Studies on intrinsic and extrinsic sources of variability in pharmacokinetics and pharmacodynamics

Johanna Mercke Odeberg

Studies on intrinsic and extrinsic sources of variability in pharmacokinetics and pharmacodynamics

Johanna Mercke Odeberg

Division of Clinical Chemistry and Pharmacology

Research output: Thesis › Doctoral Thesis (compilation)

Abstract

Variability in pharmacokinetic and pharmacodynamic parameters between individuals can be due to intrinsic and extrinsic factors. In this thesis three different areas regarding sources of variability have been investigated. 1. Formulation properties as an extrinsic source of variability. Lipophilic substances often have poor oral bioavailability and high inter- and intraindividual variability. High fat meals can increase the bioavailability. Two lipophilic substances, astaxanthin and cyclosporine, were incorporated in different lipid based formulations, given orally to healthy volunteers, and shown to alter the bioavailability when compared to reference substances. The combination of different lipid excipients, their ratios and the degree of drug incorporation were factors shown to affect the drug bioavailability. The use of a rational formulation approach in the study with cyclosporine gave successful information in a limited number of trials. 2. Intrinsic and extrinsic sources of variability in the pharmacokinetics and pharmacodynamic of desmopressin. To evaluate factors that can cause variability both the pharmacokinetics and pharmacodynamics have to be investigated. Desmopressin is a synthetic analogue of the antidiuretic hormone vasopressin. We studied in humans if different levels of water hydration had any influence on especially the pharmacokinetics, and found no statistical evidence for that. An indirect response model was described and verified for the concentration-effect relationship. Further, we investigated sex differences and the impact of concomitant medication with piroxicam , and we found a difference in the pharmacodynamics of desmopressin, but not in the pharmacokinetics.

3. Genetic polymorphism as an intrinsic source of variability in drug metabolism and drug transport. We investigated, in a Swedish cohort (248 individuals) and in a human diversity panel (HDP) (DNA from 14 ethnicities), the prevalence of different polymorphisms and haplotypes in the UGT1A- and MDR1-genes, both being associated with variations in pharmacokinetics. Also, to estimate UGT1A genotype-dependent glucuronidation efficiency, we used the endogenous substrate bilirubin as an indicator. We found that several of the genetic variants investigated in the UGT1A-gene and also the SNP (exon 26, C3435T) in the MDR1 gene are common in the cohort. The HDP indicated differences in prevalence of the allelic variants due to ethnicity. Three major haplotypes of the UGT1A-gene constitute 84% of the allelic variants.

Tools for optimisation, prediction and individualisation of drug treatment are important for attaining the aim of explaining and reducing variability in drug response.

Original language	English
Qualification	Doctor
Awarding Institution	Division of Clinical Chemistry and Pharmacology
Supervisors/Advisors	Mercke Odeberg, Johanna, Supervisor
Award date	2005 Oct 8
Publisher	Department of Clinical and Experimental Pharmacology, Lund University
ISBN (Print)	91-85439-83-5
Publication status	Published - 2005

Bibliographical note

Defence details

Date: 2005-10-08
Time: 09:00
Place: Föreläsningssal 1, Centralblocket, Universitetssjukhuset Lund

External reviewer(s)

Name: Peterson, Curt
Title: Professor
Affiliation: Klinisk farmakologi, Linköpings universitet

---

<div class="article_info">Johanna Mercke Odeberg, Å. Lignell, A. Pettersson and P. Höglund. 2003. Oral bioavailability of the antioxidant astaxanthin in humans is enhanced by incorporation of lipid based formulations. European Journal of Pharmaceutical Sciences, vol 19 pp 299-304. Elsevier B.V.</div>
<div class="article_info">Johanna Mercke Odeberg, P. Kaufmann, K. G. Kroon and P. Höglund. 2003. Lipid drug delivery and rational formulation design for lipophilic drugs with low oral bioavailability, applied to cyclosporine. European Journal of Pharmaceutical Sciences, vol 20 pp 375-382. Elsevier B.V.</div>
<div class="article_info">J. Mercke Odeberg, J. Andrade, K. Holmberg, P. Höglund and U. Malmqvist. . Prevalence of polymorphisms in the genes for UGT1A (and corresponding haplotypes) and MDR1 in a Swedish cohort and in a human diversity panel, and the relationship between UGT1A polymorphisms and bilirubin plasma levels in males and females. (manuscript)</div>
<div class="article_info">Johanna Mercke Odeberg, T. Callreus, T. Lundin, E. B. Roth and P. Höglund. 2004. A pharmacokinetic and pharmacodynamic study of desmopressin: evaluating sex differences and the effect of pre-treatment with piroxicam, and further validation of an indirect response model. Journal of Pharmacy and Pharmacology, vol 56 pp 389-398. The authors</div>
<div class="article_info">T. Callreus, Johanna Mercke Odeberg, S. Lundin and P. Höglund. 1999. Indirect-response modeling of desmopressin at different levels of hydration Journal Of Pharmacokinetics and Biopharmaceutics, vol 27 pp 513.529. Plenum Publishing company</div>

Subject classification (UKÄ)

Medicinal Chemistry
Pharmacology and Toxicology

Free keywords

toxikologi
pharmacy
pharmacognosy
Pharmacological sciences
Medicin (människa och djur)
Medicine (human and vertebrates)
genetic polymorphisms(UGT1A-and MDR1 gene)
indirect response model
desmopressin
oral lipid based formulations
farmaci
Farmakologi
toxicology
farmakognosi

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Cite this

@phdthesis{b96d485c21214350ac0058fea53868d0,

title = "Studies on intrinsic and extrinsic sources of variability in pharmacokinetics and pharmacodynamics",

abstract = "Variability in pharmacokinetic and pharmacodynamic parameters between individuals can be due to intrinsic and extrinsic factors. In this thesis three different areas regarding sources of variability have been investigated. 1. Formulation properties as an extrinsic source of variability. Lipophilic substances often have poor oral bioavailability and high inter- and intraindividual variability. High fat meals can increase the bioavailability. Two lipophilic substances, astaxanthin and cyclosporine, were incorporated in different lipid based formulations, given orally to healthy volunteers, and shown to alter the bioavailability when compared to reference substances. The combination of different lipid excipients, their ratios and the degree of drug incorporation were factors shown to affect the drug bioavailability. The use of a rational formulation approach in the study with cyclosporine gave successful information in a limited number of trials. 2. Intrinsic and extrinsic sources of variability in the pharmacokinetics and pharmacodynamic of desmopressin. To evaluate factors that can cause variability both the pharmacokinetics and pharmacodynamics have to be investigated. Desmopressin is a synthetic analogue of the antidiuretic hormone vasopressin. We studied in humans if different levels of water hydration had any influence on especially the pharmacokinetics, and found no statistical evidence for that. An indirect response model was described and verified for the concentration-effect relationship. Further, we investigated sex differences and the impact of concomitant medication with piroxicam , and we found a difference in the pharmacodynamics of desmopressin, but not in the pharmacokinetics. 3. Genetic polymorphism as an intrinsic source of variability in drug metabolism and drug transport. We investigated, in a Swedish cohort (248 individuals) and in a human diversity panel (HDP) (DNA from 14 ethnicities), the prevalence of different polymorphisms and haplotypes in the UGT1A- and MDR1-genes, both being associated with variations in pharmacokinetics. Also, to estimate UGT1A genotype-dependent glucuronidation efficiency, we used the endogenous substrate bilirubin as an indicator. We found that several of the genetic variants investigated in the UGT1A-gene and also the SNP (exon 26, C3435T) in the MDR1 gene are common in the cohort. The HDP indicated differences in prevalence of the allelic variants due to ethnicity. Three major haplotypes of the UGT1A-gene constitute 84% of the allelic variants. Tools for optimisation, prediction and individualisation of drug treatment are important for attaining the aim of explaining and reducing variability in drug response.",

keywords = "toxikologi, pharmacy, pharmacognosy, Pharmacological sciences, Medicin (m{\"a}nniska och djur), Medicine (human and vertebrates), genetic polymorphisms(UGT1A-and MDR1 gene), indirect response model, desmopressin, oral lipid based formulations, farmaci, Farmakologi, toxicology, farmakognosi",

author = "{Mercke Odeberg}, Johanna",

note = "Defence details Date: 2005-10-08 Time: 09:00 Place: F{\"o}rel{\"a}sningssal 1, Centralblocket, Universitetssjukhuset Lund External reviewer(s) Name: Peterson, Curt Title: Professor Affiliation: Klinisk farmakologi, Link{\"o}pings universitet --- <div class={"}article_info{"}>Johanna Mercke Odeberg, {\AA}. Lignell, A. Pettersson and P. H{\"o}glund. 2003. Oral bioavailability of the antioxidant astaxanthin in humans is enhanced by incorporation of lipid based formulations. European Journal of Pharmaceutical Sciences, vol 19 pp 299-304. Elsevier B.V.</div> <div class={"}article_info{"}>Johanna Mercke Odeberg, P. Kaufmann, K. G. Kroon and P. H{\"o}glund. 2003. Lipid drug delivery and rational formulation design for lipophilic drugs with low oral bioavailability, applied to cyclosporine. European Journal of Pharmaceutical Sciences, vol 20 pp 375-382. Elsevier B.V.</div> <div class={"}article_info{"}>J. Mercke Odeberg, J. Andrade, K. Holmberg, P. H{\"o}glund and U. Malmqvist. . Prevalence of polymorphisms in the genes for UGT1A (and corresponding haplotypes) and MDR1 in a Swedish cohort and in a human diversity panel, and the relationship between UGT1A polymorphisms and bilirubin plasma levels in males and females. (manuscript)</div> <div class={"}article_info{"}>Johanna Mercke Odeberg, T. Callreus, T. Lundin, E. B. Roth and P. H{\"o}glund. 2004. A pharmacokinetic and pharmacodynamic study of desmopressin: evaluating sex differences and the effect of pre-treatment with piroxicam, and further validation of an indirect response model. Journal of Pharmacy and Pharmacology, vol 56 pp 389-398. The authors</div> <div class={"}article_info{"}>T. Callreus, Johanna Mercke Odeberg, S. Lundin and P. H{\"o}glund. 1999. Indirect-response modeling of desmopressin at different levels of hydration Journal Of Pharmacokinetics and Biopharmaceutics, vol 27 pp 513.529. Plenum Publishing company</div>",

year = "2005",

language = "English",

isbn = "91-85439-83-5",

publisher = "Department of Clinical and Experimental Pharmacology, Lund University",

type = "Doctoral Thesis (compilation)",

school = "Division of Clinical Chemistry and Pharmacology",

}

TY - THES

T1 - Studies on intrinsic and extrinsic sources of variability in pharmacokinetics and pharmacodynamics

AU - Mercke Odeberg, Johanna

N1 - Defence details Date: 2005-10-08 Time: 09:00 Place: Föreläsningssal 1, Centralblocket, Universitetssjukhuset Lund External reviewer(s) Name: Peterson, Curt Title: Professor Affiliation: Klinisk farmakologi, Linköpings universitet --- <div class="article_info">Johanna Mercke Odeberg, Å. Lignell, A. Pettersson and P. Höglund. 2003. Oral bioavailability of the antioxidant astaxanthin in humans is enhanced by incorporation of lipid based formulations. European Journal of Pharmaceutical Sciences, vol 19 pp 299-304. Elsevier B.V.</div> <div class="article_info">Johanna Mercke Odeberg, P. Kaufmann, K. G. Kroon and P. Höglund. 2003. Lipid drug delivery and rational formulation design for lipophilic drugs with low oral bioavailability, applied to cyclosporine. European Journal of Pharmaceutical Sciences, vol 20 pp 375-382. Elsevier B.V.</div> <div class="article_info">J. Mercke Odeberg, J. Andrade, K. Holmberg, P. Höglund and U. Malmqvist. . Prevalence of polymorphisms in the genes for UGT1A (and corresponding haplotypes) and MDR1 in a Swedish cohort and in a human diversity panel, and the relationship between UGT1A polymorphisms and bilirubin plasma levels in males and females. (manuscript)</div> <div class="article_info">Johanna Mercke Odeberg, T. Callreus, T. Lundin, E. B. Roth and P. Höglund. 2004. A pharmacokinetic and pharmacodynamic study of desmopressin: evaluating sex differences and the effect of pre-treatment with piroxicam, and further validation of an indirect response model. Journal of Pharmacy and Pharmacology, vol 56 pp 389-398. The authors</div> <div class="article_info">T. Callreus, Johanna Mercke Odeberg, S. Lundin and P. Höglund. 1999. Indirect-response modeling of desmopressin at different levels of hydration Journal Of Pharmacokinetics and Biopharmaceutics, vol 27 pp 513.529. Plenum Publishing company</div>

PY - 2005

Y1 - 2005

N2 - Variability in pharmacokinetic and pharmacodynamic parameters between individuals can be due to intrinsic and extrinsic factors. In this thesis three different areas regarding sources of variability have been investigated. 1. Formulation properties as an extrinsic source of variability. Lipophilic substances often have poor oral bioavailability and high inter- and intraindividual variability. High fat meals can increase the bioavailability. Two lipophilic substances, astaxanthin and cyclosporine, were incorporated in different lipid based formulations, given orally to healthy volunteers, and shown to alter the bioavailability when compared to reference substances. The combination of different lipid excipients, their ratios and the degree of drug incorporation were factors shown to affect the drug bioavailability. The use of a rational formulation approach in the study with cyclosporine gave successful information in a limited number of trials. 2. Intrinsic and extrinsic sources of variability in the pharmacokinetics and pharmacodynamic of desmopressin. To evaluate factors that can cause variability both the pharmacokinetics and pharmacodynamics have to be investigated. Desmopressin is a synthetic analogue of the antidiuretic hormone vasopressin. We studied in humans if different levels of water hydration had any influence on especially the pharmacokinetics, and found no statistical evidence for that. An indirect response model was described and verified for the concentration-effect relationship. Further, we investigated sex differences and the impact of concomitant medication with piroxicam , and we found a difference in the pharmacodynamics of desmopressin, but not in the pharmacokinetics. 3. Genetic polymorphism as an intrinsic source of variability in drug metabolism and drug transport. We investigated, in a Swedish cohort (248 individuals) and in a human diversity panel (HDP) (DNA from 14 ethnicities), the prevalence of different polymorphisms and haplotypes in the UGT1A- and MDR1-genes, both being associated with variations in pharmacokinetics. Also, to estimate UGT1A genotype-dependent glucuronidation efficiency, we used the endogenous substrate bilirubin as an indicator. We found that several of the genetic variants investigated in the UGT1A-gene and also the SNP (exon 26, C3435T) in the MDR1 gene are common in the cohort. The HDP indicated differences in prevalence of the allelic variants due to ethnicity. Three major haplotypes of the UGT1A-gene constitute 84% of the allelic variants. Tools for optimisation, prediction and individualisation of drug treatment are important for attaining the aim of explaining and reducing variability in drug response.

AB - Variability in pharmacokinetic and pharmacodynamic parameters between individuals can be due to intrinsic and extrinsic factors. In this thesis three different areas regarding sources of variability have been investigated. 1. Formulation properties as an extrinsic source of variability. Lipophilic substances often have poor oral bioavailability and high inter- and intraindividual variability. High fat meals can increase the bioavailability. Two lipophilic substances, astaxanthin and cyclosporine, were incorporated in different lipid based formulations, given orally to healthy volunteers, and shown to alter the bioavailability when compared to reference substances. The combination of different lipid excipients, their ratios and the degree of drug incorporation were factors shown to affect the drug bioavailability. The use of a rational formulation approach in the study with cyclosporine gave successful information in a limited number of trials. 2. Intrinsic and extrinsic sources of variability in the pharmacokinetics and pharmacodynamic of desmopressin. To evaluate factors that can cause variability both the pharmacokinetics and pharmacodynamics have to be investigated. Desmopressin is a synthetic analogue of the antidiuretic hormone vasopressin. We studied in humans if different levels of water hydration had any influence on especially the pharmacokinetics, and found no statistical evidence for that. An indirect response model was described and verified for the concentration-effect relationship. Further, we investigated sex differences and the impact of concomitant medication with piroxicam , and we found a difference in the pharmacodynamics of desmopressin, but not in the pharmacokinetics. 3. Genetic polymorphism as an intrinsic source of variability in drug metabolism and drug transport. We investigated, in a Swedish cohort (248 individuals) and in a human diversity panel (HDP) (DNA from 14 ethnicities), the prevalence of different polymorphisms and haplotypes in the UGT1A- and MDR1-genes, both being associated with variations in pharmacokinetics. Also, to estimate UGT1A genotype-dependent glucuronidation efficiency, we used the endogenous substrate bilirubin as an indicator. We found that several of the genetic variants investigated in the UGT1A-gene and also the SNP (exon 26, C3435T) in the MDR1 gene are common in the cohort. The HDP indicated differences in prevalence of the allelic variants due to ethnicity. Three major haplotypes of the UGT1A-gene constitute 84% of the allelic variants. Tools for optimisation, prediction and individualisation of drug treatment are important for attaining the aim of explaining and reducing variability in drug response.

KW - toxikologi

KW - pharmacy

KW - pharmacognosy

KW - Pharmacological sciences

KW - Medicin (människa och djur)

KW - Medicine (human and vertebrates)

KW - genetic polymorphisms(UGT1A-and MDR1 gene)

KW - indirect response model

KW - desmopressin

KW - oral lipid based formulations

KW - farmaci

KW - Farmakologi

KW - toxicology

KW - farmakognosi

M3 - Doctoral Thesis (compilation)

SN - 91-85439-83-5

PB - Department of Clinical and Experimental Pharmacology, Lund University

ER -

Studies on intrinsic and extrinsic sources of variability in pharmacokinetics and pharmacodynamics

Abstract

Bibliographical note

Subject classification (UKÄ)

Free keywords

UN SDGs

Fingerprint

Cite this