Download haste less speed - Drug Development

PHARMACOKINETICS IN DRUG
DEVELOPMENT - more haste less speed
Dr. Jennifer Martin FRACP, PhD
Chair of Clinical Pharmacology
University of Newcastle
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OVERVIEW
• Introduction
• Pharmacokinetic principles
• Pharmacokinetic applications
• Pharmacokinetic parameters
• Pharmacokinetic characterisation
• Dosage form design
• Other issues – formulations, devices, registration in Australia
• Conclusion
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INTRODUCTION
• For clinical decision making new drugs for clinical use can be helpfully
divided into discovery and development programs (TGA).
• The former is often undertaken in University or biotechs, uses
knowledge and libraries of of the pharmacodynamic (PD) pathways or
putative targets for a particular disease, establishing suitable in vitro
models (or surrogate markers or IVIVC) to test biological activities
including cell death, effects on other pathways and activity.
• In the development stage, few potential candidates are chosen for
more thorough evaluation of the toxicity and efficacy of those agents.
Studies may include a drug device.
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PHARMACOKINETICS- what body does to drug
• Study and characterisation of the time course of ADME absorption, distribution, metabolism and excretion, and relationship
of these processes to therapeutic and toxicological effects (and
over time).
• Study of how specific mode of administration and specific
dose/dosing intervals are handled individuals, leading to the
specific drug concentrations in different tissues/organs (over time).
• Studying which part of drug will reach the site(s) of action and
exerts its pharmacodynamic (PD) action either directly or by
effects on pathways that have effect (e.g. nuclear transcription)
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PK PRINCIPLES
AND WHY IMPORTANT
• Improved safety and efficacy - AUC and Cmax related to outcome
• Better formulation e.g. transdermal/SR to reflect the required PK
parameter
• More appropriate route for indication e.g. transdermal
• Disease factors that affect PK e.g. dry or inflamed skin
• Select the right drug for a particular illness – concurrent therapies,
concurrent comorbidities
• Predict and explain drug-food and drug-drug interactions.
• Design an appropriate single or multiple dosage regimen.
• Therapeutic drug monitoring in individual patients – where
evidence exits
• Dosage adjustments in situations of altered physiology and drug
interactions.
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PK APPLICATIONS
• Rational Drug Design (quantitative structure
pharmacokinetic relationship)
• Drug Development
• Formulation Development
• Dosage Regimen – frequency, concomitant meds
• ADME study, Bioavailability and Bioequivalence
studies
• In Vitro –In Vivo correlation studies
• PK-PD Relationship
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PHARMACOKINETIC PARAMETERS
• First order elimination rate constant (K)
• Half life(t1/2)
• Clearance (Total, Renal, Hepatic etc.(Cl)
• Effective concentration range – Ctrough/Cmax
• Absorption rate constant (Ka)
• Extent of bioavailability (F)
• Fraction of dose excreted unchanged in urine (fu)
• Blood/plasma/tumour concentration ratio
• Apparent volume of distribution (Vd)
• Fraction of protein binding(Fb)
• Time to reach peak concentration(tmax)
• Toxic concentrations – relationship of effective and toxic
concentrations
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ADME
• Absorption: Site of administration to entering plasma. Factors
affecting – pH, cation binding, transit time, diet
• Distribution: Transfer from blood to the extravascular fluids (i.e
extracellular and intra cellular) and tissues.
• Metabolism: The chemical conversion of drug into another
chemical form, usually conversion of non polar to polar
• Elimination: This is the irreversible loss of drug from the site of
measurement e.g. bile
• Excretion: It is the irreversible loss of chemically unchanged
drug via faeces, urine, biliary secretion, saliva. sweat, milk,
respiratory.
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PK APPLICATIONS FOR DRUG DELIVERY SYSTEMS
• ADME affects onset and intensity of biological
response.
• PK is useful in design and utilisation of In-vitro models
that can evaluate dissolution characteristics of new
compound formulated as new drug formulations and
establish meaningful IVIVC.
• In design and development of new drug and their
appropriate dosage regimen.
• Safe and effective management of patients by
improving drug therapy (CONT.)
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PK Applications for drug delivery systems
• Knowledge of PK necessary to understand bioavailability – important
for new dosage forms and generics/biosimilars
• And to guide the bioavailability and bioequivalence studies
Eg: a drug with short half life can be formulated as controlled release
drugs by using polymers.
Or lower bioavailability of the drugs can be increased by using several
components like ß-cyclodextrin.
• A lot of drug carriers in new drug delivery systems – -Somes, micelles,
nanoparticles, microemulsion, nanosuspension, etc.
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DESIGNING A DOSE REGIMEN
Individualised Dosage Regimen: is based on the drug PK in the individual
Dosage Regimen on population Averages: based on one of several
models.
i)
Bayesian model: a priori estimates
ii)
Fixed model: Population average pharmacokinetic parameters are used
directly to calculate the dosage regimen.
ii)
Adaptive model: Based on both population average pharmacokinetic
parameters of the drug as well as patient variables (weight, age, sex, lean
body weight ?body surface area and known patient pathophysiology)
Empirical Dosage Regimen - designed by physician based on empirical
clinical data, personal experience and clinical observations
e.g. flat dosing, adjuvant (radiosensitising). NB there is a maximum (rate
of DNA intercalation, unravelling etc)
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DOSE CHOICE
• The magnitude of both therapeutic and toxic responses depends
on dose size – this relationship will differ for EVERY patient
• Dose size calculation also requires knowledge of amount of drug
absorbed after administration of each dose.
• Greater the dose size, greater the fluctuations between Css,
Cmax and min during each dosing interval and greater chances
of toxicity.
• ED50, ED90, ED100 – what is target?
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DOSING FREQUENCY
• The dosing interval (inverse of dosing frequency) is calculated
on the basis of half life of the drug.
• If the interval is increased and the dose is unchanged, Cmax,
Cmin & Cav decrease but the ratio Cmax/Cmin increases.
• Opposite is observed when dosing interval is reduced or dosing
frequency increased.
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Therapeutic Drug Monitoring
• Depending upon the drug and the disease, management of drug
therapy in individual patient can be by:
o Monitoring therapeutic effect (e.g. cancer outcome)
o Monitoring pharmacologic actions- pharmacodynamic (PD)
monitoring
o Monitoring plasma drug concentration - pharmacokinetic (PK)
monitoring.
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PK AND DRUG INTERACTIONS
• Absorption
– Transit time, effect of diet, concomitant PPI
• Bioavailability
– Complexation / chelation: Calcium, magnesium, or aluminum and iron
salts with tetracycline complexes with divalent cations, causing a
decreased bioavailability.
• Distribution
– Protein binding of warfarin/phenytoin, drug pumps at BBB (e.g. large
proteins)
• Metabolism
– P450 interactions
• Excretion
– Pgp pumps (digoxin and dihydropyridine calcium channel blockers)
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PK ENABLES INDVIDUALISATION
Important in drugs with a narrow therapeutic index
The aspects of a TDM service:
• Determine need for measuring serum drug concentrations.
• Assay for drug concentration in biological fluids.
• Perform pharmacokinetic evaluation of drug concentrations.
• Readjust dosage regimen, if necessary.
• Monitor serum drug concentrations to confirm.
• But who pays for this? Why worry when one dose fits all.
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Design of Dosage Regimen
• Overall aim of dosage regimen design is to achieve a target drug
concentration at the receptor site.
• The usual pharmacokinetics of the drug—including ADME
profile—need to be considered for each individual patient
• Pathophysiologic conditions, such as renal or hepatic disease, or
congestive heart failure, change the normal PK profile of the
drug, and dose must be carefully and regulalry adjusted with
appropriate monitoring.
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Drug Dosage Factors
The rate and extent of absorption affect drug bioavailability – do
we want high Cmax or target AUC
Patient Compliance:
• Cost of the medication.
• Complicated instructions.
• Multiple daily doses.
• Difficulty in swallowing.
• Adverse drug reactions.
Evaluation of Patient's Response:
• May need to review the drug and dosage regimen
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Measurement of Serum Drug Concentrations.
For most drugs, concentrations not doses relate to efficacy/toxicity
A single blood sample rarely gives sufficient information.
Several blood samples over a doing period are needed to clarify
the adequacy of the dosage regimen at least initially.
Dosage Adjustment.
The new dosage regimen should be calculated using the
pharmacokinetic parameters derived from the patient's serum
drug concentrations.
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DOSING OF DRUG IN SPECIAL
GROUPS - OBESITY
• Total, Lean or Ideal
• Evidence has shown that obese people are underdosed. They have
less toxicity, and poorer survival after adjustment for all other
factors known to affect survival.
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DOSING OF DRUG IN SPECIAL GROUPS - CHILDREN
• NOT SMALL ADULTS!
• How does dosing/BSA perform?
• Young’s rule (For children 2 years and above )
• Clark’s rule
• Fried’s rule
• Square meter surface area OR Mosteller’s
equation
SA in m2 = ( height
× weight ) ½
60
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• Child’s maintenance dose can be calculated from adult dose by
using the following equation :
Child’s Dose = SA of Child in m2
× Adult dose
1.73
Where 1.73 is surface area in m2 of an average 70 Kg adult .
• Since the surface area of a child is in proportion to the body
weight according to equation
SA ( in m2 ) = Body weight (in Kg )0.7
• The following relationship can also be written for child’s dose :
Child’s Dose = [ Weight of child in Kg ] 0.7 × Adult dose
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DOSING OF DRUG IN SPECIAL GROUPS - ELDERLY
WHO ADJUSTS?
Books say: Maintenance dose for a patient of any age (except
neonates and infants) when maintenance of same Css,av is desired
is :
Patient’s Dose
= (weight in Kg )0.7 (140 - Age in years) × Adult dose
1660
etc
What about renal clearance, for example
What about altered PD target in elderly
But even if you did know all this, how much are you going to
alter the dose by?
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DOSING OF DRUG IN SPECIAL GROUPS LIVER DISEASE
Influence of hepatic disease on drug PK is
unpredictable
as multiple effects that liver disease has on the drug metabolising
enzyme, binding and hepatic blood flow.
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DRUG DOSING IN RENAL DISEASE
Dose adjustment based on total body clearance. This is not
correlated with BSA, may be correlated with height but best
correlated with lean body weight, confirmed with TDM
We need to keep the concentration the same, thus the dose needs to
reduce.
C =
F
×
Cl /Dose
But how much to reduce? Depends on the reduction in CrCl and the fu
(new dose = (1-fu ) x (patients CrCl/normal CrCl) x actual dose)
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WHY PICKING THE RIGHT PD
TARGET IS IMPORTANT
RELATIONSHIP OF DOSE TO REDUCTION IN LDL
AND OVERALL MORTALITY
60
50
40
30
20
10
0
Rosuvastatin dose
(mg)
% reduction in LDL
1
1.5
% reduction in coronary events
2
2.5
% reduction in coronary mortality
5
20
% reduction in total mortality
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CONCLUSION
• Accurate and full knowledge of drug PK characteristics of drug and
factors effecting them for designing an effective dosing regiment AND
useful drug delivery systems.
• TDM is imperative, there is no other method yet validated that
improved individual outcomes.
• PK studies are important to identify variables that control the potential
success of drug delivery systems
• PK can be used to evaluate the products or delivery systems.
• Selection/design of proper experimental protocol is very important.
Suitable analytical method is necessary for proper estimation of
exposure.
• IV-IC correlation and PK /PD relationship/modelling help better design.
CONTROLLED RELEASE
FORMULATION
• CT is the target concentration to be maintained for T hour.
• Rate of elimination = K.CT.Vd or
1/2
CT.Vd
• Where K is the eliminnation rate constant of the drug.
• V is the apparent volume of distribution.
• Rate of absorption, Ka Xa should be equal to the rate of elimination to
maintain constant concentration. So ,
Ka Xa = K. CT Vd
• Then rate of release should be equal to the rates of absorption and
elimination. So,
Rate of release, Kr = K. CT Vd
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So,
Maintainence dose = rate of release x duration to be maintained
= K. CT Vd T
tmax
Log Ka
=
a
K
Where Ka is absorption rate constant
Loading dose =
CT Vd e-Ktmax
F
• Where F is bioavailability (fraction)
• Above is on the basis that drug confers one compartment distribution
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• Equation to express plasma concentration of controlled
release
product administered
C=
K0 (e-KT -1) e-Kt
K Vd
• Where K0 is zero order release rate
• ‘T’ is time of total release
• ‘t’ is anytime at which concentration is measured
• ‘t’ can be less than or equal or more than ‘T’
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