Mike J. Warwick

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.

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.

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.

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.

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 AUC0‐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 (AUC0‐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.