Aaron Dane

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.

An open-label, randomized, three-way crossover trial of the effects of coadministration of rosuvastatin and fenofibrate on the pharmacokinetic properties of rosuvastatin and fenofibric acid in healthy male volunteers

BACKGROUND Rosuvastatin and fenofibrate are lipid-regulating agents with different modes of action. Patients with dyslipidemia who have not achieved treatment targets with monotherapy may benefit from the combination of these agents. OBJECTIVE The effect of coadministration of rosuvastatin and fenofibrate on the steady-state pharmacokinetics of rosuvastatin and fenofibric acid (the active metabolite of fenofibrate) was assessed in healthy volunteers. METHODS This was an open-label, randomized, 3-way crossover trial consisting of three 7-day treatment periods. Healthy male volunteers received one of the following treatment regimens in each period: rosuvastatin 10 mg orally once daily; fenofibrate 67 mg orally TID; and rosuvastatin + fenofibrate dosed as above. The steady-state pharmacokinetics of rosuvastatin and fenofibric acid, both as substrate and as interacting drug, were investigated on day 7 of dosing. Treatment effects were assessed by construction of 90% CIs around the ratios of the geometric least-square means for rosuvastatin + fenofibrate/rosuvastatin and rosuvastatin + fenofibrate/fenofibrate for the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (derived from analysis of variance of log-transformed parameters). RESULTS Fourteen healthy male volunteers participated in the study. When rosuvastatin was coadministered with fenofibrate, there were minor increases in the AUC from 0 to 24 hours and maximum concentration (Cmax) of rosuvastatin: the respective geometric least-square means increased by 7% (90% CI, 1.00-1.15) and 21% (90% CI, 1.14-1.28). The pharmacokinetic parameters of fenofibric acid were similar when fenofibrate was dosed alone and with rosuvastatin: the geometric least-square means for fenofibric acid AUC from 0 to 8 hours and Cmax decreased by 4% (90% CI, 0.90-1.02) and 9% (90% CI, 0.84-1.00), respectively. The treatments were well tolerated alone and in combination. CONCLUSION Coadministration of rosuvastatin and fenofibrate produced minimal changes in rosuvastatin and fenofibric acid exposure.

A comprehensive regulatory framework to address the unmet need for new antibacterial treatments

To bring new antibacterial drugs to the market is challenging because discovery of new agents is difficult, two large trials per indication are needed in accordance with traditional regulatory requirements, and the economic reward is limited if the use of new antibiotics is constrained. These challenges have resulted in an alarmingly thin antibiotic pipeline, despite the rapid and continued growth in the need for new drugs. Approaches that balance the quantity of data needed for registration with the unmet medical need would encourage work in this area. Therefore, a tiered regulatory framework that allows either disease-based or pathogen-based label indications is proposed, with label wording that promotes the most appropriate use of new agents. Such a framework is within the bounds of present regulatory approaches, is amenable to international harmonisation, and would be a welcome step towards the facilitation of a robust and sustainable discovery and development infrastructure.

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.

Pharmacokinetics, dose proportionality, and tolerability of single and repeat doses of a nasal spray formulation of zolmitriptan in healthy volunteers.

The objective of this study was to investigate the pharmacokinetics, dose proportionality, and tolerability of a range of single and multiple doses of a nasal spray formulation of zolmitriptan in a randomized, double‐blind, placebocontrolled, balanced, incomplete crossover study. Thirty healthy male or female volunteers received two of five dose levels of zolmitriptan nasal spray: 0 (placebo), 0.5,1,2.5, and 5 mg. At each level, treatment comprised a single dose on day 1 and two doses (separated by 2 h) on each of days 2, 3, and 4. Zolmitriptan was well tolerated, and symptoms were generally mild and of short duration. The most commonly reported adverse events were taste disturbance, paresthesia, hyperesthesia, headache, and nasal/throat discomfort. Volunteers generally reported fewer adverse events during the multiple‐dose phase than after the single‐dose phase. Zolmitriptan was detectable in plasma within 15 minutes, and tmax was similar for each dose and after single and multiple dosing. Dose proportionality was shown for the Cmax and AUC of both zolmitriptan and its active metabolite, 183C91. Mean t1/2 for zolmitriptan and 183C91 was approximately 3 hours. It was concluded that the pharmacokinetics (Cmax and AUC) for both zolmitriptan and 183C91 was proportional to dose after both single and multiple dosing. Nasal spray zolmitriptan was well tolerated; the frequency and nature of adverse events did not increase after multiple dosing.

The effect of a combination antacid preparation containing aluminium hydroxide and magnesium hydroxide on rosuvastatin pharmacokinetics

ABSTRACT Objective: Rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor used for the treatment of dyslipidaemia, may be co-administered with antacids in clinical practice. This trial assessed the effect of simultaneous and separated administration of an antacid preparation containing aluminium hydroxide 220 mg/5 mL and magnesium hydroxide 195 mg/5 mL (co-magaldrox 195/220) on the pharmacokinetics of rosuvastatin. Research design and methods: A randomised, open-label, three-way crossover trial was performed. Healthy male volunteers (n = 14) received a single dose of rosuvastatin 40 mg alone, rosuvastatin 40 mg plus 20 mL antacid suspension taken simultaneously, and rosuvastatin 40 mg plus 20 mL antacid suspension taken 2 h after rosuvastatin on three separate occasions with a washout of ≥ 7 days between each. Main outcome measures: The primary parameters were area under the rosuvastatin plasma concentration–time curve from time zero to the last quantifiable concentration (AUC(0–t)) and maximum observed rosuvastatin plasma concentration (Cmax) in the absence and presence of antacid. Results: When rosuvastatin and antacid were given simultaneously, the antacid reduced the rosuvastatin AUC(0–t) by 54% (90% confidence interval [CI] for the treatment 0.40–0.53) and Cmax by 50% (90% CI 0.41–0.60). When the antacid was given 2 h after rosuvastatin, the antacid reduced the rosuvastatin AUC(0–t) by 22% (90% CI 0.68–0.90) and the Cmax by 16% (90% CI 0.70–1.01). The effect of repeated antacid administration was not studied and it cannot be discounted that this may have resulted in a stronger interaction than that observed here. Conclusions: Simultaneous dosing with rosuvastatin and antacid resulted in a decrease in rosuvastatin systemic exposure of approximately 50%. This effect was mitigated when antacid was administered 2 h after rosuvastatin.

Developing Outcomes Assessments as Endpoints for Registrational Clinical Trials of Antibacterial Drugs: 2015 Update From the Biomarkers Consortium of the Foundation for the National Institutes of Health

One important component in determining the benefits and harms of medical interventions is the use of well-defined and reliable outcome assessments as endpoints in clinical trials. Improving endpoints can better define patient benefits, allowing more accurate assessment of drug efficacy and more informed benefit-vs-risk decisions; another potential plus is facilitating efficient trial design. Since our first report in 2012, 2 Foundation for the National Institutes of Health Biomarkers Consortium Project Teams have continued to develop outcome assessments for potential uses as endpoints in registrational clinical trials of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. In addition, the teams have initiated similar work in the indications of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. This report provides an update on progress to date in these 4 diseases.