Use of microdose phenotyping to individualise dosing of patients.
Administering the right amount of the right drug at the right time is a key mission of clinical medicine. This comprises dose adaptation according to a patient's intrinsic and extrinsic factors influencing drug disposition. Several biomarkers are available for dose adaptation; still, prediction of individual drug disposition may be improved. Phenotyping is the quantification of drug metabolism with probe substrates specific to drug-metabolising enzymes. This allows measurement of baseline metabolism and changes after modulation of drug metabolism. This article explores the concept of phenotyping using pharmacologically ineffective microdoses of probe substrates to obtain information on drug metabolism. Several probe drugs such as midazolam for cytochrome P450 3A have already been used, but validation of other microdosed probe drugs, analytical procedures and drug formulations still face some challenges that have to be overcome. Since microdosed probe drugs have no risk of adverse drug reactions or interference with therapy, more widespread use is possible. This allows drug-drug interaction data to be safely obtained during first-in-man studies, enhancing the clinical safety of human healthy volunteers and patients in clinical trials, and, most importantly, allows determination of the drug-metabolising phenotype in severely ill patients. With harmless probe drugs at hand quantifying drug metabolism and adapting the dose accordingly, a phenotyping-based dosing strategy could become reality, offering the possibility of individualised drug therapy with reduced adverse effects and fewer therapeutic failures.
Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Nicolas
N
Hohmann
Walter E
WE
Haefeli
Gerd
G
Mikus
D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D004347:Drug Interactions; D016903:Drug Monitoring; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D010641:Phenotype; D057285:Precision Medicine / Q000379:methods*
D004364:Pharmaceutical Preparations