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Pertti J. Neuvonen - One of the best experts on this subject based on the ideXlab platform.
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Effect of voriconazole on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam
Clinical pharmacology and therapeutics, 2006Co-Authors: Teijo I. Saari, Pertti J. Neuvonen, Kari Laine, Kari Leino, Mika Valtonen, Klaus T. OlkkolaAbstract:Our objective was to assess the effect of the antimycotic voriconazole on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam. We used a randomized, crossover study design. Ten healthy male volunteers were given either no pretreatment (control phase) or voriconazole (voriconazole phase) orally, 400 mg twice daily on the first day and 200 mg twice daily on the second day. Midazolam was given, either 0.05 mg/kg intravenously or 7.5 mg orally, 1 hour after the last dose of voriconazole and during the control phase. Plasma concentrations of midazolam, Alpha-Hydroxymidazolam, and voriconazole were determined for 24 hours and pharmacodynamic variables measured for 12 hours. Voriconazole reduced the clearance of intravenous midazolam by 72% (P < .001) and increased its elimination half-life from 2.8 to 8.3 hours (P < .001). Voriconazole increased the peak concentration and the area under the plasma concentration-time curve of oral midazolam by 3.8- and 10.3-fold, respectively (P < .001). The bioavailability of oral midazolam was increased from 31% to 84% (P < .001). Voriconazole profoundly increased the psychomotor effects of oral midazolam (P < .001) but only weakly increased the effects of intravenous midazolam. When midazolam is given as small intravenous bolus doses, its effect is not increased to a clinically significant degree by voriconazole. The use of large midazolam doses increases the risk of clinically significant interactions also after its intravenous administration. The use of oral midazolam with voriconazole should be avoided, or substantially lower doses should be used.
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Interaction between fluconazole and midazolam in intensive care patients
Acta anaesthesiologica Scandinavica, 1999Co-Authors: Jouni Ahonen, Klaus T. Olkkola, A. Takala, Pertti J. NeuvonenAbstract:Midazolam is used for sedation of intensive care unit (ICU) patients and it is extensively metabolised by CYP3A4 enzymes. The antimycotic fluconazole is often used in these patients as well and has been shown to inhibit CYP3A4-mediated drug metabolism. In a study of the effect of fluconazole on midazolam in the ICU, ten mechanically ventilated patients (age 29 to 61 years, 8 male) sedated with a stable midazolam infusion were enrolled after a decision to start fluconazole treatment. Fluconazole was infused for 30 min at intervals of 24 h, with an initial dose of 400 mg and following doses of 200 mg. The midazolam infusion rate remained unchanged during the study period of 48 h. Plasma concentrations of midazolam, Alpha-Hydroxymidazolam, and Alpha-Hydroxymidazolam conjugate were determined at baseline, and at 6, 12, 18, 24, 36, and at 48 h thereafter. Concentrations of midazolam were significantly increased (range 0 to 4-fold, P < 0.05) after start of fluconazole treatment. These increases were most marked in patients with renal failure. During the study period, the ratio of Alpha-Hydroxymidazolam to midazolam decreased progressively (P < 0.05). In ICU patients receiving fluconazole, reduction of midazolam infusion rate should be considered if the degree of sedation is found to be increasing.
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Effect of saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam
Clinical pharmacology and therapeutics, 1999Co-Authors: V.j. Palkama, Jouni Ahonen, Pertti J. Neuvonen, Klaus T. OlkkolaAbstract:To assess the effect of human immunodeficiency virus protease inhibitor saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam. In a double-blind, randomized, two-phase crossover study, 12 healthy volunteers (six men and six women; age range, 21 to 32 years) received oral doses of either 1200 mg saquinavir (Fortovase soft-gel capsule formulation) or placebo three times a day for 5 days. On day 3, six subjects were given 7.5 mg oral midazolam and the other six subjects received 0.05 mg/kg intravenous midazolam. On day 5, the subjects who had received oral midazolam on day 3 received intravenously midazolam and vice versa. Plasma concentrations of midazolam, Alpha-Hydroxymidazolam, and saquinavir were determined for 18 hours after midazolam administration, and midazolam effects were measured up to 7 hours by six psychomotor tests. Saquinavir increased the bioavailability of oral midazolam from 41% to 90% (P < .005), the peak midazolam plasma concentration more than twofold, and the area under plasma concentration-time curve more than fivefold (P < .001). During saquinavir treatment, five of the six psychomotor tests revealed impaired skills and increased sedative effects after midazolam ingestion (P < .05). Saquinavir decreased the clearance of intravenous midazolam by 56% (P < .001) and increased its elimination half-life from 4.1 to 9.5 hours (P < .01). After intravenous midazolam, only the subjective feeling of drug effect was increased significantly (P < .05) by saquinavir. The dose of oral midazolam should be greatly reduced or avoided with saquinavir, but bolus doses of intravenous midazolam can probably be used quite safely. During a prolonged midazolam infusion, an initial dose reduction of 50% followed by careful titration is recommended to counteract the reduced clearance caused by saquinavir.
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Midazolam Alpha-hydroxylation by human liver microsomes in vitro: inhibition by calcium channel blockers, itraconazole and ketoconazole.
Pharmacology & toxicology, 1999Co-Authors: Jun-sheng Wang, Pertti J. Neuvonen, Xia Wen, Janne T. Backman, Päivi Taavitsainen, Kari T. KivistöAbstract:The inhibitory effects of five calcium channel blockers (diltiazem, isradipine, mibefradil, nifedipine and verapamil) and three azole antifungal agents (itraconazole, hydroxyitraconazole and ketoconazole) on the Alpha-hydroxylation of midazolam, a probe drug for CYP3A4-mediated interactions in humans, were studied in vitro using human liver microsomes. IC50 and Ki values were determined for each inhibitor. The kinetics of the formation of Alpha-Hydroxymidazolam were best described by simple Michaelis-Menten kinetics. The estimated values of Vmax and Km were 696 pmol min.-(1) mg(-1) and 7.46 micromol l(-1), respectively. All the compounds studied inhibited midazolam Alpha-hydroxylation activity in a concentration-dependent manner, but there were marked differences in their relative inhibitory potency. Ketoconazole was the most potent inhibitor of midazolam Alpha-hydroxylation (IC50 0.12 micromol l (-1)), being 10 times more potent than itraconazole (IC50 1.2 micromol l(-1)). The inhibitory effect of hydroxyitraconazole (IC50 2.3 micromol l (-1) was almost as large as that of itraconazole. Among the calcium channel blockers, mibefradil was the most potent inhibitor of the Alpha-hydroxylation of midazolam, with an IC50 value (1.6 micromol l (-1)) similar to that of itraconazole. The other calcium channel blockers were much weaker inhibitors than mibefradil: verapamil exhibited a modest inhibitory effect with an IC50 of 23 micromol l(-1), while isradipine, nifedipine and diltiazem, with IC50 values ranging from 57 to >100 micromol l (-1), were weak inhibitors. This rank order of potency against the Alpha-hydroxylation Qf midazolam was verified by the Ki values. With the exception of diltiazem, these in vitro results conform with the observed interaction potential of these agents with midazolam and many other CYP3A4 substrates in vivo in man.
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The area under the plasma concentration–time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin
European journal of clinical pharmacology, 1998Co-Authors: J. T. Backman, Kari T. Kivistö, Klaus T. Olkkola, Pertti J. NeuvonenAbstract:To determine the effects of treatment with itraconazole and rifampicin (rifampin) on the pharmacokinetics and pharmacodynamics of oral midazolam during and 4 days after the end of the treatment. Nine healthy volunteers received itraconazole (200 mg daily) for 4 days and, 2 weeks later, rifampicin (600 mg daily) for 5 days. In addition, they ingested 15 mg midazolam before the first treatment, 7.5 mg on the last day of itraconazole administration, and 4 days later, and 15 mg 1 day and 4 days after the last dose of rifampicin. The disposition of midazolam and its Alpha-hydroxy metabolite was determined and its pharmacodynamic effects were measured. During itraconazole treatment, or 4 days after, Alpha-hydroxymetabolite the dose-corrected area under the plasma midazolam concentration time curve (AUC0-infinity) was 8- or 2.6-fold larger than that before itraconazole (i.e. 1707 or 695 versus 277 ng x h x ml(-1)), respectively. One day after rifampicin treatment, the AUC0-infinity of midazolam was 2.3% (i.e. 4.4 ng x h x ml(-1)) of the before-treatment value and only 0.26% of its value during itraconazole treatment; 4 days after rifampicin, the AUC0-infinity was still only 13% (i.e. 27.1 ng x h x ml(-1)) of the before-treatment value. The peak concentration and elimination half-life of midazolam were also increased by itraconazole and decreased by rifampicin. The ratio of plasma Alpha-Hydroxymidazolam to midazolam was greatly decreased by itraconazole and increased by rifampicin. In addition, the effects of midazolam were greater during itraconazole and smaller 1 day after rifampicin than without treatment. Switching from inhibition to induction of cytochrome P450 3A (CYP3A) enzymes causes a very great (400-fold) change in the AUC of oral midazolam. During oral administration of CYP3A substrates that undergo extensive first-pass metabolism, similar changes in pharmacokinetics are expected to occur when potent inhibitors or inducers of CYP3A are added to the treatment. After cessation of treatment with itraconazole or rifampicin, the risk of significant interaction continues up to at least 4 days, probably even longer.
Klaus T. Olkkola - One of the best experts on this subject based on the ideXlab platform.
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Effect of voriconazole on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam
Clinical pharmacology and therapeutics, 2006Co-Authors: Teijo I. Saari, Pertti J. Neuvonen, Kari Laine, Kari Leino, Mika Valtonen, Klaus T. OlkkolaAbstract:Our objective was to assess the effect of the antimycotic voriconazole on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam. We used a randomized, crossover study design. Ten healthy male volunteers were given either no pretreatment (control phase) or voriconazole (voriconazole phase) orally, 400 mg twice daily on the first day and 200 mg twice daily on the second day. Midazolam was given, either 0.05 mg/kg intravenously or 7.5 mg orally, 1 hour after the last dose of voriconazole and during the control phase. Plasma concentrations of midazolam, Alpha-Hydroxymidazolam, and voriconazole were determined for 24 hours and pharmacodynamic variables measured for 12 hours. Voriconazole reduced the clearance of intravenous midazolam by 72% (P < .001) and increased its elimination half-life from 2.8 to 8.3 hours (P < .001). Voriconazole increased the peak concentration and the area under the plasma concentration-time curve of oral midazolam by 3.8- and 10.3-fold, respectively (P < .001). The bioavailability of oral midazolam was increased from 31% to 84% (P < .001). Voriconazole profoundly increased the psychomotor effects of oral midazolam (P < .001) but only weakly increased the effects of intravenous midazolam. When midazolam is given as small intravenous bolus doses, its effect is not increased to a clinically significant degree by voriconazole. The use of large midazolam doses increases the risk of clinically significant interactions also after its intravenous administration. The use of oral midazolam with voriconazole should be avoided, or substantially lower doses should be used.
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Interaction between fluconazole and midazolam in intensive care patients
Acta anaesthesiologica Scandinavica, 1999Co-Authors: Jouni Ahonen, Klaus T. Olkkola, A. Takala, Pertti J. NeuvonenAbstract:Midazolam is used for sedation of intensive care unit (ICU) patients and it is extensively metabolised by CYP3A4 enzymes. The antimycotic fluconazole is often used in these patients as well and has been shown to inhibit CYP3A4-mediated drug metabolism. In a study of the effect of fluconazole on midazolam in the ICU, ten mechanically ventilated patients (age 29 to 61 years, 8 male) sedated with a stable midazolam infusion were enrolled after a decision to start fluconazole treatment. Fluconazole was infused for 30 min at intervals of 24 h, with an initial dose of 400 mg and following doses of 200 mg. The midazolam infusion rate remained unchanged during the study period of 48 h. Plasma concentrations of midazolam, Alpha-Hydroxymidazolam, and Alpha-Hydroxymidazolam conjugate were determined at baseline, and at 6, 12, 18, 24, 36, and at 48 h thereafter. Concentrations of midazolam were significantly increased (range 0 to 4-fold, P < 0.05) after start of fluconazole treatment. These increases were most marked in patients with renal failure. During the study period, the ratio of Alpha-Hydroxymidazolam to midazolam decreased progressively (P < 0.05). In ICU patients receiving fluconazole, reduction of midazolam infusion rate should be considered if the degree of sedation is found to be increasing.
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Effect of saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam
Clinical pharmacology and therapeutics, 1999Co-Authors: V.j. Palkama, Jouni Ahonen, Pertti J. Neuvonen, Klaus T. OlkkolaAbstract:To assess the effect of human immunodeficiency virus protease inhibitor saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam. In a double-blind, randomized, two-phase crossover study, 12 healthy volunteers (six men and six women; age range, 21 to 32 years) received oral doses of either 1200 mg saquinavir (Fortovase soft-gel capsule formulation) or placebo three times a day for 5 days. On day 3, six subjects were given 7.5 mg oral midazolam and the other six subjects received 0.05 mg/kg intravenous midazolam. On day 5, the subjects who had received oral midazolam on day 3 received intravenously midazolam and vice versa. Plasma concentrations of midazolam, Alpha-Hydroxymidazolam, and saquinavir were determined for 18 hours after midazolam administration, and midazolam effects were measured up to 7 hours by six psychomotor tests. Saquinavir increased the bioavailability of oral midazolam from 41% to 90% (P < .005), the peak midazolam plasma concentration more than twofold, and the area under plasma concentration-time curve more than fivefold (P < .001). During saquinavir treatment, five of the six psychomotor tests revealed impaired skills and increased sedative effects after midazolam ingestion (P < .05). Saquinavir decreased the clearance of intravenous midazolam by 56% (P < .001) and increased its elimination half-life from 4.1 to 9.5 hours (P < .01). After intravenous midazolam, only the subjective feeling of drug effect was increased significantly (P < .05) by saquinavir. The dose of oral midazolam should be greatly reduced or avoided with saquinavir, but bolus doses of intravenous midazolam can probably be used quite safely. During a prolonged midazolam infusion, an initial dose reduction of 50% followed by careful titration is recommended to counteract the reduced clearance caused by saquinavir.
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The area under the plasma concentration–time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin
European journal of clinical pharmacology, 1998Co-Authors: J. T. Backman, Kari T. Kivistö, Klaus T. Olkkola, Pertti J. NeuvonenAbstract:To determine the effects of treatment with itraconazole and rifampicin (rifampin) on the pharmacokinetics and pharmacodynamics of oral midazolam during and 4 days after the end of the treatment. Nine healthy volunteers received itraconazole (200 mg daily) for 4 days and, 2 weeks later, rifampicin (600 mg daily) for 5 days. In addition, they ingested 15 mg midazolam before the first treatment, 7.5 mg on the last day of itraconazole administration, and 4 days later, and 15 mg 1 day and 4 days after the last dose of rifampicin. The disposition of midazolam and its Alpha-hydroxy metabolite was determined and its pharmacodynamic effects were measured. During itraconazole treatment, or 4 days after, Alpha-hydroxymetabolite the dose-corrected area under the plasma midazolam concentration time curve (AUC0-infinity) was 8- or 2.6-fold larger than that before itraconazole (i.e. 1707 or 695 versus 277 ng x h x ml(-1)), respectively. One day after rifampicin treatment, the AUC0-infinity of midazolam was 2.3% (i.e. 4.4 ng x h x ml(-1)) of the before-treatment value and only 0.26% of its value during itraconazole treatment; 4 days after rifampicin, the AUC0-infinity was still only 13% (i.e. 27.1 ng x h x ml(-1)) of the before-treatment value. The peak concentration and elimination half-life of midazolam were also increased by itraconazole and decreased by rifampicin. The ratio of plasma Alpha-Hydroxymidazolam to midazolam was greatly decreased by itraconazole and increased by rifampicin. In addition, the effects of midazolam were greater during itraconazole and smaller 1 day after rifampicin than without treatment. Switching from inhibition to induction of cytochrome P450 3A (CYP3A) enzymes causes a very great (400-fold) change in the AUC of oral midazolam. During oral administration of CYP3A substrates that undergo extensive first-pass metabolism, similar changes in pharmacokinetics are expected to occur when potent inhibitors or inducers of CYP3A are added to the treatment. After cessation of treatment with itraconazole or rifampicin, the risk of significant interaction continues up to at least 4 days, probably even longer.
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Effect of route of administration of fluconazole on the interaction between fluconazole and midazolam
European Journal of Clinical Pharmacology, 1997Co-Authors: Jouni Ahonen, Klaus T. Olkkola, Pertti J. NeuvonenAbstract:Midazolam is a short-acting benzodiazepine hypnotic extensively metabolized by CYP3A4 enzyme. Orally ingested azole antimycotics, including fluconazole, interfere with the metabolism of oral midazolam during its absorption and elimination phases. We compared the effect of oral and intravenous fluconazole on the pharmacokinetics and pharmacodynamics of orally ingested midazolam. A double-dummy, randomized, cross-over study in three phases was performed in 9 healthy volunteers. The subjects were given orally fluconazole 400 mg and intravenously saline within 60 min; orally placebo and intravenously fluconazole 400 mg; and or-ally placebo and intravenously saline. An oral dose of 7.5 mg midazolam was ingested 60 min after oral intake of fluconazole/placebo, i.e. at the end of the corresponding infusion. Plasma concentrations of midazolam, α-Hydroxymidazolam and fluconazole were determined and pharmacodynamic effects were measured up to 17 h. Both oral and intravenous fluconazole significantly increased the area under the midazolam plasma concentration-time curve (AUC0-3, AUC0-17) 2- to 3-fold, the elimination half-life of midazolam 2.5-fold and its peak concentration (Cmax) 2- to 2.5-fold compared with placebo. The AUC0-3 and the Cmax of midazolam were significantly higher after oral than after intravenous administration of fluconazole. Both oral and intravenous fluconazole increased the pharmacodynamic effects of midazolam but no differences were detected between the fluconazole phases. We conclude that the metabolism of orally administered midazolam was more strongly inhibited by oral than by intravenous administration of fluconazole.
Jouni Ahonen - One of the best experts on this subject based on the ideXlab platform.
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Effect of saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam
Clinical pharmacology and therapeutics, 1999Co-Authors: V.j. Palkama, Jouni Ahonen, Pertti J. Neuvonen, Klaus T. OlkkolaAbstract:To assess the effect of human immunodeficiency virus protease inhibitor saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenous midazolam. In a double-blind, randomized, two-phase crossover study, 12 healthy volunteers (six men and six women; age range, 21 to 32 years) received oral doses of either 1200 mg saquinavir (Fortovase soft-gel capsule formulation) or placebo three times a day for 5 days. On day 3, six subjects were given 7.5 mg oral midazolam and the other six subjects received 0.05 mg/kg intravenous midazolam. On day 5, the subjects who had received oral midazolam on day 3 received intravenously midazolam and vice versa. Plasma concentrations of midazolam, Alpha-Hydroxymidazolam, and saquinavir were determined for 18 hours after midazolam administration, and midazolam effects were measured up to 7 hours by six psychomotor tests. Saquinavir increased the bioavailability of oral midazolam from 41% to 90% (P < .005), the peak midazolam plasma concentration more than twofold, and the area under plasma concentration-time curve more than fivefold (P < .001). During saquinavir treatment, five of the six psychomotor tests revealed impaired skills and increased sedative effects after midazolam ingestion (P < .05). Saquinavir decreased the clearance of intravenous midazolam by 56% (P < .001) and increased its elimination half-life from 4.1 to 9.5 hours (P < .01). After intravenous midazolam, only the subjective feeling of drug effect was increased significantly (P < .05) by saquinavir. The dose of oral midazolam should be greatly reduced or avoided with saquinavir, but bolus doses of intravenous midazolam can probably be used quite safely. During a prolonged midazolam infusion, an initial dose reduction of 50% followed by careful titration is recommended to counteract the reduced clearance caused by saquinavir.
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Interaction between fluconazole and midazolam in intensive care patients
Acta anaesthesiologica Scandinavica, 1999Co-Authors: Jouni Ahonen, Klaus T. Olkkola, A. Takala, Pertti J. NeuvonenAbstract:Midazolam is used for sedation of intensive care unit (ICU) patients and it is extensively metabolised by CYP3A4 enzymes. The antimycotic fluconazole is often used in these patients as well and has been shown to inhibit CYP3A4-mediated drug metabolism. In a study of the effect of fluconazole on midazolam in the ICU, ten mechanically ventilated patients (age 29 to 61 years, 8 male) sedated with a stable midazolam infusion were enrolled after a decision to start fluconazole treatment. Fluconazole was infused for 30 min at intervals of 24 h, with an initial dose of 400 mg and following doses of 200 mg. The midazolam infusion rate remained unchanged during the study period of 48 h. Plasma concentrations of midazolam, Alpha-Hydroxymidazolam, and Alpha-Hydroxymidazolam conjugate were determined at baseline, and at 6, 12, 18, 24, 36, and at 48 h thereafter. Concentrations of midazolam were significantly increased (range 0 to 4-fold, P < 0.05) after start of fluconazole treatment. These increases were most marked in patients with renal failure. During the study period, the ratio of Alpha-Hydroxymidazolam to midazolam decreased progressively (P < 0.05). In ICU patients receiving fluconazole, reduction of midazolam infusion rate should be considered if the degree of sedation is found to be increasing.
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Effect of route of administration of fluconazole on the interaction between fluconazole and midazolam
European Journal of Clinical Pharmacology, 1997Co-Authors: Jouni Ahonen, Klaus T. Olkkola, Pertti J. NeuvonenAbstract:Midazolam is a short-acting benzodiazepine hypnotic extensively metabolized by CYP3A4 enzyme. Orally ingested azole antimycotics, including fluconazole, interfere with the metabolism of oral midazolam during its absorption and elimination phases. We compared the effect of oral and intravenous fluconazole on the pharmacokinetics and pharmacodynamics of orally ingested midazolam. A double-dummy, randomized, cross-over study in three phases was performed in 9 healthy volunteers. The subjects were given orally fluconazole 400 mg and intravenously saline within 60 min; orally placebo and intravenously fluconazole 400 mg; and or-ally placebo and intravenously saline. An oral dose of 7.5 mg midazolam was ingested 60 min after oral intake of fluconazole/placebo, i.e. at the end of the corresponding infusion. Plasma concentrations of midazolam, α-Hydroxymidazolam and fluconazole were determined and pharmacodynamic effects were measured up to 17 h. Both oral and intravenous fluconazole significantly increased the area under the midazolam plasma concentration-time curve (AUC0-3, AUC0-17) 2- to 3-fold, the elimination half-life of midazolam 2.5-fold and its peak concentration (Cmax) 2- to 2.5-fold compared with placebo. The AUC0-3 and the Cmax of midazolam were significantly higher after oral than after intravenous administration of fluconazole. Both oral and intravenous fluconazole increased the pharmacodynamic effects of midazolam but no differences were detected between the fluconazole phases. We conclude that the metabolism of orally administered midazolam was more strongly inhibited by oral than by intravenous administration of fluconazole.
Steen Larsen - One of the best experts on this subject based on the ideXlab platform.
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Intestinal first pass metabolism of midazolam in liver cirrhosis – effect of grapefruit juice
British journal of clinical pharmacology, 2002Co-Authors: Vibeke Andersen, Natalie Pedersen, Niels-erik Larsen, Jesper Sonne, Steen LarsenAbstract:Grapefruit juice inhibits CYP3A4 in the intestinal wall leading to a reduced intestinal first pass metabolism and thereby an increased oral bioavailability of certain drugs. For example, it has been shown that the oral bioavailability of midazolam, a CYP3A4 substrate, increased by 52% in healthy subjects after ingestion of grapefruit juice. However, this interaction has not been studied in patients with impaired liver function. Accordingly, the effect of grapefruit juice on the AUC of midazolam and the metabolite Alpha-Hydroxymidazolam was studied in patients with cirrhosis of the liver. An open randomized two-way crossover study was performed. Ten patients (3 females, 7 males) with liver cirrhosis based on biopsy or clinical criteria participated. Six patients had a Child-Pugh score of A, one B and three C. Tap water (200 ml) or grapefruit juice were consumed 60 and 15 min before midazolam (15 mg) was administered orally. Plasma samples were analysed for midazolam and Alpha-Hydroxymidazolam. Grapefruit juice increased the AUC of midazolam by 106% (16, 197%) (mean (95% confidence interval)) and the AUC of the metabolite Alpha-Hydroxymidazolam decreased to 25% (12, 37%) (P<0.05 for both). The ratio of the AUCs of the metabolite Alpha-Hydroxymidazolam to midazolam decreased from 0.77 (0.46, 1.07) to 0.11 (0.05, 0.19) (P<0.05). t(1/2) remained unaltered for both drug and metabolite. Midazolam C(max), t(max), and Alpha-Hydroxymidazolam t(max) increased, but these changes were not statistically significant, whereas C(max) of the metabolite decreased to 30% (14, 47%) (P<0.05). A marked interaction between oral midazolam and grapefruit juice was found and the data are consistent with a reduced first-pass metabolism of midazolam. This is likely to occur at the intestinal wall inhibition of CYP3A4 activity by grapefruit juice. These results indicate that patients with liver cirrhosis are more dependent on the intestine for metabolism of CYP3A4 substrates than subjects with normal liver function.
Gregory L. Kearns - One of the best experts on this subject based on the ideXlab platform.
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The Single-Dose Pharmacokinetics of Midazolam and Its Primary Metabolite in Pediatric Patients after Oral and Intravenous Administration
Journal of clinical pharmacology, 2001Co-Authors: Michael D. Reed, Jeffrey L. Blumer, Ko‐chin Khoo, Bardia Akbari, Alexander Rodarte, Sovitj Pou, Gregory L. KearnsAbstract:The first-dose pharmacokinetics of midazolam and its primary Alpha-hydroxymetabolite were studied after single-dose administration. Eligible study patients were enrolled into one of three study arms: Arm I (midazolam/metabolite pharmacokinetic evaluation after oral administration of a syrup formulation), Arm II (the absolute bioavailability of midazolam syrup), and Arm III (midazolam and metabolite pharmacokinetics after IV administration). Complete blood sampling for pharmacokinetic analysis was available in 87 subjects. Midazolam absorption after administration of the oral syrupformulation was rapid, with adolescents absorbing the drug at approximately half the rate observed in younger children (ages 2 to < 12 years). Furthermore, midazolam t 1/2 was prolonged and CL/F reducedin adolescents as compared with younger children. Although the midazolam Vd/F appeared larger in the youngest age group after oral administration, this observation was not apparent after IV dosing, suggesting subject differences in bioavailability rather than distribution. Like midazolam, the disposition characteristics for a-Hydroxymidazolam were also highly variable, with the greatest formation of metabolite (reflected by the AUC ratio) observed in children ages 2 to < 12 years. The A UC ratios of Alpha-Hydroxymidazolam to midazolam after IV dosing were similar across all age groups and were smaller than corresponding values following oral administration. The absolute bioavailability of midazolam averaged 36% with a very broad range (9%-71%). No relationship between midazolam bioavailability and age was observed. Overall, the disposition characteristics of midazolam and its a-hydroxy metabolite were highly variable, appeared independent of age and dose administered, and were linear over the dose range studied (0.25 to 1 mg/kg). These data suggest that an initial oral dose of 0.2 to 0.3 mg/kg should be adequateforsuccessful sedation of most pediatric patients. The inherent variability in midazolam bioavailability and metabolism underscores the importance of titrating midazolam dose to desired effect.
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Pediatric Pharmacodynamics of Midazolam Oral Syrup
Journal of clinical pharmacology, 2000Co-Authors: James D. Marshall, Alex Rodarte, Jeffrey L. Blumer, Ko‐chin Khoo, Bardia Akbari, Gregory L. KearnsAbstract:In this study, the authors evaluate the pharmacodynamics, safety, and acceptability of a new cherry-flavored oral syrup formulation of midazolam. This randomized, double-blind, parallel-group, dose-ranging clinical trial of oral midazolam was conducted at seven U.S. health care institutions focused on pediatric clinical pharmacology research (i.e., the PPRU Network). Pediatric patients (n = 85, ages 6 months through 15 years) underwent invasive procedures and were randomized to a single oral dose of midazolam syrup (0.25, 0.5, or 1.0 mg/kg). Patient taste acceptability of midazolam syrup was evaluated at the time of oral administration. Pharmacodynamic measurements included (1) sedation score using a 5-point scale at baseline and 10-, 20-, and 30-minute postdose intervals and (2) anxiety score using a 4-point scale at the time of separation from caretakers and, when applicable, at the time of mask anesthetic induction. Midazolam and Alpha-Hydroxymidazolam plasma concentrations were measured at all pharmacodynamic measurement time points. Adverse events were monitored continuously during the study. Most patients (99%) accepted the syrup without difficulty. Satisfactory sedation was achieved within 30 minutes by 81% of patients. The anxiety score at the time of caretaker separation and mask anesthetic induction was satisfactory for 87% and 91% of patients, respectively. A significant linear relationship between plasma drug concentration and maximal sedation score, but not anxiety score, was observed. The occurrence of adverse events was consistent with the known safety profile of midazolam. The most commonly reported adverse events were hiccoughing, hypoxemia, nausea, and emesis. It was concluded that a new oral syrup formulation of midazolam, 0.25 to 1.0 mg/kg, effectively induced rapid-onset, dose-related, adequate, and safe sedation and anxiolysis in pediatric patients who underwent operative procedures. Sedative effects were related to plasma concentrations of both midazolam and the primary metabolite, Alpha-Hydroxymidazolam. Oral midazolam, 1.0 mg/kg, administered within 30 minutes of the expected procedure or anesthetic induction should provide safe and effective sedation to a majority of children ages 6 months to 16 years.
