Drug-drug interactions (DDI) are a common problem in drug development as well as in clinical practice. DDI may be pharmacokinetic or pharmacodynamic, or both: they occur when one drug affects the concentration and/or activity of another when co-administered. While DDI are sometimes intentional and beneficial, they’re more likely to be accidental and harmful – either by reducing efficacy, or by increasing concentrations, pharmacological effects, and adverse effects. Several blockbuster drugs have been withdrawn from the market as a result of DDI causing severe toxicity – for example, terfenadine, astemizole, and cisapride.
By 2050, the number of people worldwide aged >60 years will more than double. Polypharmacy is widespread in elderly people, so DDI is set to be increasingly common and important in the future. Hence the need to investigate potential DDI now, in early drug development.
At HMR, we have extensive experience of DDI trials in healthy volunteers. In those trials, we’ve identified clinically important safety, pharmacodynamic and/or pharmacokinetic interactions of IMP with
- drugs with a narrow therapeutic window, such as digoxin and aminophylline
- oral contraceptives
- anticonvulsants, such as valproate and phenytoin
- inhibitors of CYP3A4
- P-gp inhibitors and inducers
- inducers of hepatic metabolic enzymes1
- cocktails of ‘probe’ drugs to test for effects on panels of hepatic metabolic enzymes.
Genetic polymorphisms can have a major effect on how the body metabolises a drug: 6–8% of European subjects are poor metabolisers via CYP2D6, owing to polymorphism. We have plenty of experience of drug-subject interaction trials, investigating the effect of genetic polymorphism on pharmacokinetics in subjects of a particular genotype or phenotype.
We offer a full service – trial design; subject recruitment by phenotyping or genotyping; exclusion diets; in-house pharmacy; validated drug assays; data management; PK, pharmacodynamic, and statistical analysis; and report writing. We design all our DDI trials in accord with the appropriate guidance for industry2,3.
- Boyce M, Clark E, Johnston A, et al. Effects of single and repeated oral doses of TAK-013, a new non-peptide gonadotropin-releasing hormone antagonist, in healthy women. Fertility and Sterility. 2002; 78: S281–S282
- US Department of Health and Human Services, Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER). Guidance for industry, drug interaction studies – study design, data analysis, implications for dosing, and labeling recommendations. February 2012 (Draft)
- European Medicines Agency (EMA), Science Medicines Health, Committee for Human Medicinal Products (CHMP). Guideline on the investigation of drug interactions. 21 June 2012