Impact of the CYP3A5 genotype on midazolam pharmacokinetics and pharmacodynamics during intensive care sedation.
OBJECTIVE
Information is lacking on whether the CYP3A5 genotype affects the disposition and effects of midazolam during the long-term intensive care sedation of patients. This study was undertaken to estimate whether the CYP3A5 genotype can explain a relevant portion of pharmacokinetic interindividual variability.


METHODS
We determined the CYP3A5 genotype in 71 Caucasian patients who underwent long-term sedation during intensive care treatment. We then assessed the relation between the genotype and both the plasma concentrations of midazolam and 1'-OH-midazolam in 645 plasma samples and the simultaneously estimated Ramsay sedation score, both of which were recorded during routine midazolam drug monitoring.


RESULTS
Eight patients had the CYP3A5*1/*3 genotype and 63 patients the CYP3A5*3/*3 genotype. The concentration-dose ratio [C/D; plasma concentration of midazolam (ng/ml) divided by the rate of infusion (mg/h); expressed as the mean (95% confidence interval)] was 87.4 (70.8, 108.9) for the *3/*3 patients and 79.0 (48.9, 129.0) for *1/*3 patients. The corresponding data for infusion rate (IR; in mg/h), Ramsay score (RS) and the ratio 1'-OH-midazolam concentration/midazolam concentration (ROH) for *3/*3 and *1/*3 patients were IR 7.4 (6.2, 8.6) vs. 11.4 (4.9, 17.9), RS 5.4 (5.2, 5.6) vs. 5.3 (4.2, 6.0) and ROH 0.11 (0.09, 0.13) vs. 0.17 (0.11, 0.26), respectively.


CONCLUSIONS
The CYP3A5*1/*3 genotype did not lead to an apparently lower midazolam concentration/dose ratio or Ramsay score values. As the present sedation procedure during intensive care therapy may be described as a physician closed-loop titration towards Ramsay scores of 4 +/- 1, our data do not indicate that prior determination of the genotype will result in better care or economic savings.
Fromm
Martin F
MF
Institute of Experimental and Clinical Pharmacology and Toxicology, Clinical Pharmacology and Clinical Toxicology, Friedrich-Alexander-University Erlangen-Nuremberg, Germany. martin.fromm@pharmakologie.med.uni-erlangen.de
Schwilden
Helmut
H
Bachmakov
Iouri
I
König
Jörg
J
Bremer
Frank
F
Schüttler
Jürgen
J
D000368:Aged; D016292:Procedural Sedation; D003422:Critical Care; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000494:pharmacology; D016903:Drug Monitoring / Q000379:methods*; D005838:Genotype; D006801:Humans; D006993:Hypnotics and Sedatives / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008874:Midazolam / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008875:Middle Aged