Effect of itraconazole on the pharmacokinetics of rosuvastatin.

BACKGROUND: Rosuvastatin is a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Itraconazole, an inhibitor of cytochrome P450 (CYP) 3A4 and the transport protein P-glycoprotein, is known to interact with other HMG-CoA reductase inhibitors. The current trials aimed to examine in vivo the effect of itraconazole on the pharmacokinetics of rosuvastatin. METHODS: Two randomized, double-blind, placebo-controlled, 2-way crossover trials were performed. Healthy male volunteers (trial A, n = 12; trial B, n = 14) received itraconazole, 200 mg, or placebo once daily for 5 days; on day 4, 10 mg (trial A) or 80 mg (trial B) of rosuvastatin was coadministered. Plasma concentrations of rosuvastatin, rosuvastatin-lactone (trial A only), and active and total HMG-CoA reductase inhibitors were measured up to 96 hours after dosing. RESULTS: After coadministration with itraconazole, the rosuvastatin geometric least-square mean for the treatment ratio was increased by 39% for AUC(0-ct) (area under the rosuvastatin plasma concentration-time curve from time 0 to the last common time at which quantifiable concentrations were obtained for both treatments within a volunteer in trial A) and by 28% for AUC(0-t) (area under the rosuvastatin plasma concentration-time curve from time 0 to the time of the last quantifiable concentration in trial B), with the treatment ratio for maximum observed plasma drug concentration increased by 36% in trial A and 15% in trial B compared with placebo. For trial A (but not for trial B), the upper boundary of the 90% confidence interval for the treatment ratios fell outside the preset limits (0.7-1.43). The 95% confidence intervals for all treatment ratios (except maximum observed plasma drug concentration in trial B) did not include 1. These results indicate that itraconazole produces a modest increase in plasma concentrations of rosuvastatin. Rosuvastatin accounted for the majority of the circulating active HMG-CoA reductase inhibitors (> or =87%) and most of the total inhibitors (> or =75%). CONCLUSIONS: Itraconazole produced modest increases in rosuvastatin plasma concentrations, which are unlikely to be of clinical relevance. The results support previous in vitro metabolism findings that CYP3A4 plays a minor role in the limited metabolism of rosuvastatin.

No effect of age or gender on the pharmacokinetics of rosuvastatin: a new HMG-CoA reductase inhibitor.

The effects of age and gender on the pharmacokinetics of rosuvastatin (Crestor) were assessed in healthy young (18-35 years) and elderly (> 65 years) males and females in this open, nonrandomized, noncontrolled, parallel-group trial. Sixteen males and 16 females (8 young and elderly volunteers per gender group) were enrolled. Mean (range) ages were 24 (18-33) and 68 (65-73) years for young and elderly volunteers, respectively. Volunteers were given a single oral 40 mg dose of rosuvastatin. Blood samples for measurement of rosuvastatin plasma concentration were collected up to 96 hours following dosing. Age and gender effects were assessed by constructing 90% confidence intervals (CIs) around the ratios of young/elderly and male/female geometric least square means (glsmeans) for AUC(0-t) and Cmax (derived from ANOVA of log-transformed parameters). Small differences in rosuvastatin pharmacokinetics were noted between age and gender groups. Glsmean AUC(0-t) was 6% higher (90% CI = 0.86-1.30) and glsmean Cmax, 12% higher (90% CI = 0.83-1.51) in the young compared with the elderly group. Glsmean AUC(0-t) was 9% lower (90% CI = 0.74-1.12) and glsmean Cmax 18% lower (90% CI = 0.61-1.11) in the male compared with the female group. These small differences are not considered clinically relevant, and dose adjustments based on age or gender are not anticipated. Rosuvastatin was well tolerated in all volunteers.

No effect of rosuvastatin on the pharmacokinetics of digoxin in healthy volunteers.

The effect of rosuvastatin on the pharmacokinetics of digoxin was assessed in 18 healthy male volunteers in this double-blind, randomized, two-way crossover trial. Volunteers were dosed with rosuvastatin (40 mg once daily) or placebo to steady state before being given a single dose of digoxin 0.5 mg. Blood and urine samples for the measurement of serum and urine digoxin concentrations were collected up to 96 hours following dosing. The effect of rosuvastatin was assessed by constructing 90% confidence intervals (CIs) around the treatment ratios (rosuvastatin + digoxin/placebo + digoxin) for digoxin exposure. The geometric least square mean AUC(0-t) and Cmax of digoxin were only 4% higher when the drug was coadministered with rosuvastatin compared to placebo. The 90% CIs for both treatment ratios (AUC(0-t) = 0.88-1.24; Cmax = 0.89-1.22) fell within the prespecified margin of 0.74 to 1.35; therefore, no significant pharmacokinetic interaction occurred between rosuvastatin and digoxin. The geometric mean amount of digoxin excreted into the urine and its renal clearance were similar with rosuvastatin and placebo. These results demonstrate that rosuvastatin has no effect on the pharmacokinetics of digoxin. Coadministration of rosuvastatin and digoxin was well tolerated.

Absolute oral bioavailability of rosuvastatin in healthy white adult male volunteers.

BACKGROUND: Rosuvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitor developed for the treatment of dyslipidemia. The results of clinical trials suggest that it is effective and well tolerated. OBJECTIVES: The goals of this study were to determine the absolute bioavailability of an oral dose of rosuvastatin and to describe the intravenous pharmacokinetics of rosuvastatin in healthy volunteers. METHODS: This was a randomized, open-label, 2-way crossover study consisting of 2 trial days separated by a > or =7-day washout period. Healthy male adult volunteers were given a single oral dose of rosuvastatin 40 mg on one trial day and an intravenous infusion of rosuvastatin 8 mg over 4 hours on the other. Pharmacokinetic and tolerability assessments were conducted up to 96 hours after dosing. A 3-compartment pharmacokinetic model was fitted to the plasma concentration-time profiles obtained for each volunteer after intravenous dosing. RESULTS: Ten white male volunteers entered and completed the trial. Their mean age was 35.7 years (range, 21-51 years), their mean height was 177 cm (range, 169-182 cm), and their mean body weight was 77.6 kg (range, 68-85 kg). The absolute oral bioavailability of rosuvastatin was estimated to be 20.1%,and the hepatic extraction ratio was estimated to be 0.63. The mean volume of distribution at steady state was 134 L. Renal clearance accounted for approximately 28% of total plasma clearance (48.9 L/h). Single oral and intravenous doses of rosuvastatin were well tolerated in this small number of healthy male volunteers. CONCLUSIONS: The absolute oral bioavailability of rosuvastatin in these 10 healthy volunteers was approximately 20%, and absorption was estimated to be 50%. The volume of distribution at steady state was consistent with extensive distribution of rosuvastatin to the tissues. The modest absolute oral bioavailability and high hepatic extraction of rosuvastatin are consistent with first-pass uptake into the liver after oral dosing. Rosuvastatin was cleared by both renal and nonrenal routes; tubular secretion was the predominant renal process.

A double-blind, randomized, incomplete crossover trial to assess the dose proportionality of rosuvastatin in healthy volunteers.

BACKGROUND: Rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been developed for the treatment of patients with dyslipidemia. OBJECTIVE: This study assessed the dose proportionality and pharmacokinetics of single oral doses of rosuvastatin in healthy volunteers. METHODS: This was a double-blind, randomized, incomplete crossover trial consisting of 3 trial days separated by >/=7-day washout periods. Healthy men were allocated to 1 of 2 treatment regimens: rosuvastatin 10, 20, and 80 mg, or rosuvastatin 10, 40, and 80 mg, administered as single doses on separate trial days in random order. Pharmacokinetic and tolerability assessments were made up to 96 hours after administration. Dose proportionality was tested using the power-law approach. RESULTS: Eighteen healthy white men participated in the trial (mean age, 41.2 years; mean height, 178.4 cm; mean body weight, 81.6 kg). Geometric mean rosuvastatin maximum plasma concentration (C(max)) values of 3.75, 6.79, 10.3, and 30.1 ng/mL were achieved at a median time to C(max) of 5.0 hours after doses of 10, 20, 40, and 80 mg, respectively. The corresponding geometric mean values for rosuvastatin area under the plasma concentration-time curve from time 0 to time of the last measurable concentration (AUC(0-t)) were 31.6, 56.8, 98.2, and 268 ng.h/mL. C(max) and AUC(0-t) were both linearly related to dose. The estimates of the proportionality coefficient (90% CI) for CmaX and AUC(o-t) were 0.999 (0.898-1.099) and 1.024 (0.941-1.107), respectively; all values fell within the prespecified range of 0.847 to 1.153. Rosuvastatin was well tolerated in this group of healthy men when administered orally at doses of 10 to 80 mg. CONCLUSION: Rosuvastatin systemic exposure was dose proportional over the dose range of 10 to 80 mg.

Metabolism, excretion, and pharmacokinetics of rosuvastatin in healthy adult male volunteers.

BACKGROUND: Rosuvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitor, or statin, that has been developed for the treatment of dyslipidemia. OBJECTIVE: This study assessed the metabolism, excretion, and pharmacokinetics of a single oral dose of radiolabeled rosuvastatin ([14C]-rosuvastatin) in healthy volunteers. METHODS: This was a nonrandomized, open-label, single-day trial. Healthy adult male volunteers were given a single oral dose of [14C]-rosuvastatin 20 mg (20 mL [14C]-rosuvastatin solution, nominally containing 50 microCi radioactivity). Blood, urine, and fecal samples were collected up to 10 days after dosing. Tolerability assessments were made up to 10 days after dosing (trial completion) and at a follow-up visit within 14 days of trial completion. RESULTS: Six white male volunteers aged 36 to 52 years (mean, 43.7 years) participated in the trial. The geometric mean peak plasma concentration (C(max)) of rosuvastatin was 6.06 ng/mL and was reached at a median of 5 hours after dosing. At C(max), rosuvastatin accounted for approximately 50% of the circulating radioactive material. Approximately 90% of the rosuvastatin dose was recovered in feces, with the remainder recovered in urine. The majority of the dose (approximately 70%) was recovered within 72 hours after dosing; excretion was complete by 10 days after dosing. Metabolite profiles in feces indicated that rosuvastatin was excreted largely unchanged (76.8% of the dose). Two metabolites-rosuvastatin-5S-lactone and N-desmethyl rosuvastatin-were present in excreta. [14C]-rosuvastatin was well tolerated; 2 volunteers reported 4 mild adverse events that resolved without treatment. CONCLUSIONS: The majority of the rosuvastatin dose was excreted unchanged. Given the absolute bioavailability (20%) and estimated absorption (approximately 50%) of rosuvastatin, this finding suggests that metabolism is a minor route of clearance for this agent.

The effect of rosuvastatin on oestrogen & progestin pharmacokinetics in healthy women taking an oral contraceptive.

AIMS: To assess the effect of rosuvastatin on oestrogen and progestin pharmacokinetics in women taking a commonly prescribed combination oral contraceptive steroid (OCS); the effect on endogenous hormones and the lipid profile was also assessed. METHODS: This open-label, nonrandomised trial consisted of 2 sequential menstrual cycles. Eighteen healthy female volunteers received OCS (Ortho Tri-Cyclen) on Days 1-21 and placebo OCS on Days 22-28 of Cycles A and B Rosuvastatin 40 mg was also given on Days 1-21 of Cycle B. RESULTS: Co-administration did not result in lower exposures to the exogenous oestrogen or progestin OCS components. Co-administration increased AUC[0-24] for ethinyl oestradiol (26%; 90% CI ratio 1.19-1.34), 17-desacetyl norgestimate (15%; 90% CI 1.10-1.20), and norgestrel (34%; 90% CI 1.25-1.43), and increased Cmax for ethinyl oestradiol (25%; 90% CI 1.17-1.33) and norgestrel (23%; 90% CI 1.14-1.33). The increases in exposure were attributed to a change in bioavailability rather than a decrease in clearance. Luteinizing and follicle-stimulating hormone concentrations were similar between cycles. There were no changes in the urinary excretion of cortisol and 6beta-hydroxycortisol. Rosuvastatin significantly decreased low-density lipoprotein cholesterol [-55%], total cholesterol [-27%], and triglycerides [-12%], and significantly increased high-density lipoprotein cholesterol[11%]. Co-administration was well tolerated. CONCLUSIONS: Rosuvastatin can be coadministered with OCS without decreasing OCS plasma concentrations, indicating that contraceptive efficacy should not be decreased. The results are consistent with an absence of induction of CYP3A4 by rosuvastatin. The expected substantial lipid-regulating effect was observed in this study, and there was no evidence of an altered lipid-regulating effect with OCS coadministration.

Lack of effect of ketoconazole on the pharmacokinetics of rosuvastatin in healthy subjects.

AIMS: To examine in vivo the effect of ketoconazole on the pharmacokinetics of rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. METHODS: This was a randomized, double-blind, two-way crossover, placebo-controlled trial. Healthy male volunteers (n = 14) received ketoconazole 200 mg or placebo twice daily for 7 days, and rosuvastatin 80 mg was coadministered on day 4 of dosing. Plasma concentrations of rosuvastatin, and active and total HMG-CoA reductase inhibitors were measured up to 96 h postdose. RESULTS: Following coadministration with ketoconazole, rosuvastatin geometric least square mean AUC(0,t) and Cmax were unchanged compared with placebo (treatment ratios (90% confidence intervals): 1.016 (0.839, 1.230), 0.954 (0.722, 1.260), respectively). Rosuvastatin accounted for essentially all of the circulating active HMG-CoA reductase inhibitors and most (> 85%) of the total inhibitors. Ketoconazole did not affect the proportion of circulating active or total inhibitors accounted for by circulating rosuvastatin. CONCLUSIONS: Ketoconazole did not produce any change in rosuvastatin pharmacokinetics in healthy subjects. The data suggest that neither cytochrome P450 3A4 nor P-gp-mediated transport contributes to the elimination of rosuvastatin.