer doseNormalized data

IV 14C-tracer doseNormalized data

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Biopharmaceutics utility of IV microtracer

data

Decision making regarding potential formulation “fix”

for

poor and variable bioavailability

Absolute bioavailability and absorption limited elimination.... “flip-flop”

pharmacokinetics

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Summary and take home messages

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MicrodosingCompound selection and characterisation:•

Identification of potential “develop-ability”

issues•

Bioavailability and variability

• Shape of PK profile

• Indication of potential need for MR delivery at therapeutic doses

•

Assessment of permeability from Fabs

•

Contribution of FPM to poor bioavailability•

Feed real human IV and oral PK data into “bottom up”

modelling tools•

Symcyp, Cyprotex, GastroPlus

•

Exercise caution in extrapolating bioavailability and oral PK for drugs with likely solubility limitations

•

Be aware of potential capacity limitations for transporters and metabolism

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IV MicrotracerIV PK and AbsBio:•

IV PK desirable for MR formulation definition, modelling & IVIVC

•

Assessment of the pharmaceutical challenge (Fabs

)•

Assessment of permeability....... BCS

•

Access to absolute bioavailability data to support regulatory need•

Australian authorities

•

FDA•

Straightforward to accomplish if 14C-API is available

•

If you had 14C-API available, why wouldn’t you implement a “piggyback”

IV Microtracer

on to a future clinical bioavailability or PK study ?

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Thank you

Email: [email protected]

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