건강한 한국인에서 미다졸람 집단약동학 분석: CYP3A 매개 약물상호작용 평가 Population Pharmacokinetics of Midazolam in Healthy Koreans: Effect of Cytochrome P450 3A-mediated Drug-drug Interaction원문보기
Objective: Midazolam is mainly metabolized by cytochrome P450 (CYP) 3A. Inhibition or induction of CYP3A can affect the pharmacological activity of midazolam. The aims of this study were to develop a population pharmacokinetic (PK) model and evaluate the effect of CYP3A-mediated interactions among k...
Objective: Midazolam is mainly metabolized by cytochrome P450 (CYP) 3A. Inhibition or induction of CYP3A can affect the pharmacological activity of midazolam. The aims of this study were to develop a population pharmacokinetic (PK) model and evaluate the effect of CYP3A-mediated interactions among ketoconazole, rifampicin, and midazolam. Methods: Three-treatment, three-period, crossover study was conducted in 24 healthy male subjects. Each subject received 1 mg midazolam (control), 1 mg midazolam after pretreatment with 400 mg ketoconazole once daily for 4 days (CYP3A inhibition phase), and 2.5 mg midazolam after pretreatment with 600 mg rifampicin once daily for 10 days (CYP3A induction phase). The population PK analysis was performed using a nonlinear mixed effect model ($NONMEM^{(R)}$ 7.2) based on plasma midazolam concentrations. The PK model was developed, and the first-order conditional estimation with interaction was applied for the model run. A three-compartment model with first-order elimination described the PK. The influence of ketoconazole and rifampicin, CYP3A5 genotype, and demographic characteristics on PK parameters was examined. Goodness-of-fit (GOF) diagnostics and visual predictive checks, as well as bootstrap were used to evaluate the adequacy of the model fit and predictions. Results: Twenty-four subjects contributed to 900 midazolam concentrations. The final parameter estimates (% relative standard error, RSE) were as follows; clearance (CL), 31.8 L/h (6.0%); inter-compartmental clearance (Q) 2, 36.4 L/h (9.7%); Q3, 7.37 L/h (12.0%), volume of distribution (V) 1, 70.7 L (3.6%), V2, 32.9 L (8.8%); and V3, 44.4 L (6.7%). The midazolam CL decreased and increased to 32.5 and 199.9% in the inhibition and induction phases, respectively, compared to that in control phase. Conclusion: A PK model for midazolam co-treatment with ketoconazole and rifampicin was developed using data of healthy volunteers, and the subject's CYP3A status influenced the midazolam PK parameters. Therefore, a population PK model with enzyme-mediated drug interactions may be useful for quantitatively predicting PK alterations.
Objective: Midazolam is mainly metabolized by cytochrome P450 (CYP) 3A. Inhibition or induction of CYP3A can affect the pharmacological activity of midazolam. The aims of this study were to develop a population pharmacokinetic (PK) model and evaluate the effect of CYP3A-mediated interactions among ketoconazole, rifampicin, and midazolam. Methods: Three-treatment, three-period, crossover study was conducted in 24 healthy male subjects. Each subject received 1 mg midazolam (control), 1 mg midazolam after pretreatment with 400 mg ketoconazole once daily for 4 days (CYP3A inhibition phase), and 2.5 mg midazolam after pretreatment with 600 mg rifampicin once daily for 10 days (CYP3A induction phase). The population PK analysis was performed using a nonlinear mixed effect model ($NONMEM^{(R)}$ 7.2) based on plasma midazolam concentrations. The PK model was developed, and the first-order conditional estimation with interaction was applied for the model run. A three-compartment model with first-order elimination described the PK. The influence of ketoconazole and rifampicin, CYP3A5 genotype, and demographic characteristics on PK parameters was examined. Goodness-of-fit (GOF) diagnostics and visual predictive checks, as well as bootstrap were used to evaluate the adequacy of the model fit and predictions. Results: Twenty-four subjects contributed to 900 midazolam concentrations. The final parameter estimates (% relative standard error, RSE) were as follows; clearance (CL), 31.8 L/h (6.0%); inter-compartmental clearance (Q) 2, 36.4 L/h (9.7%); Q3, 7.37 L/h (12.0%), volume of distribution (V) 1, 70.7 L (3.6%), V2, 32.9 L (8.8%); and V3, 44.4 L (6.7%). The midazolam CL decreased and increased to 32.5 and 199.9% in the inhibition and induction phases, respectively, compared to that in control phase. Conclusion: A PK model for midazolam co-treatment with ketoconazole and rifampicin was developed using data of healthy volunteers, and the subject's CYP3A status influenced the midazolam PK parameters. Therefore, a population PK model with enzyme-mediated drug interactions may be useful for quantitatively predicting PK alterations.
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문제 정의
The current study was designed to develop a population PK model of midazolam in healthy male Korean subjects. The PK samples were collected according to a serial schedule after dosing to ensure a precise estimate of the PK parameters.
제안 방법
A nonparametric bootstrap analysis was performed to validate the reliability and stability of the model developed. The 95% confidence intervals (CIs) were calculated for each PK parameter using the 2.
2. Basic model diagnosis plot constructed using final pharmacokinetic (PK) model (A) Observations (DV) vs. population predictions (PRED) and (B) DV vs. individual predictions (IPRED). (C) Individual weighted residuals (IWRES) vs.
Moreover, the PK of midazolam after IV administration was assessed and the interactions of the orally administered midazolam with ketoconazole or rifampicin should have been considered separately. Despite these limitations, this study provides the compartmental PK analysis of the most representative CYP3A substrate, midazolam, with or without a representative inhibitor or inducer. In addition, the impact of genetic polymorphism of CYP3A5 was assessed as a covariate.
Each subject arrived in the morning and received rifampicin (Rifodex®, Chong Kun Dang Pharmaceutical Corp., Seoul, Korea) 600 mg orally once daily on day 13 through 21.
I appreciate Dr. Joo-Youn Cho and staffs of Department of Clinical Pharmacology & Therapeutics, Seoul National University & Hospital for performing the clinical study and quantifying the bio-analysis.
Similar to the previous midazolam study results, the timeconcentration profiles of midazolam in this study were more fitted to a three-compartment model that they were to a twoor one-compartment model. The basic structures have been selected as three-compartment models in several studies including midazolam drug interaction study.
The adequacy and performance of the developed population PK model were evaluated using a visual predictive check. We simulated 200 data sets using the final PK model.
The clinical trial was performed at the Seoul National University Hospital Clinical Trials Center, and the determination of midazolam concentration was conducted in the Department of Clinical Pharmacology & Therapeutics, Seoul National University College of Medicine and Hospital.
DNA was extracted from the blood samples using a QIAamp DNA blood mini kit (QIAGEN GmbH, Germany) and stored at −20℃. The genotypes were determined using the TaqMan Genotyping Assays (Applied Biosystems, Foster City, CA, USA) with a 7500 Real-Time polymerase chain reaction (PCR) System (Applied Biosystems, Foster City, CA, USA). The data was analyzed using the 7500 Real-Time PCR System software (version 2.
We simulated 200 data sets using the final PK model. The model adequacy was assessed by comparing the median and the 5th and 95th percentiles calculated from simulated concentrations with measured concentrations.
This study was designed to establish a compartmental PK model for midazolam under CYP3A inhibition and induction status with ketoconazole and rifampicin co-administration, respectively. The population PK parameters of midazolam were estimated, and a feasible relationship between the PK parameters and various covariates including CYP3A5 genotypes was also investigated.
대상 데이터
The data used were obtained from 24 enrolled healthy Korean male subjects6) who were aged 20 to 38 years and weighed 56.8 to 87.3 kg. The study protocol was approved by the Institutional Review Board of Seoul National University Hospital (SNUH).
The demographics of the subjects are summarized in Table 1, which shows there were 24 male subjects in the midazolam model building dataset. The enrolled subjects were aged 20 to 38 years and weighed 56.8 to 87.3 kg. The model building population revealed that the minor allele frequency of CYP3A5*3 A6956G was 0.
2 describes the diagnostic goodness-of-fit plots for the final model. The visual predictive checks for the final model with the full data set of 24 subjects are shown in Fig. 3. The majority of the observations were located within the prediction interval, and 1993 runs were successfully minimized during the bootstrap resampling analysis.
이론/모형
A population PK model was constructed, and the concentration-time data were fitted to the compartmental models with nonlinear mixed effects regression techniques using NONMEM® (version 7.2, ICON Development Solutions, Ellicott City, MD, USA).
2, ICON Development Solutions, Ellicott City, MD, USA). The first order conditional estimation (FOCE) with interaction method was used.
The plasma midazolam concentration-time curves were well explained using a three-compartment model (Fig. 1). Because the CL of midazolam differed among the three phases, control, inhibition, and induction, we included the treatment factor while estimating CL.
성능/효과
In conclusion, in the present study, a population PK model of midazolam was developed under CYP3A inhibition and induction status in healthy male Korean subjects. The model described the influence of two drugs simultaneously.
A nonparametric bootstrap analysis was performed to validate the reliability and stability of the model developed. The 95% confidence intervals (CIs) were calculated for each PK parameter using the 2.5th, and 97.5th percentiles of 2000 bootstrap estimates and the final PK parameters were subsequently compared with bootstrap estimates.
993). The intra- and inter-day accuracy ranged from 96.6% to 99.6% and 99.4% to 102%, respectively, and the intra- and inter-batch precision, expressed as the coefficient of variation (CV, %), were less than 10%.
참고문헌 (12)
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