What population PK analysis can be used for in drug development
The application of the population approach, otherwise known as non-linear mixed effects analysis, in new drug development is now widely mentioned in ICH, FDA and CHMP guidelines. This text summarises the different areas (special populations, etc.) where a population approach can be applied during Phase III instead of conducting specific studies. The usefulness of the population approach in Phase III is highly dependent upon that the inclusion/exclusion criteria are sufficiently relaxed to allow a sufficient range of the covariate to be studied. If insufficient patients are included over the range of the covariate, then specific studies may still be required.
Of course, while the FDA Guidance on Population Pharmacokinetics does not
focus on any specific covariate, any company planning to use a population PK
approach for determining the influence of potential covariates should refer
to this guidance.
It is recognised that the evaluation of the pharmacokinetics of a new drug in the paediatric population is not going to be included in the Phase III trials; however, the references in the guidelines made to the use of a population approach in this population have been included in this text for completeness. Links to each of the guidelines referred to are given at the bottom of this page.
Geriatrics
The first ever mention in regulatory guidelines of applying a population approach was made in the ICH E7 document, released in June 1993, and was to study the influence of age (specifically old age) on the pharmacokinetics of a drug. Perhaps surprisingly, the use of the approach to evaluate the influence of old age is not mentioned in any other guideline other than in the FDA guideline on gender differences where it states that a population screen could be used to detect a gender/age interaction. Paediatrics
The use of the population approach to evaluate drug pharmacokinetics in paediatric population is the subject of specific guidelines from ICH, FDA and CHMP, albeit the FDA guideline is still a draft despite having been released in 1998. The ICH and CHMP guidelines both briefly refer to the use of the population approach. The draft FDA guideline contains more information and states that it is the preferable approach for studying pharmacokinetics in the paediatric population.
The CHMP are currently writing a Points to Consider document that will specifically focus on pharmacokinetic studies in children and this document is expected to contain the use of a population approach.
Race
Only the ICG E5 guideline refers to the use of the population approach for characterising the influence of race on the pharmacokinetics of a drug. The guidance states “Pharmacokinetic assessment could be accomplished by formal PK studies or by applying population methods to clinical trials conducted either in a population relevant to the new region, or in the new region”.
Gender
The FDA released a guideline on the study and evaluation of gender differences in June 1993 ( 2 ). The guidance briefly mentions that a population screen can be used to detect gender differences, and also a gender/age interaction.
Renal Impairment
The first mention of applying a population approach to study the influence of renal impairment was made in the ICH E7 (Geriatrics) ( 1 ) guideline where it simply stated that such an approach could be used to rule out the influence of renal impairment. The more recent, specific, guidelines from both the FDA (1998) and CHMP (2003) on studying pharmacokinetics in patients with renal impairment both state that the approach can be used to characterise the influence of renal impairment on a new drugs pharmacokinetics. Both of the more recent guidelines state that sufficient patients representing a range of renal impairment should be included. The CHMP guidelines goes further and states that if patients with severe renal impairment are poorly represented or excluded from studies then a separate study in severe renal impairment may be necessary.
Hepatic Impairment
As is the case for renal impairment, the first mention of applying a population approach to study the influence of hepatic impairment was made in the ICH E7 (Geriatrics) guideline ( 1 ) where it simply stated that such an approach could be used to rule out the influence of hepatic impairment. The FDA released a draft guideline on impaired hepatic function in 1999 and where it says that “population pharmacokinetics can be useful if hepatically impaired patients are not excluded from Phase II/III studies. Population pharmacokinetic studies should include pre-planned analysis, evaluation of the severity of the disease, sufficient impaired patients, unbound drug concentrations and parent and active metabolite concentrations.”
The CHMP released a guideline on hepatic impairment in 2005 and which contains a paragraph on population pharmacokinetics. The guideline states a population PK approach may be useful to assess the impact of hepatic diseases in Phase II/III clinical trials but that the value of approach may be limited due to the low prevalence of hepatic disease in the general population. Population PK can be used to confirm the absence of an effect of hepatic disease on the PK of the drug.
Drug Drug Interactions
Again, the first mention of applying a population approach to study the influence of drug drug interactions was made in the ICH E7 (Geriatrics) guideline ( 1 ) where it simply stated that such an approach could be used to rule out their influence. Since then both the FDA and CPMP have released guidelines that contain much more specific information. The FDA guideline includes a section on population pharmacokinetic screen where it says that this can be valuable in characterising the impact of known or newly identified drug interactions. Such a population pharmacokinetic screen could also be used to detect un-suspected drug-drug interactions and as evidence for absence of the drug-drug interactions. The population pharmacokinetic screen can't be used as evidence of absence of an interaction that has been strongly suggested from in vitro or in vivo studies. The CPMP guideline includes a section on population pharmacokinetics where it says it is useful to screen for drug interactions and that the screen should be used as hypothesis generating. The best use of the population pharmacokinetic approach is to highlight unsuspected interactions and confirm absence of suspected non-interactions. A population pharmacokinetic analysis requires that there is a good dosing history for both drugs. The report describing the population pharmacokinetic analysis should present a confidence interval for the interaction effect.
FDA Final Guidance on population pharmacokinetics. Released February 1999.
http://www.fda.gov/cder/guidance/1852fnl.pdf
ICH Final Guideline on special populations: Geriatrics (E7). Released June 1993.
http://www.ich.org/pdfICH/e7.pdf
FDA Final Guidance for study and evaluation of gender differences. Released June 1993. http://www.fda.gov/cder/guidance/old036fn.pdf
ICH Final Guideline on clinical investigation of medicinal products in the paediatric population (E11). Released June 2000. http://www.ich.org/pdfICH/e11step4.pdf
FDA Draft Guidance on paediatric PK studies. Released November 1998.
http://www.fda.gov/cder/guidance/1970dft.pdf
CHMP Final Guidance on studies in children. Released September 1997.
http://www.emea.eu.int/pdfs/human/ewp/046295en.pdf
ICH Final Guideline on ethnic factors in the acceptability of foreign clinical data (E5). Released September 1998. http://www.ich.org/pdfICH/e5.pdf
FDA Final Guidance on PK in patients with impaired renal function. Released May 1998. http://www.fda.gov/cder/guidance/1449fnl.pdf
CHMP Final Guidance on pharmacokinetic studies in patients with renal impairment. Adopted June 2004. http://www.emea.eu.int/pdfs/human/ewp/022502en.pdf
FDA Final Guidance on pharmacokinetics in patients with impaired hepatic function. Released May 2003. http://www.fda.gov/cder/guidance/3625fnl.pdf
CHMP Final guideline on the evaluation of the pharmacokinetics of medicinal products in patients with impaired hepatic function. Adopted February 2005.
http://www.emea.eu.int/pdfs/human/ewp/233902en.pdf
FDA Final Guidance on in vivo drug interaction studies. Released November 1999.
http://www.fda.gov/cder/guidance/2635fnl.pdf
CHMP Final Guidance on drug interactions. Released June 1998.
http://www.emea.eu.int/pdfs/human/ewp/056095en.pdf
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