Download Population Pharmacokinetics

Clinical Research in Children
and the
Role of Population Pharmacokinetics Analyses
Univerzitetska dečja klinika
Beograd
Gregory B. Sivolapenko
Associate Professor
Laboratory of Pharmacokinetics, Director
University of Patras, Patras, Greece
DANI
UNIVERZITETSKE DEČJE KLINIKE
Mesto održavanja:
Sava centar, Beograd
09.-10.12.2011
The Drug Research & Development
Process
st
Preclinical decision 1 human
dose
Manufacturing
1st Submission 1st Approval
Early
Development
Research
Clinical
evaluation
(interventional
studies)
(median)
Number of 10,000
NCEs
Regulatory
Authorities:
EMA, FDA,
national
In vivo
animals
humans
In vitro
Duration
Late
Development
4.2yrs
33
1.3yrs
13
5.8yrs
10
1.4yrs
1-2
Marketing
Pharmacovigilance
Post-marketing research
(non-interventional):
- Post-marketing safety
studies
- Meta-analyses
- Epidemiological studies
- Patient compliance
programmes
The Drug Research & Development
in Children
 Most prescription drugs lack the information and the appropriate pharmaceutical
formulation to support their use in children.
 Without the provision of appropriate information concerning paediatric dosing, safety or
efficacy, physicians who treat children must decide between withholding treatment proven
effective in older patients or participating in the practice of off-label use by prescribing to
children products not studied for paediatrics.
 The use of unlicensed and off-label medicines in children is widespread.
 2 surveys in the Physicians Desk Reference showed that while 78% of products
lacked sufficient information or labeling regarding paediatric use in 1973, this had
increased to 81% in 19991,2
 In the EU, >50% of medicines used in children have never been actually studies in
this population, but only in adults, and not necessarily in the same indication or the
same disease3.
1.
2.
3.
Source: Gilman JT and Gal P. Clin. Pharmacokinet., 1992; 23 (1): 1-9
Source: Wilson JT. Paediatrics, 1999; 104 (3): 585-590
Source: Conroy et al. Br. Med. J.; 2000, 320: 79-82
The Drug Research & Development
in Children
 Problems resulting from the absence of suitably adapted medicinal products for the paediatric
population include:
 Inadequate dosage information which leads to increased risk of side-effects
 Ineffective treatment through under-dosage
 No availability to the paediatric population of therapeutic advances, suitable formulations
and routes of administration
 Market forces alone have proven insufficient to stimulate adequate research into, and the
development and authorisation of medicinal products for the paediatric population, mainly due to:
 Small market size
 Need for development of paediatric formulation(s)
 Practical and ethical challenges in paediatric clinical research
 5 subgroups in paediatric population:
Regulatory Legislations for
Paediatric Drug Development
 Over the past decade, regulatory legislations for drug development in
paediatric patients were passed worldwide, dramatically increasing the number of
drugs tested in and labeled for children.
 Both the USA FDA and the EU EMA established approaches that have been
successful in generating important new information about the safety and efficacy
of drugs used by children.
 Today, the need for more studies to obtain paediatric information for
medicines used in children becomes a matter of consensus on a global basis.
However, this should be done without compromising the well-being of paediatric
patients participating in clinical studies.
Regulatory Aspects of Paediatric Drug
Development: the US perspective
 1994 Pediatric Labeling Rule: Voluntary. Required drug manufacturer to survey existing data and
extrapolate efficacy from adults, supplementing with paediatric PK studies. Few studies done.
 1997 Pediatric Rule: Required the drug manufacturer of a new drug to submit before approval,
safety and effectiveness information in relevant paediatric age groups for the claimed indications.
 1997 FDA MA: Introduced a process in which the FDA developed a list of drugs for which
additional paediatric information might be beneficial, issuing a Written Request (WR) to the drug
manufacturer for paediatric studies. If companies submitted studies in response to a WR, 6 months
additional market exclusivity were granted.
 2002 BPCA: Renewed the 6-month exclusivity incentives, created a process for on and off-patent
drugs (involving government contracts), and mandated public disclosure of study results.
 2003 PREA: Put into legislation most components of the 1994 Pediatric Rule. Required paediatric
assessment for certain applications, a paediatric plan and the development of age-appropriate
formulation.
 2007 FDA AA: Reauthorised and extended BPCA and PREA until October 2012. Introduced the
Pediatric Review Committee (PeRC).
Regulatory Aspects of Paediatric Drug
Development: the US perspective
 As of the end of August 2010, the FDA received 610 Proposed Paediatric Study Requests, and issued
394 Written Requests.
 As of the end of August 2010, the FDA granted paediatric exclusivity for 173 approved drugs
 Between September 2007 and June 2010, 273 studies were completed under the BPCA and/or the
PREA under the FDA AA.
 As of the end of August 2010, the total number of products under BPCA and PREA were 38 and 65
respectively.
 Statistics published at: FDA web page “Pediatric Exclusivity Statistics”
Regulatory Aspects of Paediatric Drug
Development: the EU perspective
 1997 EC Round Table: Experts discussed paediatric medicines at the EMA.
 1998: The Commission supported the need for international discussion on the conduct of cinical
trials in children in the context of the International Conference of Harmonisation (ICH).
 2000 ICH Guideline E11: “Clinical investigation of medicinal products in the paediatric population”
became a European guideline.
 2002 Consultation Paper: The European Helath Council requested the Commission to take specific
action to remedy the problem of usage of unauthorised medicinal products in children. Commission
produced the Consultation Paper “Better medicines for children – proposed regulatory actions on
paediatric medicinal products”.
 2006: Paediatric Regulation agreed.
 2007: Paediatric Regulation 1901/2006 and its amendment 1902/2006 entered into force. For
products already on the market for use in adults, that are not covered by a patent or a supplementary
protection certificate, the regulation created a special application mechanism, the Paediatric Use
Marketing Authorisation (PUMA). A PUMA may contain data from new clinical studies, data from
pediatric studies in the literature or data from studies in dossiers of other approved products. This
mechanism was intended to provide an incentive for small and mid-size companies to develop products
for use in children. The regulation provides 10 years of market protection as a reward for conducting
clinical trials in paediatric patients for products approved under a PUMA.
EU Paediatric Regulation
EU 1901/2006 Paediatric Regulation
 The paediatric regulation aims to:
 facilitate the development and accessibility of medicinal products for
children
 ensure that medicinal products used to treat paediatric population are
subject to ethical research of high quality
 ensure that medicines for children are appropriately authorised
 improve the information available on the use of medicinal products in
the various paediatric populations
 The above objectives should be achieved without subjecting the paediatric
population to unnecessary clinical trials and without delaying the authorisation of
medicinal products for other age populations.
EU 1901/2006 Paediatric Regulation
 No marketing authorisation is granted for new products without compliance
with an agreed Paediatric Investigation Plan (PIP)
 The PIP is agreed with the Paediatric Committe (PDCO) of the EMA and is
binding to the applicant.
 The PDCO was established within the EMA by July 26th, 2007. The PDCO is
composed of:
 5 members from the CHMP
 1 member by each EU member state
 3 members representing health professionals (appointed by the EC)
 3 members representing patients’ associations (appointed by the EC)
 Between August 2007 and December 2009, the PDCO received 629 validated
PIP applications (961 indications, average 1.5 indication per product). Report to
EC, April 27, 2010, EMA, Section Paediatric Medicines.
 Approximately 700 PIPs have been agreed up today (EMA Workshop 29-30
November, 2011).
 Estimated >300 new paediatric trials will be initiated.
EEA 2005-2010: the number of paediatric
studies have increased
from ~600 studies to 949 studies
2005
2006
2007
2008
2009
Source: Paolo Tomasi, Head of Paediatric Medicines, European Medicines Agency, March 2011
2010
Therapeutic Areas of PIP Applications:
2007 – September 2011
Source: Paolo Rossi, PDCO, European Medicines Agency, DIA/EFGCP/EMA Paediatric Forum, September 2011
Enpr-EMA
Enpr-EMA: May 2010, the EMA with the scientific support of the PDCO, developed a
European network of existing national and international networks, investigators and
centres, with specific expertise in the performance of studies in the paediatric population.
 Objective:
 to coordinate studies related to paediatric medicinal products,
 to build up competence at a European level,
 to avoid unnecessary duplication of studies and testing in the paediatric
population.
 Operational goals:
 To link together existing networks
 To provide infrastructure for industry to conduct studies in children
 To define consistent and transparent quality standards within the European
network
 To harmonise clinical trial procedures
 To define strategies for resolving major challenges
 To communicate with external stakeholders
 Recognition criteria for membership
EMA Meetings on
Paediatric Clinical Research
 The EMA regularly organises and invites expression of interest for workshops
 Workshop on Ethics of Clinical Trials in Children, 29 & 30 November
2011, London, UK
 Joint DIA/EFGCP/EMA Paediatric Forum: the paediatric regulation in
its 5th year, 26 & 27 September 2011, London, UK
 3rd Workshop on Network of Paediatric Research, Enpr-EMA, 10 & 11
March 2011
Implementing Clinical Trials
in Children
 Drug development for paediatric patients is accompanied by various
challenges.
 Clinical studies in children are different from studies in adults, and the
planning and conduct of a paediatric study needs special attention since the
patient population is more vulnerable.
 Companies performing the paediatric studies as per the agreed PIP, frequently
encounter problems during the review by the Ethics Committees.
Implementing Clinical Trials
in Children
 Practical and ethical considerations are prominent.
 The main challenges are:
 Relative small number of paediatric patients
 Consent and assent
 Defining the first dose in children
 Sampling strategies
 Right methods for data collection and analysis
 Generate knowledge about safety, efficacy, pharmacokinetics and
pharmacodynamics
 Determine the right dose and dosing regimen
 Paediatric formulations
 Dosages according to weight?
 Hydration of skin?
 Oral dosing, mixing with food?
 Parenteral, volume, needle
 Presrervatives, colourants, sweeteners
 Taste or smell?
Experience with Ethical Review
of Paediatric Trials in the EU
The EUCROF Survey: September to October 2011
Concerns from Ethics Committees:
 Child Protection
 Change of IC, assent per age group
 Burden of participants, impact on schooling
 Exclusion of mentally disabled minors
 Study Procedure
 Blood volume collection, number of vena punctures
 Study Design
 Benefit of study to paediatric subject
 Clarifications of the size sample calculations
 Use of placebo
 Others
 Qualification of investigator and paediatric experience
 Insurance coverage
Modeling & Simulation in Clinical Research
 To comply with regulatory requirements but also to optimise paediatric drug
development, in terms of ethical, operational and scientific aspects, new and
appropriate strategies for clinical studies in children need to be developed.
 Computerised modeling and simulation techniques are beneficial tools for
optimisation of the design, increasing the knowledge gained from paediatric
studies.
Population Pharmacokinetics
The study of the sources and correlates of variability in drug concentrations
among individuals of a target population when clinically relevant doses of
the drug are administered.
 Advantages
 Analysis of sparse and unbalanced data
 Conduct of PK studies in special populations
 Estimation and explanation of variability
 Development of individualized dosing regimens
 Minimisation of participant number with reduced undue risk, distress,
pain and fear
 Disadvantages
 Complex methodology: mathematics, statistics, software packages
Population Pharmacokinetics
Patient
1
Patient
2
Traditional approach
Concentration
(ug/L)
10000.00
1000.00
100.00
10.00
1.00
0
1
2
3
4
Time (hrs)
5
6
Patient
1
Patient
2
Population approach
Concentration
(ug/L)
10000.00
1000.00
100.00
10.00
1.00
0
1
2
3
4
Time
(hrs)
5
6
Population Pharmacokinetics:
analysis methods
 Naive pooled data analysis
 Standard two-stage approach
 Bayesian two-stage approach
 Nonlinear mixed effects modeling (NONMEM):
 Widespread application in paediatric PK studies
 Simultaneous analysis of all data of the study population without ignoring the individual profiles
 Analysis of sparse and unbalanced data
 Samples taken during routine treatment can be used
 Relationships between covariates and parameters are explored
 Inter-, intra-individual and inter-occasion variability of the parameters can be estimated
 Drug-specific and biological system-specific properties can be identified
Population Pharmacokinetics
Nonlinear mixed effects modeling (NONMEM)
Structural Model
Fixed
effects
(e.g.
how
many
compartments)
Covariate Model
Statistical Model
(e.g. effect of BW, (e.g. how to model
age, sex, etc on Cl) variability)
Random
effects
Population Pharmacokinetics
Cj =D/Vdj*e(Clj/Vdj )*tj + εj
Source: Vozeh S. et al. Eur J Clin Pharmacol 1982;23:445-451
Population Pharmacokinetics
in Children
 Rapid maturation of organ functions important for drug absorption, distribution
and elimination is a specific feature of very young paediatric patients, therefore
changes in dose may be necessary for a patient over time, based on individual
maturation.
 Pharmacokinetic studies in the paediatric population reveal which dose will
produce blood levels similar to those observed in adults. In this way, adults’
efficacy data may be extrapolated to the paediatric population, provided that:
 The disease process is similar in adults and children and the outcome of therapy is
likely to be comparable
 The drug’s effect is well characterised with regard to important PK parameters,
and these parameters have been well correlated with activity in adults
Population Pharmacokinetics
 Total body elimination rate constant (k) and total body Clearance (Cl) are
considered to be the main drivers of differences in pharmacological drug response
in the paediatric population.
 Covariate models which describe the developmental changes of clearance
pathways in paediatric population pharmacokinetic models are crucial to
determine the first-in-child or evidence-based dosing regimen, as this covariate
relationship describing these changes can be directly used in drug dosing
algorithms.
A population PK model for morphine
and its glucuronides in children
 Morphine: metabolic pathway through glucuronidation by uridine
diphosphate glucuronosyltransferase (UGT) 2B7
 Question: if age (maturation) influences the capacity of glucuronidation
 Patients: 248 children
 preterm and term neonates, infants and children <3 y
 Dosing:
 Loading dose= 100 μg/kg
 Maintenance dose= 10 μg/kg/h (infusion)
Source: Knibbe C.A.J. et al. Clin Pharmacokinet 2009; 48(6):371-385
A population PK model for morphine
and its glucuronides in children
V1*BW
(M)
Qeq
V2*BW
(M)
Cl1*BW1.44
Cl2*BW1.44
V3*BW
(M3G)
V4*BW
(M6G)
Cl3*BW1.44 Cl4*BW1.44
 The influence of BW on the formation and
elimination clearances of the drug’s glucuronides was
best described by an allometric equation with an
exponential scaling factor of 1.44.
 Postnatal age (PNA) <10 d. was an additional
covariate for Cl1 and Cl2 (slower Cl in newborns
<10 d.)
------Population prediction in children <10 d.
Population prediction in children >10 d.
Individual prediction in children <10 d.
Individual prediction in children >10 d.
A population PK model for morphine
and its glucuronides in children
 Model-based simulations showed that a
narrower
range
of
morphine
10 μg/kg/h
and
when a maintenance dose of 10 μg/kg1.44/h
instead of 10 μg/kg/h is administered
 50% reduction of maintenance dose is
required in neonates <10 d due to reduced
glucuronidation capacity
Morphine concentration (ng/mL)
metabolite concentrations is achieved
10 μg/kg1.44/h
and
50% <10d.
 A linear equation was found to describe
the influence of BW on the volumes of
distribution
------ children <10 d.
children >10 d
Time (min)
Extrapolation of findings on UGT maturation
 It is reasonable to assume that that the results with morphine can be
extrapolated to all drugs metabolized by the same (iso)enzyme.
 Zidovudine is also metabolized by UGT 2B7
 It was found1 that the morphine covariate model could also describe Zidovudine
glucuronidation: Cln = Clmedian * BW1.44
 Population models that describe the maturation of specific elimination
pathways are system specific properties (drug independent).
 Maturation models can be applicable to drugs that are eliminated through the
same pathway expediting the development of pediatric population models.
 Propofol, UGT 1A8/9
1. Source: Krekels E.H.J. et al. Semi-physiological model for glucuronidation in neonates and infantsapplication to zidovudine. Br J Pharmacol 2011; in press
Regulatory Authorities and
Population Pharmacokinetics Analyses
 Several regulatory guidance documents refer explicitly to computerised modeling and
simulation methodology, therefore today there is a clear regulatory basis (and a need) for
using modeling and simulation in paediatric drug development:
“Guidance for Industry: population pharmacokinetics”, FDA, CDER/CBER, Febr. 1999
“Guidance for Industry: pharmacokinetics in patients with impaired hepatic function. Study design,
data analysis and impact on dosing and labeling”, FDA, CDER,
Clinical Pharmacology, May 2003
“Guidance for Industry: pharmacokinetics in pregnancy. Study design, data analysis and impact on
dosing and labeling” FDA, CDER, Clinical Pharmacology, October 2004
“Guideline on the role of pharmacokinetics in the development of medicinal products in paediatric
population”, EMEA, CHMP/EWP/147013/04corr., 28 June 2006
“Guideline on reporting the results
CHMP/EWP/185990/06, 21 June 2007
of
population
pharmacokinetic
analyses”,
EMEA,
“Reflection paper on the use of pharmacogenetics in the pharmacokinetic evaluation of medicinal
products” EMEA, 128517/06, 25 May 2007
The Application of
Population Pharmacokinetic Analyses
in the Drug Indications
Examples (US PDR):
 Humira (adalimumab, Abbott), arthritis, + age
 ReFacto (antihaemophilic factor VIII, Wyeth), haemorrhagic episodes, gen PK
 Avastin (bevacizumab, Genentech/Roche), met. Ca-colorectal, gen PK
 Erbitux (cetuximab, Merck), Ca-colorectal, + sex
 Ciproxin (ciprofloxacin, Bayer), antibacterial, - age
 Taxotere (docetaxel, Aventis), Ca-breast, NSCLC, Ca-prostate, gen PK
 Enbrel (etanercept, Amgen/Wyeth), arthritis, - age
 Neurontin (gabapentin, Pfizer), epilepsy, post-herpetic neuralgia, + age
 Gemzar (gemcitabine, Lilly), Ca-breast, NSCLC, Ca-pancreatic, gen PK,+sex/age
 Gleevec (imatinib, Novartis), CML, GIST, gen PK
 Zofron (ondansentron, GSK), prevention of nausea and vomiting, gen PK, - age
 Pegasys (IFN-a2a, Roche), hepatitis C, + age
 Viagra (sildenafil, Pfizer), erectile dysfunction, - alc
 Risperdal (risperidone, Janssen-Cilag), schizophrenia, - sex, - race
Source: J.Z. Duan, FDA, J.Clin.Pharm.Therapeutics, 32: 57-79, 2007
Conclusions
 Drug Research and Development is still an expensive and long process.
 Relatively less research had been done in paediatruc populations.
 A large number of drugs used in children do not possess adequate information
related to the safe and effective dosing scheme.
 Recent developments in US and EU regulations, augmented paediatric clinical
research, by voluntarily and/or compulsory measurements.
 US FDA and EU EMA strengthened the flow of information and facilitated
reportings in relation to paediatric clinical trials, in order to avoid unnecessary
repetitions.
 The recent EU Regulation 1235/2010 and Directive 2010/84/EU on
Pharmacovigilance, will enhance Post Marketing Safety Studies.
Conclusions
 It is anticipated that in the foreseeable future more drugs will be used on-label
by children, despite the difficulties in implementing a paediatric clinical trial.
 Concerns exist regarding the adequacy of paediatric research in younger age
groups (infants, toddlers, younger children) and the advances in paediatric
pharmaceutical formulations.
 Concerns about the overall increase of cost of paediatric medicines.
 Our growing knowledge on pharmacogenetics and pharmacogenomics will
result in more and more detailed paediatric clinical studies.
 Population pharmacokinetic studies is a tool for dose adjustments in any
paediatric sub population, with the least discomfort for the children, providing
information on the optimal safe, and effective dosing scheme.