CYP3A activity: towards dose adaptation to the individual

Abstract

While ample data is available on the choice appropriate phenotyping drugs (midazolam, alfentanil, aplrazolam, buspirone, triazolam), less clinical trial data is available concerning strategies to usefully guide dosing in the clinical practice. Implementation into the clinical routine necessitates further research to identify (1) an easy-to-use and cheap test for CYP3A activity that (2) adequately predicts drug exposure to (3) allow a sound decision on dose adaptation and hence (4) improve clinical outcome and/or reduce the intensity or frequency of adverse drug effects.

Semisimultaneous Midazolam Administration to Evaluate the Time Course of CYP3A Activation by a Single Oral Dose of Efavirenz

“…Hepatic P‐glycoprotein is a potentially confounding factor for the interpretation of CYP3A activity measured by the erythromycin breath test . The use of midazolam is much more reliable to assess CYP3A activity . In human immunodeficiency virus–infected patients on 600 mg/d efavirenz, the mean plasma ratio for 1‐OH‐midazolam/midazolam 30 minutes after oral administration of 0.075 mg midazolam performed after a median treatment period of 29 days was increased 3‐fold, but this change was highly variable .…”

“…10 The use of midazolam is much more reliable to assess CYP3A activity. 11 In human immunodeficiency virus-infected patients on 600 mg/d efavirenz, the mean plasma ratio for 1-OH-midazolam/midazolam 30 minutes after oral administration of 0.075 mg midazolam performed after a median treatment period of 29 days was increased 3-fold, but this change was highly variable. 7 In a previous study we observed significantly increased CYP3A activity 1 day after efavirenz administration with a midazolam area under the concentrationtime curve (AUC) that was 35% lower compared to baseline.…”

Toxicity and pharmacokinetic biomarkers for personalized non-small cell lung cancer treatment

“…Both genetic and environmental factors influence CYP3A activity. To determine the real-time CYP3A activity, the phenotype is usually assessed using a probe drug [115]. The probe drug is a substance exclusively metabolized by CYP3A that is monitored in combination with the CYP3A generated metabolite in urine and/or plasma.…”

Associations of theCYP3A5*3andCYP3A4*1Gpolymorphisms with the pharmacokinetics of oral midazolam and the urinary 6β-hydroxycortisol/cortisol ratio as markers of CYP3A activity in healthy male Chinese

“…Biomarkers for evaluation of in vivo CYP3A activity would be useful in new drug development to help to predict optimal dosage ranges for individuals and to improve therapeutic outcomes and minimize adverse effects. Several substrates of CYP3A have been used to provide exogenous biomarkers of CYP3A activity . Midazolam is a widely used probe for CYP3A4 activity as it is a pure substrate for CYP3A .…”

“…Several substrates of CYP3A have been used to provide exogenous biomarkers of CYP3A activity. [13][14][15] Midazolam is a widely used probe for CYP3A4 activity as it is a pure substrate for CYP3A. 16 Limited blood sampling strategies have been examined to simplify prediction of oral midazolam pharmacokinetics for CYP3A phenotyping.…”