Midazolam AUC Research Articles

The ratio of 1-hydroxymidazolam (1-OH MDZ) to midazolam (MDZ) plasma concentrations is not an accurate measurement for CYP3A activity when using oral (PO) MDZ

Background The ratio of 1-OH MDZ to MDZ plasma concentrations has been proposed as an index to reduce sampling when measuring CYP3A activity. The aims of this study were to 1) assess if this ratio can be used to predict MDZ AUC when used as a CYP3A probe and 2) determine an optimal sampling strategy for the use of this ratio. Methods Data from 3 previous studies in 41 healthy adults were used. Subjects abstained from any drugs known to affect CYP3A. Plasma samples were collected at specified time points (Chr) after PO MDZ (0.075mg/kg) administration. 1-OH MDZ and MDZ concentrations were analyzed by LC/MS/MS. MDZ AUC0-∞ was determined by non-compartmental analysis. 20 subjects were randomly selected for the training set and the remaining 21 subjects for the validation set. The ratios of 1-OH MDZ to MDZ C0.5, 1, 2, 4, and 6 and AUC0-∞ were log-transformed. Stepwise multiple linear regression was used to derive equation models to predict MDZ AUC (AUCpred). Results One equation using C2 was statistically significant but had a low regression coefficient (R2=0.32): Log(AUCpred)=4.43–0.75[log(1-OH MDZ C2/MDZ C2)]. This equation did not meet the acceptable limits of bias and precision (Mean prediction error=−9.8%, Root mean square error=52.3%). Conclusions The ratio of 1-OH MDZ to MDZ plasma concentrations does not correlate with MDZ AUC and cannot be used to accurately predict MDZ exposure when PO MDZ is used as a CYP3A biomarker. Clinical Pharmacology & Therapeutics (2005) 77, P32–P32; doi: 10.1016/j.clpt.2004.12.016

Optimizing plasma sampling of oral (PO) midazolam (MDZ) as a biomarker for CYP3A activity

Background MDZ AUC is used to measure CYP3A activity and requires 5 to 8 blood samples. The aim of this study was to determine if minimized plasma sampling can be used to assess baseline CYP3A activity with PO MDZ. Methods 45 healthy adults taking no drugs known to affect CYP3A were included (data from 4 previous studies). Subjects received PO MDZ 0.075mg/kg. Plasma concentrations were collected at various time points (Chr) and analyzed by LC/MS/MS. MDZ AUC0-∞ was determined by non-compartmental analysis. MDZ C0.5, 1, 2, 4, and 6 and AUC0-∞ from 20 randomly selected subjects were log-transformed into normally distributed data and used to generate models to predict MDZ AUC (AUCpred). Models were validated using the MDZ data of the remaining 25 subjects and evaluated for bias and precision using mean prediction error (MPE) and root mean square error (RMSE) with acceptable limits of ≤5% and ≤15%, respectively. Results (see Table) Conclusions Two limited sampling models, using MDZ C0.5 and 6 or MDZ C0.5, 2, and 6 were acceptable and predictive of MDZ AUC. These models could reduce costs and inconvenience of greater numbers of samples when PO MDZ is used as a CYP3A biomarker. Clinical Pharmacology & Therapeutics (2005) 77, P32–P32; doi: 10.1016/j.clpt.2004.12.015 Sampling Time (hr) Log of AUCpred R2 %MPE %RMSE 0.5, 6 1.67 + 0.21(logC0.5) + 0.66(logC6) 0.97 −1.0 12.1 0.5, 2, 6 1.11 + 0.21(logC0.5) + 0.43(logC2) + 0.3(logC6) 0.99 −3.5 13.1

Effect of CYP3A-inhibitor and -inducer on the pharmacokinetics of intravenous midazolam in CYP3A5*3 allele carriers

Backgrounds CYP3A5 is found in the liver and intestinal mucosa and is expressed in 10 to 30% of human. Polymorphic CYP3A5 expression is strongly associated with a single nucleotide polymorphism, CYP3A5*3. In this study, we evaluated the effect of CYP3A-inhibitor and -inducer on the pharmacokinetics of intravenous midazolam in CYP3A5*3 allele carriers. Methods A single 1 mg of midazolam was administered intravenously to 9 healthy subjects classified to three genotypes, CYP3A5*1/*1, *1/*3, and *3/*3. After administration of itraconazole (200mg daily) for 4 days and rifampicin (600 mg daily) for 10 days, 1mg and 2mg of midazolam, respectively, were administered. Plasma concentrations of midazolam were determined by validated LC/MS/MS. Results The AUC of midazolam were not statistically different among three CYP3A5 genotypes. In contrast, mean AUC of midazolam after administration of itraconazole were 219±77%, 256±83%, and 280±60% of the before-treatment value in CYP3A5*1/*1, *1/*3, and *3/*3 genotypes, respectively. After administration of rifampicin, mean AUC of midazolam were 42±21%, 36±18%, and 36±15% of the before-treatment value in each genotypic group. Conclusion Pharmacokinetics of intravenous midazolam were altered more sensitively in CYP3A5*3 carriers than in homozygous CYP3A5*1 carriers to the effect of CYP3A-modulators such as itraconazole and rifampicin although these data were not statistically different. Clinical Pharmacology & Therapeutics (2004) 75, P38–P38; doi: 10.1016/j.clpt.2003.11.143

Limited Sampling Strategy to Predict AUC of the CYP3A Phenotyping Probe Midazolam in Adults: Application to Various Assay Techniques

Midazolam clearance is used to phenotype hepatic CYP3A activity but requires multiple plasma samples following a single intravenous dose. The authors evaluated the use of a limited sampling scheme, using different assay techniques to determine the reproducibility of such a strategy in estimating midazolam AUC. Seventy-three healthy adults received midazolam as a single intravenous bolus dose. At least eight plasma samples were collected from each subject and were assayed using either LC/MS/MS or electron capture gas chromatography. Eleven subjects were randomly selected for the training set using stepwise linear regression to determine relationships between midazolam plasma concentrations and AUC. Validation of the predictive equations was done using the remaining 62 subjects. Mean percent error (MPE), mean absolute error (MAE), and root mean square error (RMSE) were calculated to determine bias and precision. Based on the training set, five models were generated with coefficients of determination ranging from 0.87 to 0.95. Validation showed that MPE, MAE, and RMSE values were acceptable for three of the models. Intrasubject reproducibility was good. In addition, training set datafrom one institution were able to predict data from the other two institutions using other assay techniques. Minimized plasma sampling mayprovide a simpler method for estimating midazolam AUC for CYP3A phenotyping. A limited sampling strategy is more convenient and cost-effective than standard sampling strategies and is applicable to more than one assay technique.

Limited Sampling Strategy to Predict AUC of the CYP3A Phenotyping Probe Midazolam in Adults: Application to Various Assay Techniques

Limited Sampling Strategy to Predict AUC of the CYP3A Phenotyping Probe Midazolam in Adults: Application to Various Assay Techniques

Simvastatin Does Not Affect CYP3A Activity, Quantified by the Erythromycin Breath Test and Oral Midazolam Pharmacokinetics, in Healthy Male Subjects

Potential for inhibition of CYP3A activity by simvastatin, an HMG-CoA reductase inhibitor, was evaluated in 12 healthy male subjects who received placebo or 80 mg of simvastatin, the maximal recommended dose, once daily for 7 consecutive days. On day 7, an intravenous injection of 3 microCi [14C N-methyl]erythromycin for the erythromycin breath test (EBT) was coadministered with a 2 mg oral solution of midazolam. The values for percent 14C exhaled during the first hour (for EBT) and the pharmacokinetic parameters of midazolam (AUC, Cmax, t1/2) were not affected following multiple once-daily oral doses of simvastatin 80 mg. The 95% confidence interval was 0.97 to 1.18 for EBT and 0.99 to 1.23 for midazolam AUC. In addition, the total urinary recoveries of midazolam and its 1'-hydroxy metabolites (free plus conjugate) obtained from both treatments were not statistically different (p > 0.200). These data demonstrate that multiple dosing of simvastatin, at the highest recommended clinical dose, does not significantly alter the in vivo hepatic or intestinal CYP3A4/5 activity as measured by the commonly used EBT and oral midazolam probes.

Optimal plasma sampling to predict AUC of the CYP3A probe midazolam (MID)

Optimal plasma sampling to predict AUC of the CYP3A probe midazolam (MID)

The Effect of the Systemic Antimycotics, Itraconazole and Fluconazole, on the Pharmacokinetics and Pharmacodynamics of Intravenous and Oral Midazolam

We studied the interaction of azole antimycotics with intravenous (IV) and oral midazolam using a cross-over design in 12 volunteers, who ingested placebo, itraconazole, or fluconazole for 6 days. A 7.5-mg dose of midazolam was ingested on the first day, 0.05 mg/kg was administered IV on the fourth day, and 7.5 mg orally on the sixth day. Itraconazole reduced the clearance of IV midazolam by 69% and fluconazole reduced the clearance of IV midazolam by 51% (P < 0.001). A single dose of itraconazole and fluconazole increased the area under the oral midazolam concentration-time curve [AUC(0-infinity)] 3.5-fold (P < 0.001) and the peak concentration two-fold (P < 0.05) compared to placebo. On the sixth day the AUC(0- infinity) of oral midazolam was almost seven times greater with itraconazole (P < 0.001) and 3.6 times greater with fluconazole (P < 0.001) than without the antimycotics. The psychomotor effects of midazolam were also profoundly increased (P < 0.001). The psychomotor tests demonstrated only a weak interaction between the antimycotics and IV midazolam. When bolus doses of midazolam are given for shorttime sedation, the effect of midazolam is not increased to a clinically significant degree by itraconazole and fluconazole, and it can be used in normal doses. However, the use of large doses of IV midazolam increases the risk of clinically significant interactions also after IV midazolam. Use of oral midazolam with itraconazole and fluconazole should be avoided. (Anesth Analg 1996;82:511-6)

Safety of intravenous and oral midazolam in subjects receiving itraconazole or fluconazole

Midazolam is metabolized by cyto-chrome P-450 3A enzymes (CYP3A). We have studied the possible interaction of two inhibitors of CYP3A, itraconazole and fluconazole, with intravenous and oral midazolam in twelve volunteers using a cross-over study design. The subjects were given an oral placebo, itraconazole (200 mg) or fluconazole (200 mg) for six days. The first challenge dose of 7.5 mg oral midazolam was ingested on the first day of pretreatment, the second dose 0.05 mg kg−1 was administered intravenously on the fourth day, and the third dose 7.5 mg orally on the sixth day. Plasma samples were collected and psychomotor performance measured. (Figure 7)Fig. 7: (abstract 9). Concentrations (mean±SEM) of midazolam in plasma after an oral or intravenous dose of midazolam following pretreatment with itraconazole (•), fluconazole (▴) or placebo (▸).On the first day of itraconazole or fluconazole treatments, the area under the oral midazolam concentration-time curve [AUC(0-∞)] was three to four times higher (P<0.001) and peak concentration (Cmax) two or three times higher (P<0.05) than those with the placebo. On the sixth day the effect of itraconazole on AUC(0-∞) and Cmax of oral midazolam was almost twice that on the first day (P<0.001), the effect of fluconazole was similar. The higher concentrations of oral midazolam during treatment with antimycotics were associated with an increased effect (P<0.001). Itraconazole and fluconazole reduced the clearance of intravenous midazolam by 69% and 51% respectively (P<0.001) but the volume of distribution of midazolam at steady-state remained unchanged. The psychomotor tests demonstrated only a relatively weak interaction between the antimycotics and intravenous midazolam. The interaction between itraconazole and fluconazole and midazolam administered orally is of major clinical significance. Prescription of oral midazolam for patients receiving intraconazole and fluconazole should be avoided. When small bolus doses of midazolam are given for sedation during minor surgical procedures, the effect of midazolam is probably not increased to a clinically significant degree. However care should also be exercised after intravenous midazolam; doses should be adjusted and patients monitored closely.