1. International Transporter Consortium Commentary on Clinically Important Transporter Polymorphisms
Heli Parviainen, Helsinki
Giacomini KM, Balimane PV, Cho SK, Eadon M, Edeki T, Hillgren KM, Huang S-M, Sugiyama Y, Weitz D, Wen Y, Xia CQ, Yee SW, Zimdahl H, Niemi M, on behalf of the International Transporter Consortium
Clinical Pharmacology & Therapeutics 94(1), 23-26
2013

2. Objectives What are transporter polymorphisms?
Why should they be considered in drug development?
Recommendations on how polymorphisms can be taken into account in drug development
Benefits of pharmacogenomic studies
Heli Parviainen, Helsinki

3. Transporter polymorphisms
Genetic mutations
SNP = Single Nucleotide Polymorphism
Nonsynonymous polymorphism changes the amino acid sequence
Missense: amino acid exchange
Nonsense: premature stop codon
Can affect transporter activity
Heli Parviainen, Helsinki

4. Transporter polymorphisms in pharmakokinetics
One of the main reasons for variation in drug exposure and response
Effect depends on precise genotype, phenotype and transporter specificity
This should be taken into accound in drug development
Preclinical and clinical studies
Heli Parviainen, Helsinki

5. Preclinical studies
Objective is to identify transporters involved in the pharmacokinetics of the new drug
In silico
In vitro
Genetically engineered animals
Relative contribution of different transporters
Heli Parviainen, Helsinki

6. Clinical studies: DDI study
An inhibitor of the transporter is used
Inhibitors are usually not fully specific
Provides information on the maximum possible effect of a polymorphism
Interpretation of the data?
Nonspecificity
Relative to therapeutic window
Heli Parviainen, Helsinki

7. Clinical studies: Pharmacogenomic studies
Separate studies or part of phase I – III studies
Testing strategy guided by data obtained in preclinical studies and DDI studies
Preselecting test subjects by genetic profile can be concidered
Heli Parviainen, Helsinki

8. Advantages of concidering polymorphisms in drug development
Information on the safe use of the new molecule
Information on the relative importance of particular transporters in the pharmacokinetcs of a new drug
Information on the pharmacokinetic and pharmacodynamic mechanisms of the new drug
Heli Parviainen, Helsinki

9. Take home messages
Transporter polymorphisms can have a large effect on the pharmacokinetics of a drug
Pharmacogenomic data can provide new insights on the pharmacokinetic and pharmacodynamic properties of a new drug
Pharmacogenomics can guide the safe use of a new drug
Heli Parviainen, Helsinki