Janne T. Backman

Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole

Interaction between ketoconazole, itraconazole, and midazolam was investigated in a double‐blind, randomized crossover study of three phases at intervals of 4 weeks. Nine volunteers were given either 400 mg ketoconazole, 200 mg itraconazole, or matched placebo orally once daily for 4 days. On day 4, the subjects ingested 7.5 mg midazolam. Plasma samples were collected and psychomotor performance was measured. Both ketoconazole and itraconazole increased the area under the midazolam concentration‐time curve from 10 to 15 times (p < 0.001) and mean peak concentrations three to four times (p < 0.001) compared with the placebo phase. In psychomotor tests (e.g., the Digit Symbol Substitution Test), the interaction was statistically significant (p < 0.05) until at least 6 hours after drug administration. Inhibition of the cytochrome P450IIIA by ketoconazole and itraconazole may explain the observed pharmacokinetic interaction. Prescription of midazolam for patients receiving ketoconazole and itraconazole should be avoided.

The area under the plasma concentration-time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin

AbstractObjective: 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.nn Methods: Nine healthy volunteers received itraconazole (200u2009mg daily) for 4 days and, 2 weeks later, rifampicin (600u2009mg daily) for 5u2009days. 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 α-hydroxy metabolite was determined and its pharmacodynamic effects were measured.nn Results: During itraconazole treatment, or 4u2009days after, α-hydroxymetabolite the dose-corrected area under the plasma midazolam concentration–time curve (AUC0–∞) was 8- or 2.6-fold larger than that before itraconazole (i.e. 1707 or 695 versus 277u2009ngu200a·u200ahu200a·u200aml−1), respectively. One day after rifampicin treatment, the AUC0–∞ of midazolam was 2.3% (i.e. 4.4u2009ngu200a·u200ahu200a·u200aml−1) of the before-treatment value and only 0.26% of its value during itraconazole treatment; 4u2009days after rifampicin, the AUC0–∞ was still only 13% (i.e. 27.1 ngu200a·u200ahu200a·u200aml−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 α-hydroxymidazolam to midazolam was greatly decreased by itraconazole and increased by rifampicin. In addition, the effects of midazolam were greater during itraconazole and smaller 1u2009day after rifampicin than without treatment.nn Conclusion: 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.

Rifampin drastically reduces plasma concentrations and effects of oral midazolam

Midazolam is a short‐acting benzodiazepine that is metabolized by CYP3A enzymes. Rifampin is a potent enzyme inducer that may seriously interact with some substrates of CYP3A4.

Simvastatin decreases lipopolysaccharide-induced pulmonary inflammation in healthy volunteers.

RATIONALEnSimvastatin inhibits inflammatory responses in vitro and in murine models of lung inflammation in vivo. As simvastatin modulates a number of the underlying processes described in acute lung injury (ALI), it may be a potential therapeutic option.nnnOBJECTIVESnTo investigate in vivo if simvastatin modulates mechanisms important in the development of ALI in a model of acute lung inflammation induced by inhalation of lipopolysaccharide (LPS) in healthy human volunteers.nnnMETHODSnThirty healthy subjects were enrolled in a double-blind, placebo-controlled study. Subjects were randomized to receive 40 mg or 80 mg of simvastatin or placebo (n = 10/group) for 4 days before inhalation of 50 microg LPS. Measurements were performed in bronchoalveolar lavage fluid (BALF) obtained at 6 hours and plasma obtained at 24 hours after LPS challenge. Nuclear translocation of nuclear factor-kappaB (NF-kappaB) was measured in monocyte-derived macrophages.nnnMEASUREMENTS AND MAIN RESULTSnPretreatment with simvastatin reduced LPS-induced BALF neutrophilia, myeloperoxidase, tumor necrosis factor-alpha, matrix metalloproteinases 7, 8, and 9, and C-reactive protein (CRP) as well as plasma CRP (all P < 0.05 vs. placebo). There was no significant difference between simvastatin 40 mg and 80 mg. BALF from subjects post-LPS inhalation induced a threefold up-regulation in nuclear NF-kappaB in monocyte-derived macrophages (P < 0.001); pretreatment with simvastatin reduced this by 35% (P < 0.001).nnnCONCLUSIONSnSimvastatin has antiinflammatory effects in the pulmonary and systemic compartment in humans exposed to inhaled LPS.

Acute effects of pravastatin on cholesterol synthesis are associated with slco1b1 (encoding Oatp1b1) haplotype *17

Objective The aim was to investigate whether polymorphisms in the SLCO1B1 gene, encoding the hepatic uptake transporter OATP1B1, influence the short-term effects of pravastatin on cholesterol synthesis. Methods We determined plasma concentrations of lathosterol and cholesterol up to 12 h after intake of a single dose of 40u2009mg pravastatin in 41 healthy Caucasian subjects, in whom SLCO1B1 single nucleotide polymorphisms (SNP; 521T>C and −11187G>A) and haplotypes (*15B and *17) had been previously shown to be associated with considerably elevated plasma pravastatin levels. Results The effects of pravastatin on plasma lathosterol concentration and lathosterol to cholesterol concentration ratio, which are established markers of the rate of cholesterol synthesis in vivo, were significantly smaller among the three heterozygous carriers of the SLCO1B1 *17 haplotype (containing the −11187G>A, 388A>G and 521T>C SNPs) as compared with non-carriers. Significant inverse relationships were found between pravastatin area under the concentration–time curve (AUC) values and effects of pravastatin on lathosterol and lathosterol to cholesterol ratio among the whole study population. Conclusion These results suggest that uptake of pravastatin into hepatocytes is impaired in carriers of the SLCO1B1 haplotype *17, resulting in higher plasma pravastatin concentrations but lower concentrations of pravastatin in hepatocytes and thereby in a smaller inhibitory effect on cholesterol synthesis. The cholesterol-lowering response to pravastatin may be impaired in carriers of the *17 haplotype.

Concentrations and effects of oral midazolam are greatly reduced in patients treated with carbamazepine or phenytoin.

Midazolam is a short‐acting benzodiazepine which is used as an oral hypnotic agent in several countries. We studied the pharmacokinetic and pharmacody‐namic aspects of an oral 15–mg dose of midazolam in 6 patients with epilepsy who are also taking carbamazepine (CBZ) or phenytoin (PHT). We compared results with those obtained in 7 noninduced control subjects. Plasma concentrations and effects of midazolam were measured for 10 h. In patients with epilepsy, the area under the plasma concentration‐time curve (AUC) of midazolam (mean 2 SEM) was only 5.7% (0.60 ± 0.16 vs. 10.5 ± 0.6 μg ‐ min/ml), and the peak midazolam concentration was 7.4% (5.2 ± 1.2 vs. 70.4 ± 9.0 μg/ml) of its value in control subjects (p < 0.001). The elimination half‐life (t1/2) of midazolam was 1.3 ± 0.2 h in patients and 3.1 ± 0.1 h in controls (p < 0.001). The low plasma midazolam concentrations in the patient group were associated with reduced pharmacodynamic effects as compared with control subjects [e.g., the Critical Flicker Fusion Test (CFFT), p < 0.05]. Induction of CYP3A (cytochrome P‐450IIIA) enzymes by CBZ and PHT is the most likely explanation of the great difference in the pharmacokinetic and pharmacodynamic profiles of oral midazolam in the two groups.

Triazolam is ineffective in patients taking rifampin

Triazolam is metabolized predominantly by cytochrome P450 3A4 (CYP3A4). Rifampin (rifampicin) is a potent inducer of CYP3A4 and it is known to markedly reduce plasma concentrations and effects of drugs such as midazolam. The possible interaction between rifampin and triazolam was examined in this study.

Effect of fluconazole on plasma fluvastatin and pravastatin concentrations.

AbstractObjective: To study the effects of fluconazole on the pharmacokinetics of fluvastatin and pravastatin, two inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.nn Methods: Two separate randomised, double-blind, two-phase, crossover studies with identical study design were carried out. In each study, 12 healthy volunteers were given a 4-day pretreatment with oral fluconazole (400u2009mg on dayu20091 and 200u2009mg on daysu20092–4) or placebo, according to a randomisation schedule. On dayu20094, a single oral dose of 40u2009mg fluvastatin (study I) or 40u2009mg pravastatin (study II) was administered orally. Plasma concentrations of fluvastatin, pravastatin and fluconazole were measured over 24u2009h.nn Results: In study I, fluconazole increased the mean area under the plasma fluvastatin concentration–time curve (AUC0–∞) by 84% (Pu2009<u20090.01), the mean elimination half-life (t1/2) of fluvastatin by 80% (Pu2009<u20090.01) and its mean peak plasma concentration (Cmax) by 44% (Pu2009<u20090.05). In study II, fluconazole had no significant effect on the pharmacokinetics of pravastatin.nn Conclusions: Fluconazole has a significant interaction with fluvastatin. The mechanism of the increased plasma concentrations and prolonged elimination of fluvastatin is probably inhibition of the CYP2C9-mediated metabolism of fluvastatin by fluconazole. Care should be taken if fluconazole or other potent inhibitors of CYP2C9 are prescribed to patients using fluvastatin. However, pravastatin is not susceptible to interactions with fluconazole or other potent CYP2C9 inhibitors.

Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics of pioglitazone.

The thiazolidinedione antidiabetic drug pioglitazone is metabolized mainly by cytochrome P450 (CYP) 2C8 and CYP3A4 in vitro. Our objective was to study the effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics of pioglitazone to determine the role of these enzymes in the fate of pioglitazone in humans.

Polymorphisms of COX-1 and GP VI associate with the antiplatelet effect of aspirin in coronary artery disease patients

The antiplatelet effect of aspirin varies individually. This study evaluated whether the antiplatelet effect of aspirin associates with polymorphisms in the genes coding for cyclo-oxygenase-1 (COX-1) and several platelet glycoprotein (GP) receptors in patients with stable coronary artery disease (CAD). Blood samples were collected from 101 aspirin-treated (mean 100 mg/d) patients. Compliance to treatment was assessed by plasma salicylate measurement. Platelet functions were assessed by two methods: 1) Response to arachidonic acid (AA, 1.5 mmol/L in aggregometry, and 2) PFA-100, evaluating platelet activation under high shear stress in the presence of collagen and epinephrine (CEPI). Aspirin non-response was defined as: 1) slope steeper than 12%/min in AA-aggregations, and 2) by closure time shorter than 170 s in PFA-100. The methods used detected different individuals as being aspirin non-responders. Five and 21 patients, respectively, were non-responders according to AA-induced aggregation and PFA-100. Increased plasma thromboxane B2 levels correlated with poor aspirin-response measured with both AA-induced aggregations and PFA-100 (P = 0.02 and P = 0.003, respectively). Of the non-responders detected by AA, 3 of 5 (60%) carried the rare G allele for the -A842G polymorphism of COX-1 in contrast to 16 of 96 (17%) responders (P = 0.016). Diabetes was associated with poor response. Aspirin non-response detected by PFA-100 associated with C13254T polymorphism of GP VI and female gender (P = 0.012 and P = 0.019, respectively). Although two patients were possibly non-compliant, this did not effect present conclusions. Evaluation of aspirin efficacy by AA-induced aggregation and PFA-100 detected different individuals, with different genotypic profiles, as being aspirin non-responders.