Itraconazole Phase Research Articles

Pharmacokinetic and Pharmacodynamic Interaction of Nadolol With Itraconazole, Rifampicin and Grapefruit Juice in Healthy Volunteers

To evaluate effects of itraconazole, rifampicin and grapefruit juice on pharmacokinetics and pharmacodynamics of a hydrophilic non-selective β-adrenoceptor blocker nadolol, we conducted an open-label, four-way crossover study in 10 healthy male volunteers. A single oral dose of 30 mg nadolol was administered with water (control), itraconazole (100 mg), or grapefruit juice (300 mL), or after a 6-day pretreatment with rifampicin (450 mg/day). Plasma concentrations and urinary excretions of nadolol were measured over 48 hours after its dosing. Systolic and diastolic blood pressures and pulse rate were periodically recorded after nadolol administration as pharmacodynamic parameters. Itraconazole increased the peak plasma concentration and the area under the plasma concentration-time curve (AUC0-∞ ) of nadolol by 468% and 224% of control, respectively (P < .001). A slight, but not statistically significant, decrease in AUC0-∞ of nadolol was observed in rifampicin and grapefruit juice phases as compared to control. Elimination half-life for nadolol did not differ among the four phases. During itraconazole phase, nadolol reduced pharmacodynamic parameters to a greater extent than the other phases. These results suggest that itraconazole substantially increases the oral availability of nadolol possibly by the inhibition of intestinal P-glycoprotein, whereas grapefruit juice has little effect on nadolol pharmacokinetics.

Ticlopidine inhibits both O-demethylation and renal clearance of tramadol, increasing the exposure to it, but itraconazole has no marked effect on the ticlopidine-tramadol interaction

We assessed possible drug interactions of tramadol given concomitantly with the potent CYP2B6 inhibitor ticlopidine, alone or together with the potent CYP3A4 and P-glycoprotein inhibitor itraconazole. In a randomized, placebo-controlled cross-over study, 12 healthy subjects ingested 50 mg of tramadol after 4 days of pretreatment with either placebo, ticlopidine (250 mg twice daily) or ticlopidine plus itraconazole (200 mg once daily). Plasma and urine concentrations of tramadol and its active metabolite O-desmethyltramadol (M1) were monitored over 48 h and 24 h, respectively. Ticlopidine increased the mean area under the plasma concentration-time curve (AUC0-∞) of tramadol by 2.0-fold (90 % confidence interval (CI) 1.6-2.4; p < 0.001) and Cmax by 1.4-fold (p < 0.001), and reduced its oral and renal clearance (p < 0.01). Ticlopidine reduced the AUC0-3 of M1 (p < 0.001) and the ratio of the AUC0-∞ of M1 to that of tramadol, but did not influence the AUC0-∞ of M1. Tramadol or M1 pharmacokinetics did not differ between the ticlopidine alone and ticlopidine plus itraconazole phases. Ticlopidine increased exposure to tramadol, reduced its renal clearance and inhibited the formation of M1, most likely via inhibition of CYP2B6 and/or CYP2D6. The addition of itraconazole to ticlopidine did not modify the outcome of the drug interaction. Concomitant clinical use of ticlopidine and tramadol may enhance the risk of serotonergic effects, especially when higher doses of tramadol are used.

Fluconazole but not the CYP3A4 inhibitor, itraconazole, increases zafirlukast plasma concentrations

Zafirlukast is a substrate of cytochrome P450 2C9 (CYP2C9) and cytochrome P450 3A4 (CYP3A4) in vitro, but the role of these enzymes in its metabolism in vivo is unknown. To investigate the contribution of CYP2C9 and CYP3A4 to zafirlukast metabolism, we studied the effects of fluconazole and itraconazole on its pharmacokinetics (PK). In a randomized crossover study, 12 healthy volunteers ingested fluconazole 200 mg (first dose 400 mg) once daily, itraconazole 100 mg (first dose 200 mg) twice daily, or placebo twice daily for 5 days, and on day 3, 20 mg zafirlukast. Plasma concentrations of zafirlukast and the antimycotics were measured up to 72 h. Fluconazole increased the total area under the plasma concentration-time curve (AUC) of zafirlukast 1.6-fold [95% confidence interval (CI) 1.3-2.0-fold, P < 0.001), and its peak plasma concentration 1.5-fold (95% CI 1.2-2.0-fold, P < 0.05). Fluconazole did not affect the time of peak plasma concentration or elimination half-life of zafirlukast. None of the zafirlukast PK variables differed significantly from the control in the itraconazole phase; e.g., the ratio to control of the total AUC of zafirlukast was 1.0 (95% CI 0.82-1.2) during the itraconazole phase. Fluconazole, but not itraconazole, increases zafirlukast plasma concentrations, strongly suggesting that CYP2C9 but not CYP3A4 participates in zafirlukast metabolism in humans.

Exposure to Oral S-ketamine Is Unaffected by Itraconazole but Greatly Increased by Ticlopidine

This study examined drug-drug interactions of oral S-ketamine with the cytochrome P450 (CYP) 2B6 inhibitor ticlopidine and the CYP3A inhibitor itraconazole. In this randomized, blinded, crossover study, 11 healthy volunteers ingested 0.2 mg/kg S-ketamine after pretreatments with oral ticlopidine (250 mg twice daily), itraconazole (200 mg once daily), or placebo in 6-day treatment periods at intervals of 4 weeks. Ticlopidine treatment increased the mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0-∞)) of oral ketamine by 2.4-fold (P < 0.001), whereas itraconazole treatment did not increase the exposure to S-ketamine. The ratio of norketamine AUC(0-∞) to ketamine AUC(0-∞) was significantly decreased in the ticlopidine (P < 0.001) and itraconazole phases (P = 0.006) as compared to placebo. In the ticlopidine and itraconazole phases, the areas under the effect-time curves (self-reported drowsiness and performance) were significantly higher than those in the placebo phase (P < 0.05). The findings suggest that the dosage of S-ketamine should be reduced in patients receiving ticlopidine.

Itraconazole, a P-Glycoprotein and CYP3A4 Inhibitor, Markedly Raises the Plasma Concentrations and Enhances the Renin-Inhibiting Effect of Aliskiren

In a randomized crossover study, 11 healthy volunteers took 100 mg (first dose 200 mg) of the antifungal drug itraconazole, a P-glycoprotein and CYP3A4 inhibitor, or placebo twice daily for 5 days. On day 3, they ingested a single 150-mg dose of aliskiren, a renin inhibitor used in the treatment of hypertension. Itraconazole raised the peak plasma aliskiren concentration 5.8-fold (range, 1.1- to 24.3-fold; P < .001) and the area under the plasma aliskiren concentration-time curve 6.5-fold (range, 2.6- to 20.5-fold; P < .001) but had no significant effect on aliskiren elimination half-life. Itraconazole increased the amount of aliskiren excreted into the urine during 12 hours 8.0-fold (P < .001) and its renal clearance 1.2-fold (P = .042). Plasma renin activity 24 hours after aliskiren intake was 68% lower during the itraconazole phase than during the placebo phase (P = .011). In conclusion, itraconazole markedly raises the plasma concentrations and enhances the renin-inhibiting effect of aliskiren. The interaction is probably mainly explained by inhibition of the P-glycoprotein-mediated efflux of aliskiren in the small intestine, with a minor contribution from inhibition of CYP3A4. Concomitant use of aliskiren and itraconazole is best avoided.

Aging behavior of pharmaceutical formulations of itraconazole on SBA-15 ordered mesoporous silica carrier material

SBA-15 ordered mesoporous material is an excellent carrier material for the poorly soluble drug molecule itraconazole. Immediate itraconazole release is obtained upon contacting the formulation with simulated biological fluid. The stability of the formulation upon storage was investigated. Samples were stored for 3, 6 and 12 months at 4 and 25 °C and relative humidity of 0%, 52% and 97%. The original release behavior was maintained upon storage in dry conditions. Surprisingly, long-term storage at a relative humidity of 52% or 97% had a beneficial effect on the release. The surface chemical modification of the formulation upon storage in humid atmosphere was investigated using nitrogen adsorption, 29Si MAS NMR, TGA–MS, XPS and DSC. Itraconazole phase analysis using DSC and analysis of the presence of itraconazole concentration gradients using XPS revealed that storage did not cause migration, aggregation nor crystallization of itraconazole. The surface of the pores of SBA-15 was found to undergo hydroxylation at high relative humidity. The enhanced hydrophilicity was responsible for the observed improvement of itraconazole release upon contact with water. These findings contribute to the understanding of drug delivery systems based on mesoporous silica carrier materials.

Voriconazole Increases while Itraconazole Decreases Plasma Meloxicam Concentrations

This study investigated the effect of voriconazole, an inhibitor of cytochrome P450 2C9 (CYP2C9) and CYP3A4, and itraconazole, an inhibitor of CYP3A4, on the pharmacokinetics and pharmacodynamics of meloxicam. Twelve healthy volunteers in a crossover study ingested 15 mg of meloxicam without pretreatment (control), after voriconazole pretreatment, and after itraconazole pretreatment. The plasma concentrations of meloxicam, voriconazole, itraconazole, and thromboxane B(2) (TxB(2)) generation were monitored. Compared to the control phase, voriconazole increased the mean area under the plasma concentration-time curve from 0 to 72 h (AUC(0-72)) of meloxicam by 47% (P < 0.001) and prolonged its mean half-life (t(1/2)) by 51% (P < 0.01), without affecting its mean peak concentration (C(max)). In contrast, itraconazole decreased the mean AUC(0-72) and C(max) of meloxicam by 37% (P < 0.001) and by 64% (P < 0.001), respectively, and prolonged its t(1/2) and time to C(max). The plasma protein unbound fraction of meloxicam was unchanged by voriconazole and itraconazole. Lowered plasma meloxicam concentrations during the itraconazole phase were associated with decreased pharmacodymic effects of meloxicam, as observed by weaker inhibition of TxB(2) synthesis compared to the control and voriconazole phases. Voriconazole increases plasma concentrations of meloxicam, whereas itraconazole, unexpectedly, decreases plasma meloxicam concentrations, possibly by impairing its absorption.

The different effects of itraconazole on the pharmacokinetics of fexofenadine enantiomers

Recently, we have shown that the plasma concentration of R-fexofenadine is greater than that of the S-enantiomer. Although itraconazole co-administration is known to increase the bioavailability of a racemic mixture of fexofenadine, little is known about the stereoselective inhibition of P-gp activity by itraconazole. This study indicates that the stereoselective pharmacokinetics of fexofenadine are due to P-gp-mediated transport and its stereoselectivity is altered by itraconazole, a an inhibitor of P-gp. The aim of this study was to determine the inhibitory effect of itraconazole, a P-glycoprotein (P-gp) inhibitor, on the stereoselective pharmacokinetics of fexofenadine. A two-way double-blind, placebo-controlled crossover study was performed with a 2-week washout period. Twelve healthy volunteers received either itraconazole 200 mg or matched placebo in a randomized fashion with a single oral dose of fexofenadine 60 mg simultaneously. The plasma concentrations and the amount of urinary excretion (Ae) of fexofenadine enantiomers were measured up to 24 h after dosing. After placebo administration, mean AUC(0,24 h) of S- and R-fexofenadine was 474 ng ml(-1) h (95% CI 311, 638) and 798 ng ml(-1) h (95% CI 497, 1101), respectively. Itraconazole affected the pharmacokinetic parameters of S-fexofenadine more, and increased AUC(0,24 h) of S-fexofenadine and R-fexofenadine by 4.0-fold (95% CI of differences 2.8, 5.3; P < 0.001) and by 3.1-fold (95% CI of differences 2.2, 4.0; P = 0.014), respectively, and Ae(0,24 h) of S-fexofenadine and R-fexofenadine by 3.6-fold (95% CI of differences 2.6, 4.5; P < 0.001) and by 2.9-fold (95% CI of differences 2.1, 3.8; P < 0.001), respectively. Additionally, the R : S ratio for AUC(0,24 h) and Ae(0,24 h) were significantly reduced in the itraconazole phase, while t(max), t(1/2) and renal clearance were constant during the study. This study indicates that the stereoselective pharmacokinetics of fexofenadine are due to P-gp-mediated transport and its stereoselectivity is altered by itraconazole, a P-gp inhibitor. However, further study will be needed because the different affinities of the two enantiomers for P-gp have not been supported by in vitro studies.

Formulation and characterization of ternary solid dispersions made up of Itraconazole and two excipients, TPGS 1000 and PVPVA 64, that were selected based on a supersaturation screening study

Both d-alpha-tocopheryl polyethylene glycol 1000 (TPGS 1000) and polyvidone-vinylacetate 64 (PVPVA 64) provided an increase in the degree of supersaturation and stability of supersaturated Itraconazole solutions, compared to a blanc without excipient. Therefore, both components were combined as carrier in order to make ternary solid dispersions of Itraconazole by spray drying. This way, TPGS 1000 could be incorporated into a powder. Dissolution experiments on the ternary solid dispersions revealed that during the first hour the release was much higher than for the binary Itraconazole/PVPVA 64 solid dispersions. For some compositions a release of more than 80% was reached after 10min. However, after the first hour the drug started to precipitate. The ternary solid dispersions were all XRD amorphous, but MDSC revealed the coexistence of multiple amorphous phases and a crystalline Itraconazole phase, depending on the composition. Therefore the burst effect during the first hour can be ascribed to an accelerated dissolution of the amorphous Itraconazole fraction in the presence of TPGS 1000. The precipitation after 1h, however, is probably due to the combination of the surfactant properties of TPGS and the small crystalline Itraconazole fraction.

Delivery of Itraconazole from Extruded HPC Films

ABSTRACTThe treatment of onychomycosis by oral delivery is problematic due to the high concentrations required and if available, a topical transcuticular route would be preferred. Towards this end the hot-melt extruded hydroxypropylcellulose based films containing anti-fungal drug itraconazole and α−tocopherol topical treatment for onychomycosis were studied. DSC and X-ray measurements did not show a crystalline itraconazole phase indicating the drug is present in the amorphous state. The rate of itraconazole release trended directly with the degree of film hydration and inversely to the hydroxypropylcellulose molecular weight. This results from a higher degree of crystallinity of the HPC films which also changes the release kinetics from first order to zero order as a more tortuous path is created.

Lack of Dose-Dependent Effects of Itraconazole on the Pharmacokinetic Interaction with Fexofenadine

The aim of this study was to determine the inhibitory effect of itraconazole at different coadministered doses on fexofenadine pharmacokinetics. In a randomized four-phase crossover study, 11 healthy volunteers were administered a 60-mg fexofenadine hydrochloride tablet alone on one occasion (control phase) and with three different doses of 50, 100, and 200 mg of itraconazole simultaneously on the other three occasions (itraconazole phase). Although the elimination half-life and the renal clearance of fexofenadine remained relatively constant, a single administration of itraconazole with fexofenadine significantly increased mean area under the plasma concentration-time curve (AUC(0-infinity)) of fexofenadine (1701/3554, 4308, and 4107 ng h/ml for control; 50 mg, 100 mg, and 200 mg of itraconazole, respectively). Although mean itraconazole AUC(0-48) from 50 mg to 200 mg increased dose dependently from 214 to 772 ng h/ml (p = 0.003), no significant difference was noted in the three parameters, AUC (p = 0.423), C(max) (p = 0.636), and renal clearance (p = 0.495), of fexofenadine among the three doses of itraconazole. Itraconazole exposure at a lower dose (50 mg) compared with the clinical dose (200 mg once or twice daily) had the maximal effect on fexofenadine pharmacokinetics, even though itraconazole plasma concentrations gradually increased after higher doses. These findings suggest that the interaction may occur at the gut wall before reaching the portal vein circulation, and the inhibitory effect must be saturated by substantial local concentrations of itraconazole in the gut lumen after 50-mg dosing.

Effects of itraconazole and diltiazem on the pharmacokinetics of fexofenadine, a substrate of P‐glycoprotein

Fexofenadine is a substrate of several drug transporters including P-glycoprotein. Our objective was to evaluate the possible effects of two P-glycoprotein inhibitors, itraconazole and diltiazem, on the pharmacokinetics of fexofenadine, a putative probe of P-glycoprotein activity in vivo, and compare the inhibitory effect between the two in healthy volunteers. In a randomized three-phase crossover study, eight healthy volunteers were given oral doses of 100 mg itraconazole twice daily, 100 mg diltiazem twice daily or a placebo capsule twice daily (control) for 5 days. On the morning of day 5 each subject was given 120 mg fexofenadine, and plasma concentrations and urinary excretion of fexofenadine were measured up to 48 h after dosing. Itraconazole pretreatment significantly increased mean (+/-SD) peak plasma concentration (Cmax) of fexofenadine from 699 (+/-366) ng ml-1 to 1346 (+/-561) ng ml-1 (95% CI of differences 253, 1040; P<0.005) and the area under the plasma concentration-time curve [AUC0,infinity] from 4133 (+/-1776) ng ml-1 h to 11287 (+/-4552) ng ml-1 h (95% CI 3731, 10575; P<0.0001). Elimination half-life and renal clearance in the itraconazole phase were not altered significantly compared with those in the control phase. In contrast, diltiazem pretreatment did not affect Cmax (704+/-316 ng ml-1, 95% CI -145, 155), AUC0, infinity (4433+/-1565 ng ml-1 h, 95% CI -1353, 754), or other pharmacokinetic parameters of fexofenadine. Although some drug transporters other than P-glycoprotein are thought to play an important role in fexofenadine pharmacokinetics, itraconazole pretreatment increased fexofenadine exposure, probably due to the reduced first-pass effect by inhibiting the P-glycoprotein activity. As diltiazem pretreatment did not alter fexofenadine pharmacokinetics, therapeutic doses of diltiazem are unlikely to affect the P-glycoprotein activity in vivo.

Itraconazole increases but grapefruit juice greatly decreases plasma concentrations of celiprolol

Our objective was to evaluate the effects of itraconazole and grapefruit juice on the pharmacokinetics of the beta-adrenergic receptor-blocking agent celiprolol in healthy volunteers. In a randomized 3-phase crossover study, 12 healthy volunteers took itraconazole 200 mg orally or placebo twice a day or 200 mL grapefruit juice 3 times a day for 2 days. On the morning of day 3, 1 hour after ingestion of itraconazole, placebo, or grapefruit juice, each subject ingested 100 mg celiprolol with 200 mL of water (placebo and itraconazole phases) or grapefruit juice. In addition, 200 mL of water or grapefruit juice was ingested 4 and 10 hours after celiprolol intake. The plasma concentrations of celiprolol, itraconazole, and hydroxyitraconazole and the excretion of celiprolol into urine were measured up to 33 hours after dosing. Systolic and diastolic blood pressures and heart rate were recorded with subjects in a sitting position before the administration of celiprolol and 2, 4, 6, and 10 hours later. During the itraconazole phase, the mean area under the plasma concentration-time curve from 0 to 33 hours [AUC(0-33)] of celiprolol was 80% greater (P <.05) than in the placebo phase. During the grapefruit juice phase, the mean AUC(0-33) and peak plasma concentration values of celiprolol were reduced to about 13% (P <.001) and 5% (P <.001) of the respective placebo phase values. The cumulative excretion into urine of celiprolol was increased by 59% by itraconazole (P <.05) and decreased by 85% by grapefruit juice (P <.001). Hemodynamic variables did not differ between the phases. Itraconazole almost doubles but grapefruit juice greatly reduces plasma concentrations of celiprolol. The itraconazole-celiprolol interaction most likely resulted from increased absorption of celiprolol possibly as a result of P-glycoprotein inhibition in the intestine. The reduced celiprolol concentrations during the grapefruit juice phase were probably caused by physicochemical factors that interfered with celiprolol absorption, although other mechanisms cannot be excluded. The grapefruit juice-celiprolol interaction is probably of clinical relevance.

Itraconazole drastically increases plasma concentrations of lovastatin and lovastatin acid

Lovastatin is a cholesterol-lowering drug that can cause myopathy as a rare side effect. Concomitant use of certain drugs (e.g., cyclosporine) increases the risk of skeletal muscle toxicity. Lovastatin is metabolized by CYP3A4. Because itraconazole is a potent inhibitor of CYP3A4, we wanted to study a possible interaction between these drugs. In this double-blind, randomized, two-phase crossover study, 12 healthy volunteers received either 200 mg itraconazole or placebo orally once a day for 4 days. On day 4, each subject ingested a single 40 mg dose of lovastatin. Plasma concentrations of lovastatin, lovastatin acid, itraconazole, hydroxyitraconazole, and creatine kinase were measured up to 24 hours. On average, itraconazole increased the peak concentration (Cmax) of lovastatin and the area under the lovastatin concentration-time curve (AUC) more than twentyfold (p < 0.001). The mean Cmax of the active metabolite, lovastatin acid, was increased 13-fold (range, tenfold to 23-fold; p < 0.001) and the AUC(0-24) twentyfold (p < 0.001). In one subject plasma creatine kinase was increased tenfold within 24 hours of lovastatin administration during the itraconazole phase but not during the placebo phase. No increase in creatine kinase was observed in the other subjects. Itraconazole greatly increases plasma concentrations of lovastatin and lovastatin acid. Inhibition of CYP3A4-mediated metabolism probably explains the increased toxicity of lovastatin caused not only by itraconazole but also by cyclosporine, erythromycin, and other inhibitors of CYP3A4. Their concomitant use with lovastatin and simvastatin should be avoided, or the dose of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors should be reduced accordingly.

Effect of itraconazole and terbinafine on the pharmacokinetics and pharmacodynamics of midazolam in healthy volunteers

Twelve healthy volunteers were given orally placebo, itraconazole 100 mg or terbinafine 250 mg for 4 days. Midazolam 7.5 mg was ingested on the fourth day, after which plasma samples were collected and psychomotor performance tests carried out for 17 h. Itraconazole increased the area under the midazolam concentration-time curve six-fold (P < 0.001), the peak concentration 2.5-fold (P < 0.001) and the elimination half-life two-fold (P < 0.001) compared with placebo and terbinafine pretreatments. The pharmacokinetic parameters did not differ between placebo and terbinafine phases. The higher concentrations of midazolam during the itraconazole phase were associated with increased effects. In contrast to itraconazole, terbinafine had no effect on midazolam pharmacokinetics and psychomotor performance tests were unchanged from placebo.

Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole

Triazolam is metabolized by CYP3A4 isozyme. Ketoconazole and itraconazole may seriously interact with some of the substrates of CYP3A4 (e.g., terfenadine); hence their possible interaction with triazolam in humans is important to uncover. In this double-blind, randomized, three-phase crossover study, the interaction between ketoconazole, itraconazole, and triazolam was investigated. Nine healthy young volunteers received either 400 mg ketoconazole, 200 mg itraconazole, or matched placebo (control phase) orally once a day for 4 days. On day 4, each ingested a single 0.25 mg dose of triazolam. Plasma concentrations of triazolam and antimycotics were determined, and pharmacodynamic effects were measured up to 17 hours. On average, ketoconazole and itraconazole increased the area under the triazolam concentration-time curve [AUC(0-infinity)] 22-fold and 27-fold (p < 0.001), the peak concentrations threefold (p < 0.001), and the elimination half-life sixfold and sevenfold (p < 0.001), respectively. In seven of the nine subjects, even the maximum concentration of triazolam in plasma was lower without the antimycotics than were the 17-hour concentrations during the ketoconazole and itraconazole phases. All pharmacodynamic effects (e.g., the Digit Symbol Substitution Test) revealed a significant difference between the antimycotic and placebo phases. Both ketoconazole and itraconazole seriously affect the pharmacokinetics of triazolam and increase the intensity and duration of its effects. Inhibition of CYP3A4 during the absorption and elimination phases of triazolam seems to explain the interaction observed. Because of the potentially hazardous consequences of this interaction, triazolam should be avoided if patients are using ketoconazole or itraconazole.