Proposal of a new limited sampling strategy to predict CYP3A activity using a partial AUC of midazolam.
OBJECTIVE
Midazolam metabolic clearance to 1'-hydroxymidazolam is an accurate measure of CYP3A activity which requires extensive plasma and urine sampling. The objective of this study was to find a new limited sampling strategy (LSS) to predict midazolam metabolic clearance to 1'-hydroxymidazolam and subsequently CYP3A activity in an easy and reliable way, reducing costs and labour.


METHODS
The development of this LSS is based on data from an in vivo drug-drug interaction study carried out in our clinical research unit. Various partial AUCs of midazolam were calculated and correlated with metabolic clearance of midazolam to 1'-hydroxymidazolam by non-linear regression. The correlation with highest r (2) values was chosen to predict the midazolam metabolic clearance. Statistical significance of this method was verified by calculating the 95% confidence interval of the differences (%) between predicted and measured metabolic clearance of midazolam to 1'-hydroxymidazolam.


RESULTS
The midazolam partial AUC from 2 to 4 h after oral administration correlated best with metabolic clearance of midazolam to 1'-hydroxymidazolam with r (2) = 0.9816. This partial AUC comprised four midazolam concentrations at 2, 2.5, 3 and 4 h after oral administration of a midazolam solution. The 95% confidence interval of the differences between predicted metabolic clearance and measured metabolic clearance of midazolam to 1'-hydroxymidazolam was -0.97 to +13.2.


CONCLUSIONS
The determination of the partial AUC using four plasma samples from 2 to 4 h after oral administration of a midazolam solution is proposed to be an easy and reliable CYP3A phenotyping measure which of course needs to be validated in prospective clinical trials.
Katzenmaier
Stephanie
S
Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Markert
Christoph
C
Mikus
Gerd
G
D000759:Adjuvants, Anesthesia / Q000097:blood; D000284:Administration, Oral; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D008432:Mathematical Computing; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood* / Q000493:pharmacokinetics; D011237:Predictive Value of Tests; D013048:Specimen Handling / Q000379:methods*; D013997:Time Factors
D000759:Adjuvants, Anesthesia; C040081:1-hydroxymethylmidazolam; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam