ABSTRACT
A drug-drug interaction (DDI) trial of cytochrome P450 3A (CYP3A) is a necessary part of early-phase trials of drugs mainly metabolized by this enzyme, but CYP3A DDI clinical trials do not have a standard design, especially for Chinese people. We aimed to offer specific recommendations for CYP3A DDI clinical trial design. This was an open, three-cycle, self-controlled study. Healthy subjects were given different administration strategies of CYP3A4 perpetrators. In each cycle, blood samples were collected before and within 24 h after the administration of midazolam, the CYP3A indicator substrate. The plasma concentrations of midazolam and 1-hydroxymidazolam was obtained using liquid chromatography tandem mass spectrometry assay. For CYP3A inhibition, itraconazole exposure with a loading dose could increase the exposure of midazolam by 3.21-fold based on maximum plasma concentration (Cmax), 8.37-fold based on area under the curve Pharmacology Research & Perspectives for review only from zero to the time point (AUC0-t), and 11.22-fold based on area under the curve from zero to infinity (AUC0-∞). The data were similar for itraconazole pretreatment without a loading dose. For CYP3A induction, the exposure of rifampin for 7 days decreased the plasma concentration of midazolam ~0.27-fold based on Cmax, ~0.18-fold based on AUC0-t, and ~0.18-fold based on AUC0-∞. Midazolam exposure did not significantly change when the pretreatment of rifampin increased to 14 days. This study showed that itraconazole pretreatment for 3 days without a loading dose was enough for CYP3A inhibition, and pretreatment with rifampin for 7 days could induce near-maximal CYP3A levels.
Subject(s)
Asian People , Cytochrome P-450 CYP3A Inhibitors , Cytochrome P-450 CYP3A , Drug Interactions , Itraconazole , Midazolam , Humans , Midazolam/pharmacokinetics , Midazolam/administration & dosage , Midazolam/blood , Midazolam/analogs & derivatives , Itraconazole/pharmacology , Itraconazole/administration & dosage , Cytochrome P-450 CYP3A/metabolism , Male , Adult , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Cytochrome P-450 CYP3A Inhibitors/administration & dosage , Young Adult , Rifampin/pharmacology , Rifampin/administration & dosage , Healthy Volunteers , Female , Cytochrome P-450 CYP3A Inducers/pharmacology , Area Under Curve , Research Design , Clinical Trials as Topic , East Asian PeopleABSTRACT
Background: Standard dosages of analgesic and sedative drugs are given to intensive care patients. The resulting range of blood concentrations and corresponding clinical responses need to be better examined. The purpose of this study was to describe daily dosages, measured blood concentrations, and clinical responses in critically ill patients. The purpose was also to contribute to establishing whole blood concentration reference values of the drugs investigated. Methods: A descriptive study of prospectively collected data from 302 admissions to a general intensive care unit (ICU) at a university hospital. Ten drugs (clonidine, fentanyl, morphine, dexmedetomidine, ketamine, ketobemidone, midazolam, paracetamol, propofol, and thiopental) were investigated, and daily dosages recorded. Blood samples were collected twice daily, and drug concentrations were measured. Clinical responses were registered using Richmond agitation-sedation scale (RASS) and Numeric rating scale (NRS). Results: Drug dosages were within recommended dose ranges. Blood concentrations for all 10 drugs showed a wide variation within the cohort, but only 3% were above therapeutic interval where clonidine (57 of 122) and midazolam (38 of 122) dominated. RASS and NRS were not correlated to drug concentrations. Conclusion: Using recommended dose intervals for analgesic and sedative drugs in the ICU setting combined with regular monitoring of clinical responses such as RASS and NRS leads to 97% of concentrations being below the upper limit in the therapeutic interval. This study contributes to whole blood drug concentration reference values regarding these 10 drugs.
Subject(s)
Analgesics , Hypnotics and Sedatives , Intensive Care Units , Midazolam , Humans , Hypnotics and Sedatives/administration & dosage , Hypnotics and Sedatives/pharmacokinetics , Hypnotics and Sedatives/blood , Analgesics/administration & dosage , Analgesics/pharmacokinetics , Analgesics/blood , Male , Female , Middle Aged , Aged , Prospective Studies , Adult , Midazolam/administration & dosage , Midazolam/pharmacokinetics , Midazolam/blood , Critical Care/methods , Dexmedetomidine/administration & dosage , Dexmedetomidine/pharmacokinetics , Dexmedetomidine/blood , Fentanyl/administration & dosage , Fentanyl/blood , Fentanyl/pharmacokinetics , Critical Illness , Propofol/administration & dosage , Propofol/pharmacokinetics , Propofol/blood , Clonidine/administration & dosage , Clonidine/pharmacokinetics , Clonidine/blood , Ketamine/administration & dosage , Ketamine/blood , Ketamine/pharmacokinetics , Morphine/administration & dosage , Morphine/blood , Morphine/pharmacokinetics , Aged, 80 and over , Dose-Response Relationship, Drug , Thiopental/administration & dosage , Thiopental/pharmacokinetics , Acetaminophen/administration & dosage , Acetaminophen/blood , Acetaminophen/pharmacokineticsABSTRACT
OBJECTIVE: We sought to explore relationships of acute dissociative effects of intravenous ketamine with change in depression and suicidal ideation and with plasma metabolite levels in a randomized, midazolam-controlled trial. METHODS: Data from a completed trial in suicidal, depressed participants (n = 40) randomly assigned to ketamine was used to examine relationships between ketamine treatment-emergent dissociative and psychotomimetic symptoms with pre/post-infusion changes in suicidal ideation and depression severity. Nonparametric correlational statistics were used. These methods were also used to explore associations between dissociative or psychotomimetic symptoms and blood levels of ketamine and metabolites in a subset of participants (n = 28) who provided blood samples immediately post-infusion. RESULTS: Neither acute dissociative nor psychotomimetic effects of ketamine were associated with changes in suicidal ideation or depressive symptoms from pre- to post-infusion. Norketamine had a trend-level, moderate inverse correlation with dissociative symptoms on Day 1 post-injection (P = .064; P =.013 removing 1 outlier). Dehydronorketamine correlated with Clinician-Administered Dissociative States Scale scores at 40 minutes (P = .034), 230 minutes (P = .014), and Day 1 (P = .012). CONCLUSION: We did not find evidence that ketamine's acute, transient dissociative, or psychotomimetic effects are associated with its antidepressant or anti-suicidal ideation actions. The correlation of higher plasma norketamine with lower dissociative symptoms on Day 1 post-treatment suggests dissociation may be more an effect of the parent drug.
Subject(s)
Antidepressive Agents , Dissociative Disorders , Ketamine , Ketamine/analogs & derivatives , Midazolam , Suicidal Ideation , Humans , Ketamine/administration & dosage , Ketamine/blood , Ketamine/pharmacology , Male , Adult , Midazolam/administration & dosage , Midazolam/pharmacology , Midazolam/blood , Female , Antidepressive Agents/blood , Antidepressive Agents/administration & dosage , Antidepressive Agents/pharmacology , Dissociative Disorders/chemically induced , Dissociative Disorders/blood , Middle Aged , Young Adult , Double-Blind MethodABSTRACT
AIM: To evaluate BAY 2433334, an oral activated factor XI (FXIa) inhibitor, in volunteers. METHODS: Phase 1 study of healthy men at a German centre. Part A: randomized, single-blind, multiple dose-escalation study of BAY 2433334 (25/50/100 mg once daily [OD]) vs. placebo. Part B: similar design to Part A; evaluated BAY 2433334 25 mg twice daily. Part C: nonrandomized, open-label study; evaluated potential interactions between BAY 2433334 (25/75 mg OD) and midazolam (7.5 mg), a CYP3A4 index substrate. Primary variables: treatment-emergent adverse events (TEAEs; Parts A and B); area under the plasma concentration-time curve (AUC) and maximum plasma concentration of midazolam and α-hydroxymidazolam (Part C). STUDY PERIOD: 18 days plus follow-up visit. RESULTS: Parts A and B: 36 participants randomized to BAY 2433334; 12 to placebo. Part C: 48 participants assigned to BAY 2433334 plus midazolam. BAY 2433334 was well tolerated in all study parts. AUC and maximum plasma concentration of BAY 2433334 in plasma appeared dose proportional over 25-100 mg OD, with low-to-moderate variability in pharmacokinetic parameters. Multiple dosing caused minor-to-moderate accumulation and a mean terminal half-life (15.8-17.8 h) supporting once-daily dosing. Dose-dependent FXIa activity inhibition and activated partial thromboplastin time prolongation were observed. BAY 2433334 appeared to have a minor effect on AUC for midazolam (ratio [90% confidence interval]: 1.1736 [1.0963-1.2564]) and α-hydroxymidazolam (0.9864 [0.9169-1.0612]) only for BAY 2433334 75 mg OD on day 10. CONCLUSION: Multiple dosing of BAY 2433334 in healthy volunteers was well tolerated, with a predictable pharmacokinetic/pharmacodynamic profile and no clinically relevant CYP3A4 induction or inhibition.
Subject(s)
Cytochrome P-450 CYP3A , Factor XIa/antagonists & inhibitors , Area Under Curve , Dose-Response Relationship, Drug , Double-Blind Method , Follow-Up Studies , Half-Life , Healthy Volunteers , Humans , Male , Midazolam/adverse effects , Midazolam/blood , Midazolam/pharmacokinetics , Partial Thromboplastin Time , Single-Blind MethodABSTRACT
A cocktail study is an in vivo evaluation method to assess multiple CYP activities via a single trial and single administration of a cocktail drug that is a combination of multiple CYP substrates. However, multiple blood samples are required to evaluate the pharmacokinetics of a CYP probe drug. A limited-point sampling method is generally beneficial in clinical studies because of the simplified protocol and reduced participant burden. The aim of this study was to evaluate whether a limited-point plasma concentration analysis of CYP substrates in a cocktail drug could predict their area under the curve (AUC). We created prediction models of five CYP substrates (caffeine, losartan, omeprazole, dextromethorphan, and midazolam) using multiple linear regressions from the data of two cocktail studies, and then performed predictability analysis of these models using data derived from data in the co-administration with inducer (rifampicin) and inhibitors (fluvoxamine and cimetidine). For the administration of inhibitors, the AUC prediction accuracy (mean absolute error (MAE)) were <39.5% in Model 1 and <26.2% in Model 2 which were created using 1- and 4-point sampling data. MAE shows larger values in the administration of inducer in compared with the administration of inhibitors. The accuracy of the prediction in Model 2 could be acceptable for screening of inhibitions. MAE for caffeine, dextromethorphan, and midazolam were acceptable in the model that used 4 sampling points from all data. The use of this method could reduce the burden on the subject and make it possible to evaluate each AUC in a minimally invasive manner.
Subject(s)
Area Under Curve , Cytochrome P-450 Enzyme System/metabolism , Models, Biological , Administration, Oral , Adult , Caffeine/blood , Caffeine/pharmacokinetics , Dextromethorphan/blood , Dextromethorphan/pharmacokinetics , Humans , Losartan/blood , Losartan/pharmacokinetics , Male , Midazolam/blood , Midazolam/pharmacokinetics , Omeprazole/blood , Omeprazole/pharmacokinetics , Young AdultABSTRACT
RATIONALE & OBJECTIVE: Midazolam is one of top three drugs used in palliative care. Its use increases in the last days of hospice patients' lives while safe dosage can be challenging. Equations currently used to estimate glomerular filtration rate, e.g: the Cockroft-Gault (eGFRCR) and the Modification of Diet in Renal Disease (eGFRMDRD) ones, do not generate precise calculations, especially in palliative patients exhibiting variations in body parameters. Our aim was to seek new relationships between mean midazolam (Mavg) and alfahydroxymidazolam (OH-Mavg) concentrations in plasma, and selected biochemical and physiological parameters of palliative patients, to enable optimal midazolam pharmacotherapy. STUDY DESIGN, PARTICIPANTS AND INTERVENTIONS: The pilot study included 11 Caucasians, aged 42-95, with advanced cancer disease, receiving midazolam in a hospice in-patient unit. We tested correlations among Mavg, BMI, eGFRMDRD, midazolam clearance (CL), OH-Mavg, bilirubin (Bil) and blood creatinine concentration (Cr). F test and leave-one out (LOO) validation was applied to verify the correlations' significance and predictive ability. RESULTS: We found ten statistically significant (p < 0.05) correlations related to midazolam pharmacokinetics and physiological factors. We formulated two equations with high degree of predictive ability, based on the eGFRMDRDâCL and the (Bil + BMI × Ln(Cr))âMavg-(OH-Mavg) correlations. The limitations of the study mainly revolve around its pilot nature and the need to continue testing the results on a bigger population. No funding to disclose. CONCLUSIONS: The significance of correlations corresponding to the arithmetic expressions confirms that Bil, BMI, Ln(Cr) analyzed simultaneously report a series of processes on which midazolam metabolism depends. Two of ten correlations proposed came close to meet all LOO validation criteria. Current findings can help optimize midazolam treatment in palliative therapy.
Subject(s)
Drug Monitoring , Hypnotics and Sedatives/pharmacokinetics , Midazolam/pharmacokinetics , Models, Biological , Palliative Care , Adult , Aged , Aged, 80 and over , Bilirubin/blood , Biomarkers/blood , Body Mass Index , Creatinine/blood , Drug Dosage Calculations , Female , Glomerular Filtration Rate , Humans , Hypnotics and Sedatives/blood , Male , Midazolam/analogs & derivatives , Midazolam/blood , Middle Aged , Pilot Projects , Reproducibility of ResultsABSTRACT
Midazolam (MDZ) is routinely employed as a marker compound of cytochrome P450 3A (CYP3A) activity. Despite the many HPLC-UV methods described to quantify MDZ in plasma, all of them use acetonitrile (ACN) or a mixture of methanol-isopropanol as organic solvent of the mobile phase. Since the ACN shortage in 2008, efforts have been made to replace this solvent during HPLC analysis. A simple, sensitive, accurate and repeatable HPLC-UV method (220 nm) was developed and validated to quantify MDZ in rat plasma using methanol instead. The method was applied during a herb-drug interaction study involving Maytenus ilicifolia, a Brazilian folk medicine used to treat gastric disorders. Plasma samples were alkalinized and MDZ plus alprazolam (internal standard) were extracted with diethyl ether. After solvent removal, the residue was reconstituted with methanol-water (1:1). The analyte was eluted throughout a C18 column using sodium acetate buffer (10 mm, pH 7.4)-methanol (40:60, v/v). The precision at the lower limit of quantification never exceeded 19.40%, and 13.86% at the higher levels of quality control standards, whereas the accuracy ranged from -19.81 to 14.33%. The analytical curve was linear from 50 to 2,000 ng/ml. The activity of the hepatic CYP3A enzymes was not affected by the extract.
Subject(s)
Chromatography, High Pressure Liquid/methods , Herb-Drug Interactions , Maytenus/chemistry , Midazolam/blood , Animals , Cytochrome P-450 CYP3A/metabolism , Linear Models , Male , Methanol , Midazolam/administration & dosage , Midazolam/pharmacokinetics , Plant Preparations/administration & dosage , Plant Preparations/blood , Plant Preparations/pharmacokinetics , Rats , Rats, Wistar , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
For the quantification of the sedative and anesthetic drug midazolam and its main (active) metabolites 1-hydroxymidazolam, 4-hydroxymidazolam and 1-hydroxymidazolam glucuronide in human serum, human EDTA plasma, human heparin plasma and human urine a single accurate method by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) has been developed. Protein precipitation as sample preparation, without the need of a time-consuming deglucuronidation step for the quantification of 1-hydroxymidazolam glucuronide, resulted in a simple and rapid assay suitable for clinical practice with a total runtime of only 1.1 min. The four components and the isotope-labeled internal standards were separated on a C18 column and detection was performed with a triple-stage quadrupole mass spectrometer operating in positive ionization mode. The method was validated based on the "Guidance for Industry Bioanalytical Method Validation" (Food and Drug Administration, FDA) and the "Guideline on bioanalytical method validation" of the European Medicines Agency (EMA). Linearity was proven over the ranges of 5-1500 µg/L for midazolam, 1-hydroxymidazolam and 4-hydroxymidazolam and 25-5000 µg/L for 1-hydroxymidazolam glucuronide, using a sample volume of 100 µL. Matrix comparison indicated that the assay is also applicable to other human matrices like EDTA and heparin plasma and urine. Stability experiments showed good results for the stability of midazolam, 1-hydroxymidazolam and 1-hydroxymidazolam glucuronide in serum, EDTA and heparin plasma and urine stored for 7 days under different conditions. At room temperature, 4-hydroxymidazo-lam is stable for 7 days in EDTA plasma, but stable for only 3 days in serum and heparin plasma and less than 24 h in urine. All four compounds were found to be stable in serum, EDTA plasma, heparin plasma and urine for 7 days after sample preparation and for 3 freeze-thaw cycles. The assay has been applied in therapeutic drug monitoring of midazolam for (pediatric) intensive care patients.
Subject(s)
Chromatography, High Pressure Liquid/methods , Midazolam , Tandem Mass Spectrometry/methods , Aged , Drug Stability , Female , Humans , Infant, Newborn , Limit of Detection , Linear Models , Midazolam/analogs & derivatives , Midazolam/blood , Midazolam/pharmacokinetics , Midazolam/urine , Reproducibility of ResultsABSTRACT
Intestinal cytochrome P450 3A (CYP3A) plays an important role in oral drug metabolism, but only endogenous metabolic markers for measuring hepatic CYP3A activity were identified. Our study evaluated whether hepatic CYP3A markers reflected intestinal CYP3A activity. An open-label, three-period, six-treatment, one-sequence clinical trial was performed in 16 healthy Korean males. In the control phase, all subjects received a single dose of intravenous (IV) and oral midazolam (1 mg and 5 mg, respectively). Clarithromycin (500 mg) was administered twice daily for 4 days to inhibit hepatic and intestinal CYP3A, and 500 mL of grapefruit juice was given to inhibit intestinal CYP3A. Clarithromycin significantly inhibited total CYP3A activity, and the clearance of IV and apparent clearance of oral midazolam decreased by 0.15- and 0.32-fold, respectively. Grapefruit juice only reduced the apparent clearance of oral midazolam by 0.84-fold, which indicates a slight inhibition of intestinal CYP3A activity. Urinary markers, including 6ß-OH-cortisol/cortisol and 6ß-OH-cortisone/cortisone, were significantly decreased 0.5-fold after clarithromycin administration but not after grapefruit juice. The fold changes in 6ß-OH-cortisol/cortisol and 6ß-OH-cortisone/cortisone did not correlate to changes in intestinal availability but did correlate to hepatic availability. In conclusion, endogenous metabolic markers are only useful to measure hepatic, but not intestinal, CYP3A activity.
Subject(s)
Citrus paradisi/metabolism , Clarithromycin/urine , Cytochrome P-450 CYP3A/urine , Intestinal Mucosa/metabolism , Liver/metabolism , Midazolam/urine , Administration, Intravenous , Administration, Oral , Adult , Biomarkers/blood , Biomarkers/urine , Clarithromycin/administration & dosage , Clarithromycin/blood , Cytochrome P-450 CYP3A/blood , Cytochrome P-450 CYP3A/genetics , Food-Drug Interactions/physiology , Healthy Volunteers , Humans , Intestinal Mucosa/drug effects , Liver/drug effects , Male , Metabolic Clearance Rate/drug effects , Metabolic Clearance Rate/physiology , Midazolam/administration & dosage , Midazolam/bloodABSTRACT
OBJECTIVE: We developed and validated a sensitive and reliable UPLC-MS/MS method for simultaneous determination of dezocine (DEZ), midazolam (MDZ) and its metabolite 1-hydroxymidazolam (1-OH-MDZ) in beagle plasma and investigated the effect of dexmedetomidine (DEX) on the pharmacokinetics of DEZ, MDZ and 1-OH-MDZ in beagles. MATERIALS AND METHODS: Diazepam was used as the internal standard (IS); the three analytes and IS were extracted by acetonitrile precipitation and separated on an Acquity UPLC BEH C18 column using acetonitrile-0.1% formic acid as mobile phase in gradient mode. In positive ion mode, the three analytes and IS were monitored by multiple reaction monitoring (MRM). Six beagles were designed as a double cycle self-control experiment with 0.15 mg/kg in the first cycle (Group A). After a 1-week washout period, the same six beagles were slowly injected intravenously with 2 µg/kg DEX in the second cycle (Group B), with continuous injection for 7 days. On the seventh day, 0.5 hr after intravenous injection of 2 µg/kg DEX, the six beagles were intramuscularly given with DEZ 0.33 mg/kg and MDZ 0.15 mg/kg. RESULTS: Under the conditions of this experiment, this method exhibited a good linearity for each analyte. The accuracy and precision were all within the acceptable limits in the bioanalytical method, and the results of recovery, matrix effect and stability have also met the requirements. CONCLUSION: The developed UPLC-MS/MS method for simultaneous determination of DEZ, MDZ and 1-OH-MDZ in beagles plasma was accurate, reproducible, specific, and suitable. DEX could inhibit the metabolism of DEZ and MDZ and increase the exposure of DEZ and MDZ in beagles. Therefore, the change of therapeutic effect and the occurrence of adverse reactions caused by drug-drug interaction should be paid attention to when the drugs were used in combination.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/blood , Dexmedetomidine/blood , Midazolam/analogs & derivatives , Midazolam/blood , Tetrahydronaphthalenes/blood , Animals , Bridged Bicyclo Compounds, Heterocyclic/metabolism , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Chromatography, High Pressure Liquid , Dexmedetomidine/metabolism , Dexmedetomidine/pharmacokinetics , Dogs , Female , Male , Midazolam/metabolism , Midazolam/pharmacokinetics , Tandem Mass Spectrometry , Tetrahydronaphthalenes/metabolism , Tetrahydronaphthalenes/pharmacokineticsABSTRACT
ANS-6637, a pro-drug of GS-548351, is a selective, reversible inhibitor of aldehyde dehydrogenase isoform 2 under development as an anticraving agent for the treatment of substance use disorders. In vitro testing indicates that GS-548351 is an inhibitor and inducer of cytochrome P450 family 3, subfamily A (CYP3A). In this phase 1 single-center, open-label, fixed-sequence drug-drug interaction study we assessed the impact of steady-state GS-548351 on single-dose pharmacokinetics of midazolam, an index substrate for CYP3A. Twelve healthy volunteers received 600 mg of ANS-6637 by mouth daily from study days 3 to 8 and a single 5-mg oral dose of midazolam on days 1 and 8. Pharmacokinetic samples were collected over 24 hours on days 1 and 8, then analyzed using liquid chromatography-tandem mass spectrometry. The prespecified no-effect range for the 90% confidence interval (CI) of the geometric mean ratio (GMR) of midazolam coadministered with ANS-6637 (day 8) compared with midazolam alone (day 1) was 0.7-1.43. There was an increase in midazolam AUC0-∞ (GMR [90%CI]) that was within the no-effect range (1.26 [1.12-1.425]) and an increase in midazolam Cmax that was outside the range (1.22 [1.03-1.45]). The AUC0-∞ (1.08 [0.91-1.27]) and Cmax (0.95 [0.75-1.2]) of 1-hydroxymidazolam, the primary metabolite of midazolam, were also within the no-effect range. A single grade 3 adverse event (alanine aminotransferase elevation) was identified and resolved following discontinuation of the study drug. Overall, multidose ANS-6637 was well tolerated and did not alter the PK of midazolam beyond a small increase in AUC0-∞ that is unlikely to be clinically significant.
Subject(s)
Enzyme Inhibitors/pharmacology , Midazolam/pharmacokinetics , Organic Chemicals/pharmacology , Prodrugs/pharmacology , Administration, Oral , Adult , Aldehyde Dehydrogenase/antagonists & inhibitors , Area Under Curve , Cytochrome P-450 CYP3A/metabolism , Drug Administration Schedule , Drug Interactions , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/blood , Female , Half-Life , Healthy Volunteers , Humans , Male , Midazolam/administration & dosage , Midazolam/analogs & derivatives , Midazolam/blood , Midazolam/metabolism , Organic Chemicals/administration & dosage , Prodrugs/administration & dosage , Prodrugs/adverse effects , Prodrugs/metabolismABSTRACT
PURPOSE: Fedratinib, an oral selective kinase inhibitor with activity against both wild type and mutationally activated Janus kinase 2, has been approved for the treatment of adult patients with intermediate-2 or high-risk myelofibrosis by the US Food and Drug Administration. In vitro studies indicated that fedratinib was an inhibitor of several cytochrome P450 (CYP) enzymes. The primary objective of this study was to evaluate the effects of repeated doses of fedratinib on the activity of CYP2D6, CYP2C19, and CYP3A4 in patients with solid tumors using a CYP probe cocktail. METHODS: An open-label, one-sequence, two-period, two-treatment crossover study was conducted. Patients were administered a single oral dose cocktail of metoprolol (100 mg), omeprazole (20 mg), and midazolam (2 mg) used as probe substrates for CYP2D6, CYP2C19, and CYP3A4 enzyme activities, respectively, without fedratinib on Day -1 or with fedratinib on Day 15. RESULTS: Coadministration of 500 mg once-daily doses of fedratinib for 15 days increased the mean area under the plasma concentration-time curve from time zero to infinity following a single-dose cocktail containing metoprolol (CYP2D6 substrate), omeprazole (CYP2C19 substrate), and midazolam (CYP3A4 substrate) by 1.77-fold (90% confidence interval [CI] 1.27-2.47) for metoprolol, 2.82-fold (90% CI 2.26-3.53) for omeprazole, and 3.84-fold (90% CI 2.62-5.63) for midazolam, respectively. The mean plasma Day 14/Day 1 ratio of 4ß-hydroxycholesterol, an endogenous biomarker of CYP3A4 activity, was 0.59 (90% CI 0.54-0.66), suggesting a net inhibition of CYP3A4 by fedratinib. CONCLUSION: Fedratinib is a weak inhibitor of CYP2D6, and a moderate inhibitor of CYP2C19 and CYP3A4. These results serve as the basis for dose modifications of these CYP substrate drugs when co-administered with fedratinib.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cytochrome P-450 Enzyme Inhibitors/pharmacokinetics , Neoplasms/drug therapy , Pyrrolidines/administration & dosage , Sulfonamides/administration & dosage , Administration, Oral , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Cross-Over Studies , Cytochrome P-450 CYP2C19/blood , Cytochrome P-450 CYP2D6/blood , Cytochrome P-450 CYP3A/blood , Cytochrome P-450 Enzyme Inhibitors/administration & dosage , Drug Interactions , Female , Humans , Hydroxycholesterols/blood , Male , Metoprolol/administration & dosage , Metoprolol/blood , Midazolam/administration & dosage , Midazolam/blood , Middle Aged , Omeprazole/administration & dosage , Omeprazole/blood , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Pyrrolidines/adverse effects , Pyrrolidines/pharmacokinetics , Sulfonamides/adverse effects , Sulfonamides/pharmacokineticsABSTRACT
BACKGROUND: The impact of major liver resection (LR) on the detoxifying function of the remaining liver tissue as represented by CYP3A activity has yet to be assessed. Therefore, this study evaluates the changes in CYP3A activity between preoperative values and after liver resection. MATERIAL AND METHODS: To determine CYP3A activity, midazolam (MDZ) was used as a marker substance, 3 µg were applied intravenously one day before surgery and on the 3rd day after surgery. Subsequently blood was withdrawn at 0, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3, 4 and 6 h post application of the study drug. Plasma MDZ and 1-OH-MDZ concentration was assessed using a LC-MS/MS method. Volumetric analysis of the resected liver was done by syngo.CT liver analysis software (Siemens Healthineers) using preoperative multidetector computed tomography. RESULTS: N = 13 (8 male/5 female) patients were included in this study and received preoperative evaluation, 11 patients were studied also after liver resection. The mean age was 62 (±15.3) years with a mean BMI of 23.6 ± 4.8 kg/m2. No patient suffered from acute liver dysfunction postoperatively. None of the pharmacokinetic parameters assessed were significantly altered by liver resection. CYP3A activity over time was not significantly reduced by major liver resection. CONCLUSION: This study gives first time data on the impact of major liver resection on CYP3A activity. It was shown that MDZ clearance representing in vivo CYP3A activity is not altered by major liver resection. This suggests no dose adjustment of commonly applied drugs which are CYP3A substrates needs to be carried out.
Subject(s)
Cytochrome P-450 CYP3A/metabolism , Hepatectomy , Adult , Aged , Controlled Before-After Studies , Female , Humans , Male , Midazolam/blood , Middle Aged , Postoperative Period , Prospective StudiesABSTRACT
PURPOSE: We report the case of a male neonate with a respiratory disorder who developed adverse cardiorespiratory symptoms after the continuous infusion of midazolam. METHODS: To clarify the cause of cardiogenic shock, we performed whole exome sequencing and screened relative single-nucleotide variants of 2 cytochrome P450 (CYP) isoforms, CYP3A4 and CYP3A5, which play a dominant role in the metabolic elimination of midazolam. We measured endogenous cortisol 6ß-hydroxylation clearance to phenotypically assess CYP3A activity. FINDINGS: The CYP3A activity level in the patient was significantly lower than the mean CYP3A activity level in healthy adults. Three intronic mutations in the CYP3A4 and CYP3A5 isoforms were detected in the patient. IMPLICATIONS: Our findings suggest that the midazolam concentration in plasma was achieved at above the steady-state concentration during continuous infusion used to sedate neonates receiving mechanical ventilatory support. Evaluation of the drug-metabolizing ability based on CYP3A might be useful if adverse electrophysiologic variables or the induction of tachycardia occur because of delayed elimination.
Subject(s)
Cytochrome P-450 CYP3A/metabolism , Hypnotics and Sedatives/adverse effects , Midazolam/adverse effects , Shock, Cardiogenic/chemically induced , Cytochrome P-450 CYP3A/genetics , Humans , Hydrocortisone/metabolism , Hydroxylation , Hypnotics and Sedatives/blood , Infant, Newborn , Infant, Premature , Male , Midazolam/blood , Phenotype , Polymorphism, Single Nucleotide , Exome SequencingABSTRACT
Growth and development affect drug-metabolizing enzyme activity thus could alter the metabolic profile of a drug. Traditional studies to create metabolite profiles and study the routes of excretion are unethical in children due to the high radioactive burden. To overcome this challenge, we aimed to show the feasibility of an absorption, distribution, metabolism, and excretion (ADME) study using a [14 C]midazolam microtracer as proof of concept in children. Twelve stable, critically ill children received an oral [14 C]midazolam microtracer (20 ng/kg; 60 Bq/kg) while receiving intravenous therapeutic midazolam. Blood was sampled up to 24 hours after dosing. A time-averaged plasma pool per patient was prepared reflecting the mean area under the curve plasma level, and subsequently one pool for each age group (0-1 month, 1-6 months, 0.5-2 years, and 2-6 years). For each pool [14 C]levels were quantified by accelerator mass spectrometry, and metabolites identified by high resolution mass spectrometry. Urine and feces (n = 4) were collected up to 72 hours. The approach resulted in sufficient sensitivity to quantify individual metabolites in chromatograms. [14 C]1-OH-midazolam-glucuronide was most abundant in all but one age group, followed by unchanged [14 C]midazolam and [14 C]1-OH-midazolam. The small proportion of unspecified metabolites most probably includes [14 C]midazolam-glucuronide and [14 C]4-OH-midazolam. Excretion was mainly in urine; the total recovery in urine and feces was 77-94%. This first pediatric pilot study makes clear that using a [14 C]midazolam microtracer is feasible and safe to generate metabolite profiles and study recovery in children. This approach is promising for first-in-child studies to delineate age-related variation in drug metabolite profiles.
Subject(s)
Carbon Radioisotopes/pharmacokinetics , Hypnotics and Sedatives/pharmacokinetics , Midazolam/pharmacokinetics , Administration, Intravenous , Administration, Oral , Age Factors , Biotransformation , Carbon Radioisotopes/administration & dosage , Carbon Radioisotopes/blood , Carbon Radioisotopes/urine , Child , Child, Preschool , Critical Illness , Feasibility Studies , Feces/chemistry , Female , Humans , Hypnotics and Sedatives/administration & dosage , Hypnotics and Sedatives/blood , Hypnotics and Sedatives/urine , Infant , Infant, Newborn , Intensive Care Units, Pediatric , Intestinal Elimination , Male , Mass Spectrometry , Midazolam/administration & dosage , Midazolam/blood , Midazolam/urine , Proof of Concept Study , Renal EliminationABSTRACT
It is known that co-administration of CYP3A inducers may decrease the effectiveness of oral contraceptives containing progestins as mono-preparations or combined with ethinylestradiol. In a randomized clinical drug-drug interaction study, we investigated the effects of CYP3A induction on the pharmacokinetics of commonly used progestins and ethinylestradiol. Rifampicin was used to induce CYP3A. The progestins chosen as victim drugs were levonorgestrel, norethindrone, desogestrel, and dienogest as mono-products, and drospirenone combined with ethinylestradiol. Postmenopausal women (n = 12-14 per treatment group) received, in fixed sequence, a single dose of the victim drug plus midazolam without rifampicin, with rifampicin 10 mg/day (weak induction), and with rifampicin 600 mg/day (strong induction). The effects on progestin exposure were compared with the effects on midazolam exposure (as a benchmark). Unbound concentrations were evaluated for drugs binding to sex hormone binding globulin. Weak CYP3A induction, as confirmed by a mean decrease in midazolam exposure by 46%, resulted in minor changes in progestin exposure (mean decreases: 15-37%). Strong CYP3A induction, in contrast, resulted in mean decreases by 57-90% (mean decrease in midazolam exposure: 86%). Namely, the magnitude of the observed induction effects varied from weak to strong. Our data might provide an impetus to revisit the currently applied clinical recommendations for oral contraceptives, especially for levonorgestrel and norethindrone-containing products, and they might give an indication as to which progestin could be used, if requested, by women taking weak CYP3A inducers-although it is acknowledged that the exact exposure-response relationship for contraceptive efficacy is currently unclear for most progestins.
Subject(s)
Contraceptives, Oral, Hormonal/pharmacokinetics , Cytochrome P-450 CYP3A Inducers/administration & dosage , Cytochrome P-450 CYP3A/metabolism , Ethinyl Estradiol/pharmacokinetics , Midazolam/pharmacokinetics , Progestins/pharmacokinetics , Rifampin/administration & dosage , Aged , Contraceptives, Oral, Hormonal/administration & dosage , Contraceptives, Oral, Hormonal/blood , Cross-Over Studies , Cytochrome P-450 CYP3A Inducers/adverse effects , Drug Interactions , Ethinyl Estradiol/administration & dosage , Ethinyl Estradiol/blood , Female , Germany , Humans , Midazolam/administration & dosage , Midazolam/blood , Middle Aged , Patient Safety , Progestins/administration & dosage , Progestins/blood , Protein Binding , Rifampin/adverse effects , Risk Assessment , Sex Hormone-Binding Globulin/metabolismABSTRACT
TAS-303 (4-piperidinyl 2,2-diphenyl-2-[propoxy-1,1,2,2,3,3,3-d7 ] acetate hydrochloride) is a novel selective noradrenaline reuptake inhibitor being developed for the treatment of stress urinary incontinence. An in vitro study and a physiologically based pharmacokinetic model simulation showed that TAS-303 had inhibitory potential against cytochrome P450 (CYP) 3A. This open-label, single-group study investigated the effect of TAS-303 on CYP3A activity by evaluating the pharmacokinetics (PK) of single-dose oral simvastatin 5 mg or intravenous midazolam 1 mg after repeated oral administration of TAS-303 3 mg in 12 healthy participants. TAS-303 plus simvastatin resulted in a 1.326-fold and a 1.420-fold increase of simvastatin in peak plasma concentration and area under the plasma concentration-time curve from time zero to time t, where t is the final time of detection (AUC0-t ), respectively. The addition of midazolam resulted in a 1.090-fold increase in the midazolam AUC0-t . TAS-303 had a weak PK interaction with simvastatin but no apparent interaction with midazolam. TAS-303 at 3 mg/day is a weak inhibitor of intestinal but not hepatic CYP3A activity. No clinically important safety concerns related to TAS-303 were raised.
Subject(s)
Adrenergic Uptake Inhibitors/pharmacokinetics , Cytochrome P-450 CYP3A Inhibitors/adverse effects , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Cytochrome P-450 CYP3A/metabolism , Administration, Intravenous , Administration, Oral , Adrenergic Uptake Inhibitors/administration & dosage , Adult , Anesthetics, Intravenous/administration & dosage , Anesthetics, Intravenous/blood , Anesthetics, Intravenous/pharmacokinetics , Anticholesteremic Agents/administration & dosage , Anticholesteremic Agents/blood , Anticholesteremic Agents/pharmacokinetics , Area Under Curve , Computer Simulation , Cytochrome P-450 CYP3A/drug effects , Cytochrome P-450 CYP3A Inhibitors/administration & dosage , Drug Interactions , Healthy Volunteers , Humans , Intestine, Small/metabolism , Liver/metabolism , Male , Midazolam/administration & dosage , Midazolam/blood , Midazolam/pharmacokinetics , Models, Biological , Simvastatin/administration & dosage , Simvastatin/blood , Simvastatin/pharmacokinetics , Young AdultABSTRACT
ACT-539313 is a potent and selective orexin-1 receptor antagonist. CYP3A is the major cytochrome P450 (CYP) enzyme involved in the metabolism and clearance of ACT-539313 in man. The main objective of this study was to investigate the effect of ACT-539313 on the pharmacokinetics of orally administered midazolam. Thereby, this single-center, open-label, fixed-sequence study investigated the CYP3A interaction potential of ACT-539313 following single- (on day 2) and repeated-dose (on day 11) twice-daily administration of 200 mg ACT-539313. Exposure to midazolam was higher during concomitant administration of single as well as after repeated doses of ACT-539313 over 10 days compared to midazolam alone (day 1). In the presence of ACT-539313, the geometric mean ratio of the maximum plasma concentration and the area under the plasma concentration-time curve from time 0 to 24 hours increased by 1.18- and 1.79-fold on day 2, and by 2.13- and 4.54-fold on day 11, respectively. A similar outcome was also shown in the additionally evaluated urinary 6ß-hydroxycortisol/cortisol ratio (6ß-CR), as the geometric mean ratio of the 6ß-CR showed a decrease to 0.78 on day 2 and to 0.61 on day 11. The most commonly reported adverse events (AEs) included somnolence and headache. All AEs were transient and of mild intensity. No treatment-related effects on vital signs, clinical laboratory, and electrocardiogram were observed. In summary, the observed corresponding decrease of both the validated, exogenous (midazolam/1-hydroxymidazolam ratio) and a frequently used endogenous (6ß-CR) marker of CYP3A activity is indicative of CYP3A inhibition occurring after ACT-539313 treatment.
Subject(s)
Cytochrome P-450 CYP3A Inhibitors/pharmacokinetics , Cytochrome P-450 CYP3A/metabolism , Midazolam/pharmacokinetics , Orexin Receptor Antagonists/pharmacokinetics , Orexin Receptors/metabolism , Adult , Area Under Curve , Biomarkers/blood , Cytochrome P-450 CYP3A/drug effects , Cytochrome P-450 CYP3A Inhibitors/administration & dosage , Cytochrome P-450 CYP3A Inhibitors/adverse effects , Cytochrome P-450 CYP3A Inhibitors/blood , Drug Administration Schedule , Drug Interactions , Healthy Volunteers , Humans , Hydrocortisone/analogs & derivatives , Hydrocortisone/urine , Male , Midazolam/administration & dosage , Midazolam/adverse effects , Midazolam/analogs & derivatives , Midazolam/blood , Middle Aged , Orexin Receptor Antagonists/administration & dosage , Orexin Receptor Antagonists/adverse effects , Orexin Receptor Antagonists/blood , Orexin Receptors/drug effects , Young AdultABSTRACT
PURPOSE: The aim of the present study was to develop a population pharmacokinetic model of midazolam, and to evaluate the influence of maturation process and other variability factors in critically ill children with severe acute bronchiolitis, who received a long-term intravenous infusion of midazolam. METHODS: In the study were included 49 critically ill children of both genders (from 0 to 130 weeks of age) with severe acute bronchiolitis hospitalised in intensive care units. Nonlinear mixed effects modelling approach was applied for data analyses and simulations. RESULTS: The final model is a two-compartment model that includes the effects of body weight using allometric scaling with fixed exponents and maturation of clearance. For a typical subject, scaled to the adult body weight of 70â¯kg, population pharmacokinetic values were estimated at 8.52â¯L/h for clearance (when maturation function was 1), 25.5â¯L/h for intercompartmental clearance, and 5.71â¯L and 39.8â¯L for the volume of the central and peripheral compartment, respectively. Based on the final model, maturation reaches 50% of the adult clearance in 45.9 weeks of postmenstrual age. The influence of gender, ABCB1 genotype and biochemical parameters on midazolam clearance was not detected. Results of simulations indicate the need for reduced dosing in certain groups of patients in order to maintain plasma concentrations of midazolam within recommended values. CONCLUSIONS: The developed population pharmacokinetic model can contribute to the dosing optimisation of midazolam, especially in critically ill children as it includes the influence of size and maturation of clearance, which are important parameters for achieving the desired plasma concentrations of midazolam.
Subject(s)
Hypnotics and Sedatives/pharmacokinetics , Midazolam/pharmacokinetics , Models, Biological , ATP Binding Cassette Transporter, Subfamily B/genetics , Bronchiolitis/genetics , Bronchiolitis/metabolism , Bronchiolitis/therapy , Critical Illness , Female , Humans , Hypnotics and Sedatives/administration & dosage , Hypnotics and Sedatives/blood , Infant , Infant, Newborn , Infusions, Intravenous , Male , Midazolam/administration & dosage , Midazolam/blood , Polymorphism, Single Nucleotide , Respiration, ArtificialABSTRACT
Genetic polymorphism can result in abnormal pharmacodynamics that subsequently leads to the individual variance in sedative effects and adverse reactions. The aim of this study was to elucidate the association between midazolam-related genetic polymorphism and sedative effects, including adverse reactions, under conscious sedation during upper gastrointestinal endoscopy. We prospectively enrolled 100 eligible patients undergoing upper gastrointestinal endoscopy. The efficacy of the sedation, adverse reactions, plasma concentration of midazolam and 1-hydroxymidazolam were investigated as well as the genetic polymorphism of MDR1 and CYP3A5. The correlation between genetic polymorphism and sedative effects was assessed. Regarding MDR1 gene, the plasma concentration of midazolam was greater in patients with CGC haplotype (P = 0.012), while it was lower in patients with CAC haplotype (P = 0.005) than in those with other haplotypes. However, genetic polymorphism of neither MDR1 nor CYP3A5 correlated with the plasma concentration of 1-hydroxymidazolam. CGT haplotype of MDR1 was significantly correlated with sedation grade after midazolam administration (P = 0.042). In contrast, genetic polymorphism of CYP3A5 was not correlated with sedation grade. There was no association between genetic polymorphism of MDR1 or CYP3A5 and selected adverse reactions related to midazolam. Genetic polymorphism of MDR1 influences the concentration of midazolam and the sedation grade. However, it is not associated with adverse reactions such as paradoxical response and retrograde amnesia.