Pharmacokinetic drug interactions with vandetanib during coadministration with rifampicin or itraconazole

Objective: The aim of this study was to investigate the effects of a potent CYP3A4 inducer, rifampicin (Study A), and a potent CYP3A4 inhibitor, itraconazole (Study B), on the pharmacokinetics of a single 300mg dose of vandetanib in healthy subjects.Study Design and Setting: Two phase I, randomized, open-label, two-way crossover, single-center studies. Participants and Intervention: Study A: 18 healthy male subjects aged 21–44 years were randomized to receive each of the following two regimens, separated by a ≥6-week washout period: (i) oral rifampicin 600mg/day on days 1–31 with a single oral dose of vandetanib 300mg on day 10; and (ii) a single oral dose of vandetanib 300mg on day 1. Study B: 16 healthy male subjects aged 20–44 years were randomized to receive each of the following two regimens, separated by a 3-month washout period: (i) oral itraconazole 200mg/day on days 1–24 with a single oral dose of vandetanib 300mg on day 4; and (ii) a single oral dose of vandetanib 300mg on day 1.Main Outcome Measure: Blood samples for measurement of vandetanib (both studies) concentrations and its metabolites, N-desmethylvandetanib and vandetanib N-oxide (Study A only), were collected before and at various timepoints after vandetanib administration for up to 28 days (Study A) and 37 days (Study B). Pharmacokinetic parameters were determined using noncompartmental methods. The area under the plasma concentration-time curve from time 0 to 504 hours (AUC₅₀₄) and maximum plasma concentration (C_max) of vandetanib were compared in the presence and absence of rifampicin, and in the presence and absence of itraconazole.Results: Study A: coadministration of vandetanib with rifampicin resulted in a statistically significant reduction in AUC₅₀₄ (geometric least square [GLS]mean ratio [vandetanib + rifampicin/vandetanib alone] 0.60; 90% CI 0.58, 0.63). There was no significant difference in C_max of vandetanib (GLSmean ratio 1.03; 90% CI 0.95, 1.11). AUC₅₀₄ and C_max of N-desmethylvandetanib increased by 266.0% and 414.3%, respectively, in the presence of rifampicin compared with vandetanib alone. Exposure to vandetanib N-oxide was very low compared with that of vandetanib, but was increased in the presence of rifampicin. Study B: coadministration of vandetanib with itraconazole resulted in a significant increase in AUC₅₀₄ (GLSmean ratio [vandetanib + itraconazole/vandetanib alone] 1.09; 90% CI 1.01, 1.18) and no significant change in C_max (GLSmean ratio 0.96; 90% CI 0.83, 1.11). Vandetanib was well tolerated in both studies.Conclusions: Exposure to vandetanib, as assessed byAUC₅₀₄ in healthy subjects, was reduced by around 40% when a single dose was given in combination with the potent CYP3A4 inducer rifampicin. Because of this, it may be appropriate to avoid coadministration of potent CYP3A4 inducers with vandetanib. Vandetanib exposure was increased by about 9% when it was taken in combination with the CYP3A4 inhibitor itraconazole. It is unlikely that coadministration of vandetanib and potent CYP3A4 inhibitors will need to be contraindicated.     

Absolute bioavailability of imidafenacin after oral administration to healthy subjects

Aims

To investigate the absolute bioavailability of imidafenacin, a new muscarinic receptor antagonist, a single oral dose of 0.1 mg imidafenacin was compared with an intravenous (i.v.) infusion dose of 0.028 mg of the drug in healthy subjects.

Methods

Fourteen healthy male subjects, aged 21–45 years, received a single oral dose of 0.1 mg imidafenacin or an i.v. infusion dose of 0.028 mg imidafenacin over 15 min at two treatment sessions separated by a 1-week wash-out period. Plasma concentrations of imidafenacin and the major metabolites M-2 and imidafenacin-N-glucuronide (N-Glu) were determined. The urinary excretion of imidafenacin was also evaluated. Analytes in biological samples were measured by liquid chromatography tandem mass spectrometry.

Results

The absolute oral bioavailability of imidafenacin was 57.8% (95% confidence interval 54.1, 61.4) with a total clearance of 29.5 ± 6.3 l h⁻¹. The steady-state volume of distribution was 122 ± 28 l, suggesting that imidafenacin distributes to tissues. Renal clearance after i.v. infusion was 3.44 ± 1.08 l h⁻¹, demonstrating that renal clearance plays only a minor role in the elimination of imidafenacin. The ratio of AUC_t of both M-2 and N-Glu to that of imidafenacin was reduced after i.v. infusion from that seen after oral administration, suggesting that M-2 and N-Glu in plasma after oral administration were generated primarily due to first-pass metabolism. No serious adverse events were reported during the study.

Conclusions

The absolute mean oral bioavailability of imidafenacin was determined to be 57.8%. Imidafenacin was well tolerated following both oral administration and i.v. infusion.

What is already known about this subject

• The absolute bioavailability of imidafenacin in rats and dogs is 5.6% and 36.1%, respectively.
• The pharmacokinetic profiles of imidafenacin after oral administration have been revealed.
• Imidafenacin is primarily metabolized to metabolites by CYP3A4 and UGT1A4.

What this study adds

• The absolute bioavailability of imidafenacin in human is 57.8%.
• The pharmacokinetic profiles of imidafenacin after intravenous administration are revealed.
• The formation of metabolites in the plasma is caused mainly by first-pass effects.

     

Effect of itraconazole on the pharmacokinetics of prednisolone and methylprednisolone and cortisol secretion in healthy subjects

AIMS: Itraconazole is a potent inhibitor of CYP3A4 activity and is often used in combination with corticosteroids. Since the latter are partly metabolized by CYP3A4, we studied the interaction between itraconazole, prednisone and methylprednisolone in healthy male subjects. METHODS: The effects of 4 days administration of oral itraconazole (400 mg on the first day then 200 mg day-1 for 3 days) on the pharmacokinetics of prednisolone after a single oral dose of prednisone (60 mg) and the pharmacokinetics of methylprednisolone after single oral dose of methylprednisolone (48 mg) were studied in 14 healthy male subjects in a two-period cross-over trial. Plasma cortisol concentrations were determined as a pharmacodynamic index. RESULTS: Itraconazole increased the mean area under the methylprednisolone concentration-time curve from 2773 ng ml-1 h to 7011 ng ml-1 h (P < 0.001) and the elimination half-life from 3.2 h to 5.5 h (P < 0.001). The pharmacokinetics of prednisolone were unchanged. Cortisol concentrations at 24 h were lower after administration of methylprednisolone with itraconazole than after methylprednisolone alone (24 ng ml-1 vs 109 ng ml-1, P < 0.001). CONCLUSIONS: Itraconazole increased methylprednisolone concentrations markedly with enhanced suppression of endogenous cortisol secretion, but had no effect on prednisolone pharmacokinetics. The pharmacokinetic interaction between methylprednisolone and itraconazole is probably related to inhibition of hepatic CYP3A4 activity by itraconazole.     

No effect of imidafenacin, a novel antimuscarinic drug, on digoxin pharmacokinetics in healthy subjects

Plasma digoxin concentrations are increased by the coadministration of anticholinergic drugs, such as propantheline, which decrease gastrointestinal motility. The present study evaluated the effect of imidafenacin, a novel anticholinergic drug, on the pharmacokinetics of digoxin. The effect of imidafenacin on the pharmacokinetics of digoxin was examined in 14 healthy Japanese male subjects in a single-centre, open-label, randomized, two-way crossover study. Subjects received a daily oral dose of digoxin 0.25 mg on days 1 and 2 and digoxin 0.125 mg on days 3 to 8 (period 1). Following a 2-week washout period, digoxin was administered orally for 8 days in a similar manner (period 2). A twice daily dose of imidafenacin 0.1 mg was concomitantly administered with digoxin for 8 days either in period 1 or 2. The geometric mean ratios [GMR] (90% confidence intervals [CIs]) for digoxin C(max) and AUC(0-24) (with/without imidafenacin) at steady state were 0.88 (0.74, 1.04) and 1.00 (0.90, 1.10), respectively. The 90% CIs of GMR for digoxin trough concentration, urinary excretion amount and renal clearance at steady state fell within the range of 0.8 to 1.25. The steady-state pharmacokinetics of digoxin is not affected by concomitant administration of imidafenacin in healthy subjects.     

Effects of itraconazole on the plasma kinetics of quazepam and its two active metabolites after a single oral dose of the drug

The effects of itraconazole, a potent inhibitor of cytochrome P450 (CYP) 3A4, on the plasma kinetics of quazepam and its two active metabolites after a single oral dose of the drug were studied. Ten healthy male volunteers received itraconazole 100 mg/d or placebo for 14 days in a double-blind randomized crossover manner, and on the fourth day of the treatment they received a single oral 20-mg dose of quazepam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test and Stanford Sleepiness Scale were conducted up to 240 h after quazepam dosing. Itraconazole treatment did not change the plasma kinetics of quazepam but significantly decreased the peak plasma concentration and area under the plasma concentration-time curve of 2-oxoquazepam and N-desalkyl-2-oxoquazepam. Itraconazole treatment did not affect either of the psychomotor function parameters. The present study thus suggests that CYP 3A4 is partly involved in the metabolism of quazepam.     

Pharmacokinetics of Cinacalcet Hydrochloride When Administered with Ketoconazole

BACKGROUND AND OBJECTIVE: The calcimimetic cinacalcet hydrochloride (cinacalcet) is used for treatment of patients with chronic kidney disease with secondary hyperparathyroidism, a population that commonly receives multiple concurrent medications. Cinacalcet is eliminated primarily via oxidative metabolism mediated, in part, through cytochrome P450 (CYP) 3A4. Thus, the potential for an inhibitor of CYP3A4 to alter the pharmacokinetics of cinacalcet is of clinical importance. The objective of this study was to evaluate the pharmacokinetics of cinacalcet during treatment with a potent CYP3A4 inhibitor, ketoconazole. SUBJECTS AND METHODS: Twenty-four healthy subjects were enrolled in an open-label, crossover, phase I study to receive a single oral dose of cinacalcet (90 mg) alone and with 7 days of ketoconazole (200mg twice daily). Blood samples for pharmacokinetics were collected for up to 72 hours postdose. Cinacalcet plasma concentration-time data were analysed by noncompartmental methods. Pharmacokinetic parameters were analysed using a crossover ANOVA model that included subjects who completed both treatment arms. RESULTS: Twenty subjects completed both treatment arms. The mean area under the plasma concentration-time curve of cinacalcet increased 2.3-fold (90% CI 1.92, 2.67) [range 1.15- to 7.12-fold] and the mean maximum plasma concentration increased 2.2-fold (90% CI 1.67, 2.78) [range 0.904- to 10.8-fold] when administered with ketoconazole, relative to when administered alone. The time to reach the maximum plasma concentration was not significantly affected, and the terminal elimination half-lives were similar between treatments. CONCLUSIONS: Co-administration of a potent CYP3A4 inhibitor moderately increased cinacalcet exposure in study subjects. This suggests that clinicians should monitor parathyroid hormone and calcium concentrations when a patient receiving cinacalcet initiates or discontinues therapy with a strong CYP3A4 inhibitor.     

Effect of itraconazole on the pharmacokinetics and pharmacodynamics of a single oral dose of brotizolam

AIMS: To assess the effect of itraconazole, a potent inhibitor of cytochrome P450 (CYP)3A4, on the single oral dose pharmacokinetics and pharmacodynamics of brotizolam. METHODS: In this randomized, double-blind, cross-over trial 10 healthy male subjects received either itraconazole 200 mg or matched placebo once daily for 4 days. On day 4, a single 0.5 mg dose of brotizolam was administered orally. Plasma concentrations of brotizolam were followed up to 24 h, together with assessment of psychomotor function measured by the digit symbol substitution test (DSST), visual analogue scales and UKU side-effect rating scale. RESULTS: Itraconazole significantly (P < 0.001) decreased the apparent oral clearance (CL/F) (16.47 +/- 4.3 vs 3.91 +/- 2.1), increased the area under the concentration-time curves (AUC) from 0 h to 24 h (28.37 +/- 10.8 vs 68.71 +/- 24.1 ng ml h(-1)), and prolonged the elimination half-life (4.56 +/- 1.4 vs 23.27 +/- 10.3 h) of brotizolam. The AUC(0,24 h) of the DSST (P < 0.001) and the item 'sleepiness' of UKU (P < 0.05) were significantly decreased. CONCLUSIONS: Itraconazole increases plasma concentrations of brotizolam probably via its inhibitory effect on CYP3A4 brotizolam metabolism.     

The role of CYP2C and CYP3A in the disposition of 3-keto-desogestrel after administration of desogestrel

AIMS: Our objective was to study in vivo the role of CYP2C and CYP3A4 in the disposition of 3-keto-desogestrel after administration of desogestrel, by using the selective inhibitors fluconazole (CYP2C) and itraconazole (CYP3A4). METHODS: This study had a three-way crossover design and included 12 healthy females, the data from 11 of whom were analyzed. In the first (control) phase all subjects received a single 150 microg oral dose of desogestrel alone. In the second and third phases subjects received a 4 day pretreatment with either 200 mg fluconazole or 200 mg itraconazole once daily in a randomized balanced order. Desogestrel was given 1 h after the last dose of the CYP inhibitor. Plasma 3-keto-desogestrel concentrations were determined for up to 72 h post dose. RESULTS: Pretreatment with itraconazole for 4 days significantly increased the area under the plasma concentration-time curve (AUC) of 3-keto-desogestrel by 72.4% (95% confidence interval on the difference 12%, 133%; P = 0.024) compared with the control phase, whereas fluconazole pretreatment had no significant effect (95% CI on the difference -42%, 34%). Neither enzyme inhibitor affected significantly the maximum concentration (95% CI on the difference 14%, 124% for itraconazole and -23%, 40% for fluconazole) or elimination half-life (95% CI on the difference -42%, 120% for itraconazole and -24%, 61% for fluconazole) of 3-keto-desogestrel. CONCLUSIONS: According to the present study, the biotransformation of desogestrel to 3-keto-desogestrel did not appear to be mediated by CYP2C9 and CYP2C19 as suggested earlier. However, the further metabolism of 3-keto-desogestrel seems to be catalyzed by CYP3A4.     

Effect of erythromycin and itraconazole on the pharmacokinetics of oral lignocaine

Lignocaine is metabolized by cytochrome P450 3A4 enzyme (CYP3A4), and has a moderate to high extraction ratio resulting in oral bioavailability of 30%. We have studied the possible effect of two inhibitors of CYP3A4, erythromycin and itraconazole, on the pharmacokinetics of oral lignocaine in nine volunteers using a cross-over study design. The subjects were given erythromycin orally (500 mg three times a day), itraconazole (200 mg once a day) or placebo for four days. On day 4, each subject ingested a single dose of 1 mg/kg of oral lignocaine. Plasma samples were collected until 10 hr and concentrations of lignocaine and its major metabolite, monoethylglycinexylidide were measured by gas chromatography. Both erythromycin and itraconazole increased the area under the lignocaine plasma concentration-time curve [AUC(0-infinity)] and lignocaine peak concentrations by 40-70% (P<0.05). Compared to placebo and itraconazole, erythromycin increased monoethylglycinexylidide peak concentrations by approximately 40% (P<0.01) and AUC(0-infinity) by 60% (P<0.01). The clinical implication of this study is that erythromycin and itraconazole may significantly increase the plasma concentrations and toxicity of oral lignocaine. The extent of the interaction of lignocaine with these CYP3A4 inhibitors was, however, less than that of, e.g. midazolam or buspirone, and it did not correlate with the CYP3A4 inhibiting potency of erythromycin and itraconazole.     

Effects of itraconazole and tandospirone on the pharmacokinetics of perospirone

Perospirone is an atypical antipsychotic agent originated and clinically used in Japan. Based on an in vitro study, it is reported that perospirone is mainly metabolized to ID-15036 by cytochrome P450 (CYP) 3A4. In this study, the authors investigated the effects of itraconazole, which is a specific inhibitor of CYP3A4, or tandospirone, which is mainly metabolized by CYP3A4 and is expected to competitively inhibit the activity of this enzyme, on single oral dose pharmacokinetics of perospirone. After pretreatment with 200 mg daily of itraconazole or 10 mg daily of tandospirone for 5 days, 9 healthy male subjects received 8 mg of perospirone. Plasma concentrations of perospirone and ID-15036 up to 10 hours after perospirone dosing were measured by high-performance liquid chromatography (HPLC). The metabolism of perospirone was significantly inhibited by treatment with itraconazole but not by tandospirone. The present study suggests that CYP3A4 is significantly involved in metabolism of perospirone in humans.     

The effect on sotrastaurin pharmacokinetics of strong CYP3A inhibition by ketoconazole

AIMS

Sotrastaurin is an immunosuppressant that reduces T-lymphocyte activation via protein kinase C inhibition. The effect of CYP3A4 inhibition by ketoconazole on the pharmacokinetics of sotrastaurin, a CYP3A4 substrate, was investigated.

METHODS

This was a two-period, single-sequence crossover study in 18 healthy subjects. They received a single 50 mg oral dose of sotrastaurin in period 1 followed by a 14-day inter-treatment phase. In period 2 they received ketoconazole 200 mg twice daily for 6 days and a single 50 mg dose of sotrastaurin on the fourth day of ketoconazole administration.

RESULTS

Co-administration of single-dose sotrastaurin during steady-state ketoconazole increased sotrastaurin C_max by 2.5-fold (90% confidence interval 2.2, 2.9) from 285 ± 128 to 678 ± 189 ng ml⁻¹ and increased AUC by 4.6-fold (4.1, 5.2) from 1666 ± 808 to 7378 ± 3011 ng ml⁻¹ h. Sotrastaurin half-life was nearly doubled from 5.9 ± 1.7 to 10.6 ± 2.5 h. The AUC of the active metabolite N-desmethyl-sotrastaurin was increased by 6.8-fold. Sotrastaurin did not alter ketoconazole steady-state predose plasma concentrations.

CONCLUSIONS

The strong CYP3A4 inhibitor ketoconazole increased sotrastaurin AUC by 4.6-fold. A compensatory reduction in the dose of sotrastaurin is warranted when strong CYP3A4 inhibitors are co-administered.     

Itraconazole decreases the clearance and enhances the effects of intravenously administered methylprednisolone in healthy volunteers.

A possible interaction of itraconazole, a potent inhibitor of CYP3A4, with intravenously administered methylprednisolone, was examined. In this double-blind, randomized, two-phase cross-over study, 9 healthy volunteers received either 200 mg itraconazole or matched placebo orally once a day for 4 days. On day 4, a dose of 16 mg methylprednisolone as sodium succinate was administered intravenously. Plasma concentrations of methylprednisolone, cortisol, itraconazole, and hydroxyitraconazole were determined up to 24 hr. Itraconazole increased the total area under the plasma methylprednisolone concentration-time curve (AUC(0-infinity) 2.6-fold) (P<0.001), while the AUC (12-24) of methylprednisolone was increased 12.2-fold (P<0.001). The systemic clearance of methylprednisolone during the itraconazole phase was 40% of that during the placebo phase (P<0.01). The volume of distribution of methylprednisolone was not affected by itraconazole. The mean elimination half-life of methylprednisolone was increased from 2.1+/-0.3 hr to 4.8+/-0.8 hr (P<0.001) by itraconazole. The mean morning plasma cortisol concentration during the itraconazole phase, measured 24 hr after the administration of methylprednisolone, was only about 9% of that during the placebo phase (11.0+/-9.0 ng/ml versus 117+/-49.2 ng/ml; P<0.001). In conclusion, itraconazole decreases the clearance and increases the elimination half-life of intravenously administered methylprednisolone, resulting in greatly increased exposure to methylprednisolone during the night time and in enhanced adrenal suppression. Care should be taken when itraconazole or other potent inhibitors of CYP3A4 are used concomitantly with methylprednisolone.     

Effect of single and repeat doses of casopitant on the pharmacokinetics of CYP450 3A4 substrates midazolam and nifedipine

AIM

To evaluate the impact of single and repeated doses casopitant on the pharmacokinetics of single dose midazolam and nifedipine (CYP3A substrates) in healthy subjects. The effect on debrisoquine metabolism (CYP2D6 substrate) was also assessed.

METHODS

Three open-label studies were conducted in healthy subjects. In the first study subjects received single dose 50 or 100 mg oral casopitant, single dose 5 mg oral midazolam and single dose 10 mg oral debrisoquine. In the other two studies subjects received repeated doses of 10 mg (study 2), 30, or 120 mg oral casopitant and single doses of 5 mg oral midazolam (study 2) and single doses of 10 mg oral nifedipine (study 3). Plasma concentration–time data were analyzed using standard non-compartmental methods. The effect of casopitant on all probes was assessed using geometric means ratios and corresponding 90% confidence intervals (CIs).

RESULTS

The AUC(0,∞) of midazolam was increased 1.44-fold (90% CI 1.35, 1.54) and 1.52-fold (90% CI 1.41, 1.65) after co-administration with a single dose of 50 or 100 mg casopitant, respectively. Debrisoquine metabolism was unchanged. After 3 days of casopitant administration, midazolam AUC(0,∞) was increased 1.45- (90% CI 1.32, 1.59), 2.02- (90% CI 1.75, 2.32), and 2.67-fold (90% CI 2.18, 3.27) after co-administration with 10, 30 or 120 mg casopitant, respectively. After 14 days of casopitant administration, midazolam AUC(0,∞) was increased 1.51- (90% CI 1.40, 1.63) to 3.49-fold (90% CI 2.98, 4.08). After 3 days of casopitant administration, nifedipine AUC(0,∞) was increased 1.56- (90% CI 1.37, 1.78) and 1.77-fold (90% CI 1.54, 2.04) after co-administration with 30 or 120 mg casopitant, respectively. Similar increases in nifedipine exposure were observed after 14 days of casopitant administration.

CONCLUSIONS

Casopitant is a dose- and duration-dependent weak to moderate inhibitor of CYP3A.     

The utility of CYP3A activity endogenous markers for evaluating drug-drug interaction between sildenafil and CYP3A inhibitors in healthy subjects

Cytochrome P450 (CYP) 3A-related drug-drug interaction (DDI) studies are needed during drug development to determine clinical interaction effects. We aimed to evaluate DDI between sildenafil and two CYP3A inhibitors, clarithromycin and itraconazole, regarding the changes in pharmacokinetics and endogenous markers. An open-label, one-sequence, one-period, two-treatment parallel study was conducted in 32 healthy Korean subjects. Each of 16 subjects were randomly assigned to the clarithromycin and itraconazole groups. Both groups received a single dose of sildenafil 25 mg as a control, and either clarithromycin 250 mg or itraconazole 100 mg was administered four times to inhibit CYP3A activity. Pharmacokinetics of sildenafil showed the similar magnitude of inhibitory effects of the two inhibitors on total CYP3A activity; both inhibitors similarly increased systemic exposure of sildenafil by 2-fold. Urinary 6β–OH–cortisone/cortisone and plasma 4β–OH–cholesterol were significantly decreased after clarithromycin administration but not after itraconazole. A significant correlation between sildenafil CL/F and metabolic markers of CYP3A activity was observed after clarithromycin administration. We confirmed that sildenafil has moderate pharmacokinetic interaction with clarithromycin and itraconazole. Endogenous markers well reflected the CYP3A inhibition of clarithromycin, suggesting possible utility in DDI study with moderate to strong CYP3A inhibition; however, there are limitations in predicting intestinal CYP3A mediated DDI.     

Effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of alprazolam

To assess the effect of itraconazole, a potent inhibitor of cytochrome P450 (CYP) 3A4, on the single oral dose pharmacokinetics and pharmacodynamics of alprazolam, the study was conducted in a double-blind randomized crossover manner with two phases of treatment with itraconazole-placebo or placebo-itraconazole. Ten healthy male subjects receiving itraconazole 200?mg/day or matched placebo orally for 6 days took an oral 0.8?mg dose of alprazolam on day 4 of each treatment phase. Plasma concentration of alprazolam was measured up to 48?h after alprazolam dosing, together with the assessment of psychomotor function by the Digit Symbol Substitution Test, Visual Analog Scale and Udvalg for kliniske undersøgelser side effect rating scale. Itraconazole significantly (P?相似文献   

Itraconazole Decreases the Clearance and Enhances the Effects of Intravenously Administered Methylprednisolone in Healthy Volunteers

Abstract: A possible interaction of itraconazole, a potent inhibitor of CYP3A4, with intravenously administered methylprednisolone, was examined. In this double-blind, randomized, two-phase cross-over study, 9 healthy volunteers received either 200 mg itraconazole or matched placebo orally once a day for 4 days. On day 4, a dose of 16 mg methylprednisolone as sodium succinate was administered intravenously. Plasma concentrations of methylprednisolone, cortisol, itraconazole, and hydroxyitraconazole were determined up to 24 hr. Itraconazole increased the total area under the plasma methylprednisolone concentration-time curve (AUC(0-∞) 2.6-fold) (P<0.001), while the AUC (12–24) of methylprednisolone was increased 12.2-fold (P<0.001). The systemic clearance of methylprednisolone during the itraconazole phase was 40% of that during the placebo phase (P<0.01). The volume of distribution of methylprednisolone was not affected by itraconazole. The mean elimination half-life of methylprednisolone was increased from 2.1±0.3 hr to 4.8±0.8 hr (P<0.001) by itraconazole. The mean morning plasma cortisol concentration during the itraconazole phase, measured 24 hr after the administration of methylprednisolone, was only about 9% of that during the placebo phase (11.0±9.0 ng/ml versus 117±49.2 ng/ml; P<0.001). In conclusion, itraconazole decreases the clearance and increases the elimination half-life of intravenously administered methylprednisolone, resulting in greatly increased exposure to methylprednisolone during the night time and in enhanced adrenal suppression. Care should be taken when itraconazole or other potent inhibitors of CYP3A4 are used concomitantly with methylprednisolone.     

Exposure to oral oxycodone is increased by concomitant inhibition of CYP2D6 and 3A4 pathways, but not by inhibition of CYP2D6 alone

AIM

The aim of this study was to find out whether the inhibition of cytochrome P450 2D6 (CYP2D6) with paroxetine or concomitant inhibition of CYP2D6 and CYP3A4 with paroxetine and itraconazole, altered the pharmacokinetics and pharmacological response of orally administered oxycodone.

METHODS

A randomized placebo-controlled cross-over study design with three phases was used. Eleven healthy subjects ingested 10 mg of oral immediate release oxycodone on the fourth day of pre-treatment with either placebo, paroxetine (20 mg once daily) or paroxetine (20 mg once daily) and itraconazole (200 mg once daily) for 5 days. The plasma concentrations of oxycodone and its oxidative metabolites were measured for 48 h, and pharmacological (analgesic and behavioural) effects were evaluated.

RESULTS

Paroxetine alone reduced the area under concentration–time curve (AUC(0,0–48 h)) of the CYP2D6 dependent metabolite oxymorphone by 44% (P < 0.05), but had no significant effects on the plasma concentrations of oxycodone or its pharmacological effects when compared with the placebo phase. When both oxidative pathways of the metabolism of oxycodone were inhibited with paroxetine and itraconazole, the mean AUC(0,∞) of oxycodone increased by 2.9-fold (P < 0.001), and its C_max by 1.8-fold (P < 0.001). Visual analogue scores for subjective drug effects, drowsiness and deterioration of performance were slightly increased (P < 0.05) after paroxetine + itraconazole pre-treatment when compared with placebo.

CONCLUSIONS

Drug interactions arising from CYP2D6 inhibition most likely have minor clinical importance for oral oxycodone if the function of the CYP3A4 pathway is normal. When both CYP2D6 and CYP3A4 pathways are inhibited, the exposure to oral oxycodone is increased substantially.     

Cinacalcet does not affect the activity of cytochrome P450 3A enzymes, a metabolic pathway for common immunosuppressive agents : a randomized, open-label, crossover, single-centre study in healthy volunteers

BACKGROUND and objective: Cinacalcet HCl (cinacalcet) is approved for the treatment of secondary hyperparathyroidism in subjects receiving dialysis and for the reduction of hypercalcaemia in patients with parathyroid carcinoma. The drug may also be co-administered with medications used in the renal transplantation setting, such as immunosuppressants. Cinacalcet, as well as some immunosuppressants such as ciclosporin, tacrolimus and sirolimus, is partially metabolized by the cytochrome P450 3A enzymes (CYP3A). This study aimed to evaluate the potential inhibitory effects of cinacalcet on CYP3A activity using midazolam as a probe substrate in healthy volunteers. METHODS: In this randomized, open-label, crossover, two-treatment, two-period, single-centre study, 12 healthy volunteers received either oral cinacalcet 90 mg once daily for 5 days plus a single oral dose of midazolam 2 mg on day 5, or a single oral dose of midazolam 2 mg on day 1. Following a 10-day washout period, subjects received the alternate treatment. Blood samples were collected predose and at selected time points up to 24 hours after dosing with midazolam for measurement of midazolam pharmacokinetic parameters. RESULTS: Eleven subjects completed the study. Mean (standard deviation) midazolam maximum plasma concentrations (C(max)) and area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) were 9.31 (3.09) ng/mL and 24.1 (7.7) ng . h/mL, respectively, when administered in combination with cinacalcet, compared with 9.76 (2.81) ng/mL and 22.8 (6.1) ng . h/mL when administered alone. The mean geometric ratios (90% confidence interval) were 0.95 (0.84, 1.06) and 1.05 (0.95, 1.16) for C(max) and AUC(infinity), respectively. All adverse events were mild to moderate in severity, and consistent with the safety profile of cinacalcet. CONCLUSION: Once-daily administration of cinacalcet did not alter the pharmacokinetics of midazolam relative to administration of midazolam alone. These data suggest that cinacalcet administration does not affect CYP3A activity, and thus would not have an effect on any drug eliminated via CYP3A, including some commonly used immunosuppressant therapies.     

Pharmacokinetics of moxifloxacin are not influenced by a 7-day pretreatment with 200 mg oral itraconazole given once a day in healthy subjects

AIM: The primary objective of this interaction study was to confirm preclinical data suggesting that moxifloxacin is not metabolized by CYP 450 isozymes. Itraconazole, a strong CYP 3A4 inhibitor, was used as comedication. METHODS: Twelve healthy male subjects were enrolled in this randomized study using 400 mg of oral moxifloxacin (MXF) administered alone and on the 7th day of a 9-day treatment regimen with itraconazole (ITR) 200 mg p.o., o.d. In addition to the assessment of safety and tolerability, non-compartmental pharmacokinetics of moxifloxacin, itraconazole and their respective metabolites were analyzed using plasma concentrations obtained using HPLC. RESULTS: All treatment regimens were safe and well-tolerated. No interaction with itraconazole was observed for moxifloxacin (relative bioavailability: 111.6% (90% CI 106.5 to 117.0%), C(max) ratio: 103.7% (84.8-126.9%) and its sulfometabolite (Ml) (AUC ratio: 107.7% (95.6, 121.4%), C(max) ratio: 105.8% (89.9-124.5%)). There was a 30% decrease in AUC with M2 moxifloxacin metabolite (glucuronide) accompanied by an approximately 54% increase in renal excretion, which may be due to changes in phase 2 metabolism and/or transport mechanisms altered by itraconazole. Exposure (AUC) to itraconazole and its hydroxymetabolite were marginally altered by moxifloxacin (AUC +5% for itraconazole and -5% for hydroxy-itraconazole (OH-ITR)) indicating the absence of a clinically relevant influence of moxifloxacin on itraconazole. Mean peak concentrations in plasma (C(max)) were reduced for ITR and OH-ITR by approximately 14% and 18%, respectively, when administered concomitantly with moxifloxacin. This was attributed to the sensitivity of itraconazole absorption to changes in gastric physiology (pH, gastric transit, administration after fasting) and was deemed as clinically irrelevant. CONCLUSION: Results of this study indicate that moxifloxacin is not a substrate for CYP 450 3A4 isozymes confirming previous preclinical in vitro data. Moxifloxacin can therefore be safely coadministered with CYP 3A4 inhibitors without the need for dose adjustment. No clinically relevant changes in the pharmacokinetics of itraconazole were observed during the study.     

Pharmacokinetic interaction between verapamil and everolimus in healthy subjects

AIMS: We sought to define the influence of verapamil, an inhibitor of CYP3A and P-glycoprotein, on the pharmacokinetics of everolimus, a substrate of this enzyme and transporter. METHODS: This was a two-period, single-sequence, crossover study in 16 healthy subjects. In period 1 subjects received a single 2 mg oral dose of everolimus. In period 2 they received verapamil 80 mg three times daily for a total of 6 days and a single 2 mg dose of everolimus co-administered on the second day of verapamil therapy. RESULTS: During verapamil co-administration, everolimus C(max) increased 2.3-fold (90% CI, 1.9, 2.7) from 21 +/- 8 to 47 +/- 18 ng ml(-1) and AUC increased 3.5-fold (90% CI, 3.1, 3.9) from 115 +/- 45 to 392 +/- 142 ng ml(-1) h. Everolimus half-life was only prolonged to a minor extent (32 +/- 6 vs. 37 +/- 6 h). Verapamil predose concentrations doubled from 32 +/- 16 to 74 +/- 42 ng ml(-1) after single dose administration of everolimus. CONCLUSIONS: Multiple dosing with verapamil increased blood concentrations of everolimus after a single dose by an average 3.5-fold. During verapamil treatment, dose reduction for everolimus should be made guided by blood monitoring and for verapamil by blood pressure monitoring.