- Email: [email protected]
Absolute oral bioavailability of rosuvastatin in healthy white adult male volunteers
CLINICAL THERAPEUTICS® / VOL. 25, NO. 10, 2003
Absolute Oral Bioavailability of Rosuvastatin in Healthy White Adult Male Volunteers Paul D. Martin, PhD,1 Mike J. Warwick, PhD,1 Aaron L. Dane, MSc,1 Charlie Brindley, PhD,2 and Tracy Short, BSc2 1AstraZeneca,
Alderley Park, Macclesfield, Cheshire, and 2Quintiles Ltd., Riccarton, Edinburgh, United Kingdom
ABSTRACT
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 ≥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 ~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. Accepted for publication August 6, 2003. Printed in the USA. Reproduction in whole or part is not permitted. Copyright © 2003 Excerpta Medica, Inc.
0149-2918/03/$19.00
2553
CLINICAL THERAPEUTICS®
Conclusions: The absolute oral bioavailability of rosuvastatin in these 10 healthy volunteers was ~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. (Clin Ther. 2003;25:2553– 2563) Copyright © 2003 Excerpta Medica, Inc. Key words: rosuvastatin, HMG-CoA–reductase inhibitor, absolute bioavailability, pharmacokinetics.
INTRODUCTION
The 3-hydroxy-3-methylglutaryl coenzyme A–reductase inhibitor rosuvastatin* was developed for the treatment of dyslipidemia.1 The results of clinical trials suggest that it is effective and well tolerated.2–6 Rosuvastatin is a hepatoselective drug that is taken up into the liver by an active transport process known to involve the liver-specific organic anion transport protein C.7–9 In vitro, the drug has been shown to undergo extremely slow metabolism (5%–50% over 3 days) in human hepatocytes; cytochrome P450 (CYP) 2C9 was the primary isozyme involved.10 In pharmacokinetic trials in healthy volunteers, the time to the maximum plasma concentration (Tmax) ranged from 3 to 5 hours after administration of doses of rosuvastatin 10 to 80 mg PO, and the elimination half-life (t1/2) was ~20 hours.11–16 The pharmacokinetic properties of rosuvastatin did not appear to be affected by age, sex, or the time of day that the drug was administered.15,16 The results of rosuvastatin drug-interaction trials support the in vitro metabolic findings noted above. Coadministration of fluconazole, a potent CYP2C9 inhibitor, produced only small increases in systemic exposure to rosuvastatin—the area under the plasma concentration–time curve (AUC) and maximum observed plasma concentration (Cmax) increased by 14% and 9%, respectively.11 This finding supports limited metabolism of rosuvastatin via CYP2C9. Coadministration with the CYP3A4 inhibitor ketoconazole produced no change in rosuvastatin exposure.12 Itraconazole produced modest increases in rosuvastatin AUC and Cmax (≤39% and ≤36%, respectively) that were thought to be the result of inhibition by itraconazole of an as yet undefined rosuvastatin transport protein,13 and erythromycin reduced the rosuvastatin AUC and Cmax by a respective 20% and 31%, an effect probably associated with an increase in gastrointestinal motility induced by erythromycin.14 *Trademark:
2554
Crestor® (licensed by AstraZeneca, London, United Kingdom, from Shionogi & Co., Ltd., Osaka, Japan).
P.D. Martin et al.
The objectives of the present trial were to determine the absolute bioavailability of an oral dose of rosuvastatin and to describe the intravenous pharmacokinetics of rosuvastatin in healthy volunteers. SUBJECTS AND METHODS Inclusion and Exclusion Criteria
Healthy male volunteers aged 18 to 65 years with no clinically relevant conditions identified from the medical history, physical examination, or electrocardiography (ECG) were eligible for inclusion. Volunteers were excluded if any clinically relevant laboratory abnormality was identified on clinical chemistry tests (including tests of hepatic and renal biochemistry), hematology tests, or urinalysis, or if values for total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, or creatine kinase were outside the normal reference ranges at the start of the trial. Study Design
This randomized, open-label, crossover study (trial 4522/IL0010) was conducted at the AstraZeneca Clinical Pharmacology Unit (CPU) in Alderley Park, Macclesfield, Cheshire, United Kingdom. At the start of the trial, all eligible volunteers who satisfied the entry criteria were allocated to a treatment sequence (oral followed by intravenous rosuvastatin, or intravenous followed by oral rosuvastatin). The treatment sequence for each volunteer was determined through use of a randomization scheme prepared by the AstraZeneca Biostatistics Group, also in Alderley Park. The trial consisted of 2 trial days separated by a ≥7-day washout period. On each of the trial days, volunteers were given a single oral dose of rosuvastatin 40 mg (one 40-mg encapsulated tablet taken with 200 mL purified water) or an intravenous infusion of rosuvastatin 8 mg (40 mL of 0.2-mg/mL solution infused over 4 hours using a pilot anesthesia pump (Becton, Dickinson and Company, Plymouth, United Kingdom). The trial was designed and monitored in accordance with good clinical practice guidelines and the Declaration of Helsinki (South Africa, 1996). An ethics committee approved the protocol before initiation of the trial, and all volunteers gave written informed consent. Study Procedures
All doses of rosuvastatin were administered in the CPU. Volunteers fasted for 6 hours before dosing and remained in the CPU until 24 hours after dosing. Pharmacokinetic and tolerability assessments were conducted up to 96 hours after dosing. Strenuous exercise, alcohol and caffeine consumption, and smoking were restricted during the trial. Concomitant medications were not permitted unless 2555
CLINICAL THERAPEUTICS®
approved by the investigator. A final tolerability assessment took place within 14 days of trial completion. Blood Sampling and Analysis
Blood samples (7.5 mL of venous blood) were drawn for determination of rosuvastatin concentrations in plasma. For oral dosing, samples were obtained before dosing and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 30, 48, 54, 72, and 96 hours after dosing. For intravenous dosing, samples were obtained before dosing and at 1, 2, 3, and 4 hours; 4 hours 5 minutes, 4 hours 10 minutes, 4 hours 15 minutes, 4 hours 20 minutes, and 4 hours 30 minutes; and 5, 6, 7, 8, 10, 12, 14, 17, 20, 24, 30, 36, 48, and 54 hours after the start of the infusion. An intravenous cannula was inserted into a forearm vein to facilitate blood sampling. Samples were collected into tubes containing lithium heparin anticoagulant and centrifuged (1500g at 4°C for 10 minutes) within 30 minutes of collection. The plasma was harvested, mixed 1:1 with sodium acetate buffer 0.1 mol/L (pH 4.0), and stored at –70°C until assay. Urine samples were also collected for determination of rosuvastatin concentrations. Samples were collected from 0 to 24 hours and from 24 to 48 hours after oral dosing, and from 0 to 12 hours, 12 to 24 hours, and 24 to 48 hours after intravenous dosing. Samples were collected into sealable plastic containers holding 100 mL sodium acetate buffer 0.5 mol/L (pH 4.0) and stored at –20°C until assay. Samples were prepared and analyzed at Quintiles Ltd., Edinburgh, United Kingdom. Plasma samples were prepared by automated solid-phase extraction on 96-well plates containing a hydrophobic-lipophilic balanced copolymer sorbent using a Tecan (Maennedorf, Switzerland) Genesis RSP100 robotic sample preparation system.17 Urine samples were diluted with aqueous acetic acid (0.5 mol/L) before analysis and were analyzed using high-performance liquid chromatography with tandem mass-spectrometric detection. Briefly, samples were chromatographed on a Phenomenex (Macclesfield, United Kingdom) Luna C18 column (2) 5 µm (4.6 mm i.d. × 150 mm) with a mobile phase consisting of methanol:formic acid (0.2%) in distilled water (70:30 v/v); the flow rate was 1 mL/min. Rosuvastatin was detected using a Sciex (Applied Biosystems, Foster City, California) API 365 triple quadrupole mass spectrometer fitted with a turboionspray source. The lower limit of quantification (LoQ) for rosuvastatin in plasma was 0.1 ng/mL; the LoQ for rosuvastatin in urine was 10 ng/mL. Correlation coefficients for rosuvastatin calibration curves (plasma and urine) were 0.996 to 1.00. Mean imprecision values and inaccuracy levels for quality control samples were <8% and ≤9%, respectively, at all concentrations. Pharmacokinetic Methods
The following noncompartmental pharmacokinetic parameters were derived using standard methods: AUC from time zero to infinity (AUC0–∞) and from time 2556
P.D. Martin et al.
zero to the time of the last measurable concentration (AUC0–t); Cmax; Tmax; and terminal t1/2. Pharmacokinetic parameters were also determined by fitting pharmacokinetic models to the plasma concentration–time profiles for each volunteer after intravenous dosing. A 3-compartment model with 1/y predicted weighting (iterative reweighting) was considered the most appropriate pharmacokinetic model (model 19, WinNonlin version 2.1, Pharsight Corporation, Mountain View, California). The choice of model was based on the Akaike criterion.18 The pattern of residuals was used to assign the appropriate weighting scheme. Absolute oral bioavailability (F) was calculated using the dose-normalized logtransformed AUC values for the 2 rosuvastatin formulations. The log-transformed values were analyzed using an analysis-of-variance model with factors fitted for the effects of volunteer, period, and formulation. The results are presented in terms of estimated F and 90% CI. The hepatic extraction ratio (EH) was calculated as CLb/QH, where CLb is hepatic blood clearance of rosuvastatin and QH is hepatic blood flow. CLb was estimated using the formula CLnr (Cp/Cb), with CLnr representing nonrenal plasma clearance (calculated as plasma clearance [CLp] – renal clearance [CLr]) and Cp/Cb representing the ratio of plasma to blood concentrations (taken as 1.45; study ZD4522 KPJ062, data on file, AstraZeneca, 2000). QH was taken as 1350 mL/min.19 Tolerability Assessments
Vital signs (blood pressure and heart rate) and 12-lead ECGs were monitored, physical examinations carried out, and adverse events recorded throughout the trial. In addition, the following clinical laboratory tests were performed: hematology (red and white blood cell and platelet counts, hemoglobin levels, hematocrit, and prothrombin parameters), urinalysis (urine pH, glucose, blood, ketones, protein, bilirubin, and specific gravity), and clinical chemistry (including hepatic and renal biochemistry). All tests were performed at an accredited laboratory. 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). Pharmacokinetic Profiles
After oral dosing of rosuvastatin, a geometric mean Cmax of 18.8 ng/mL was achieved at a median Tmax of 5.0 hours (Table, Figure). After this peak, rosuvastatin concentrations declined in a biexponential manner, with a terminal phase beginning at 18 to 24 hours after dosing, and a mean terminal t1/2 of 20.3 hours. Individual profiles showed late peaks suggestive of enterohepatic recirculation (data not shown). 2557
CLINICAL THERAPEUTICS®
Table. Plasma pharmacokinetic parameters and urinary excretion after administration of a single oral dose of rosuvastatin 40 mg and an intravenous infusion of rosuvastatin 8 mg in healthy male volunteers. Summary Statistic*
Rosuvastatin 40 mg PO (n = 10)
Rosuvastatin 8 mg IV (n = 10)
176 (32.3)†
NC‡
Plasma parameters AUC0–∞, ng•h/mL
gmean (CV%)
AUC0–t, ng•h/mL
gmean (CV%)
165 (35.9)
164 (21.7)
Cmax, ng/mL
gmean (CV%)
18.8 (33.9)
NR§
Tmax, h
Median (range)
5.0 (1–6)
NR§
t1/2, h
Arithmetic mean (SD)
20.3 (5.46)†
NC‡
Arithmetic mean (SD)
NR¶
0.08 (0.02)
Arithmetic mean (SD)
NR¶
2.01 (0.46)
Arithmetic mean (SD)
NR¶
NC
Cinf , ng/mL
gmean (CV%)
NR¶
37.1 (16.2)
Vss, L**
Arithmetic mean (SD)
NR¶
134 (40.10)
EH
Arithmetic mean (SD)
NR¶
0.63 (0.13)
CLp , L/h**
gmean (CV%)
NR¶
48.9 (21.7)
CLr, L/h
gmean (CV%)
11.9 (39.4)
13.6 (39.1)
fe, %
Arithmetic mean (SD)
5.09 (1.77)
29.5 (7.32)
t1/21,
h||
t1/22,
h||
t1/23 , h||#
Urinary excretion
AUC0–∞ = area under the plasma concentration–time curve from time zero to infinity; gmean = geometric mean; CV% = coefficient of variation expressed as a percentage of the geometric mean (derived from SDs calculated on the log scale and back-transformed); NC = not calculable (could not be determined for >50% of volunteers); AUC0–t = area under the plasma concentration–time curve from time zero to the time of the last measurable concentration; Cmax = maximum observed plasma concentration; NR = not relevant; Tmax = time to Cmax; t1/2 = terminal elimination half-life; t1/21–3 = half-life associated with the first, second, and third exponents of a multiexponential equation; Cinf = concentration at the end of the infusion; Vss = volume of distribution at steady state; EH = hepatic extraction ratio; CLp = plasma clearance; CLr = renal clearance; fe = fraction of drug excreted unchanged in urine. *SD calculated using untransformed data. †n = 8. ‡n = 2. §These parameters are not relevant to an intravenous dose. ||Estimated by compartmental analysis. ¶These parameters were not calculated because a model was not fitted to the oral data. #It was not possible to make reliable estimates of the terminal elimination phase (t 1/23) in the majority of volunteers because there were secondary concentration spikes, which meant that this parameter could not be estimated with adequate precision. **Estimated by noncompartmental analysis using AUC 0–t rather than AUC0–∞ (which was not determinable because of poor definition of t1/2) and AUMC0–t rather than AUMC0–∞ (area under the curve of a plot of the product of concentration and time versus time from zero to infinity).
2558
P.D. Martin et al. 40 mg PO 8 mg IV
Plasma Concentration (ng/mL)
A 100
10
1
0.1 0
20
40
60
80
Time (h)
Plasma Concentration (ng/mL)
B 100
10
1
0.1 0
5
10
15
20
25
Time (h)
Figure. Geometric mean (SD) plasma concentration–time profiles (A) up to 72 hours and (B) up to 24 hours after administration of a single oral dose of rosuvastatin 40 mg and an intravenous infusion of rosuvastatin 8 mg in healthy male volunteers.
After the end of the intravenous infusion, rosuvastatin concentrations declined in a triexponential manner, with a terminal phase beginning at approximately the same time as that after the oral dose (Figure). On observation, the terminal t1/2 appeared comparable to that after oral dosing in most individuals. Reliable estimates of terminal t1/2 were made in 2 volunteers; these were 14.6 and 16.6 hours. 2559
CLINICAL THERAPEUTICS®
After the intravenous infusion, the mean volume of distribution at steady state (Vss) was 134 L. The EH was estimated as 0.63. The mean CLp was 48.9 L/h (Table). CLr was ~28% of total CLp. The absolute oral bioavailability of rosuvastatin was estimated to be 20.1% (90% CI, 17.2–23.4). AUC0–t was used for determining pharmacokinetic parameters rather than AUC0–∞, because difficulty in estimating the t1/2 also made the latter parameter difficult to determine. An estimate of AUC0–∞ was available for 2 volunteers after both oral and intravenous dosing. For these volunteers, absolute bioavailability values estimated using AUC0–t were <0.3% different from those obtained using AUC0–∞. Tolerability
In this small number of healthy male volunteers, rosuvastatin was well tolerated both as a 40-mg oral dose and as an 8-mg IV infusion. There were no withdrawals from the trial and no serious adverse events. No adverse events were associated with liver or muscle symptoms. The adverse-event profile of rosuvastatin in this trial was as expected, with the emergence of no new safety concerns. DISCUSSION
The results of this trial provide information about the absorption of an oral dose of rosuvastatin. Rosuvastatin’s absolute oral bioavailability was estimated to be 20.1%, which, together with the estimated EH of 0.63, implies that absorption was appreciably >20%. A realistic value for absorption—based on F/(1 – EH)— is ~50%. The finding of a Vss of 134 L is consistent with extensive distribution of rosuvastatin to the tissues. By analogy with animal data,7 rosuvastatin is likely to be distributed principally to the liver. This is supported by rosuvastatin’s high proportion of CLnr (>70%) and the high EH. Rosuvastatin’s modest absolute oral bioavailability and high EH—indicating that absorption is much greater than bioavailability—are consistent with first-pass uptake into the liver after oral dosing. The CLr of rosuvastatin (13.6 L/h) after the intravenous infusion was ~28% of total plasma clearance (48.9 L/h, 815 mL/min), demonstrating renal as well as hepatic routes of elimination from the systemic circulation. Plasma protein binding of rosuvastatin is 88% (ZD4522 KPJ062, data on file, AstraZeneca, 2000). The expected contribution of glomerular filtration rate to the CLr of a drug with 10% free fraction is 12 mL/min,19 which is only ~5% of the CLr observed in the present trial. Net tubular secretion is therefore responsible for ≥90% of the CLr of rosuvastatin. The estimated absolute oral bioavailability of rosuvastatin in this study (20.1%) is similar to that of pravastatin (~18%20), fluvastatin (~29%21), and atorvastatin (~14%22), but much lower than that of cerivastatin (~60%23). In addition, the 2560
P.D. Martin et al.
CLp of rosuvastatin (48.9 L/h), pravastatin (~60 L/h20), fluvastatin (~70 L/h21), atorvastatin (37.5 L/h22), and simvastatin (31.8 L/h24) is higher than that of cerivastatin (12.9 L/h23). To our knowledge, CLr data have been published only for pravastatin (>400 mL/min), which, like rosuvastatin, is actively secreted by the kidney.20 The pharmacokinetics of rosuvastatin observed in this trial are consistent with those reported elsewhere.11–16 It should be noted that this trial was performed in healthy volunteers under carefully controlled conditions. The inclusion/exclusion criteria and dietary/lifestyle restrictions employed affect the ability to extrapolate the results to the general population. CONCLUSIONS
The absolute oral bioavailability of rosuvastatin was ~20%, and absorption was estimated to be 50%. The Vss was consistent with extensive distribution of rosuvastatin to the tissues. The modest absolute oral bioavailability and high EH of rosuvastatin are consistent with first-pass uptake into the liver after oral dosing. Rosuvastatin was also eliminated from the systemic circulation by CLr (which was ~28% of CLp); tubular secretion was the predominant renal process. ACKNOWLEDGMENT
The authors thank Elizabeth Eaton, PhD, for assistance with manuscript preparation. REFERENCES 1. Chapman MJ, McTaggart F. Optimizing the pharmacology of statins: Characteristics of rosuvastatin. Atheroscler Suppl. 2002;2:33–36. 2. Olsson AG, Pears J, McKellar J, et al. Effect of rosuvastatin on low-density lipoprotein cholesterol in patients with hypercholesterolemia. Am J Cardiol. 2001;88:504– 508. 3. Paoletti R, Fahmy M, Mahla G, et al. Rosuvastatin demonstrates greater reduction of low-density lipoprotein cholesterol compared with pravastatin and simvastatin in hypercholesterolaemic patients: A randomized, double-blind study. J Cardiovasc Risk. 2001;8:383–390. 4. Davidson M, Ma P, Stein EA, et al. Comparison of effects on low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with rosuvastatin versus atorvastatin in patients with type IIa or IIb hypercholesterolemia. Am J Cardiol. 2002;89:268–275. 5. Olsson AG, Istad H, Luurila O, et al. Effects of rosuvastatin and atorvastatin compared over 52 weeks of treatment in patients with hypercholesterolemia. Am Heart J. 2002; 144:1044–1051. 6. Brown WV, Bays HE, Hassman DR, et al. Efficacy and safety of rosuvastatin compared with pravastatin and simvastatin in patients with hypercholesterolemia: A randomized, double-blind, 52-week trial. Am Heart J. 2002;144:1036–1043. 2561
CLINICAL THERAPEUTICS®
7. Nezasa K, Higaki K, Matsumura T, et al. Liver-specific distribution of rosuvastatin in rats: Comparison with pravastatin and simvastatin. Drug Metab Dispos. 2002;30:1158– 1163. 8. Nezasa K, Higaki K, Hasegawa H, et al. Uptake of HMG-CoA reductase inhibitor ZD4522 into hepatocytes and distribution into liver and other tissues of the rat. Atherosclerosis. 2000;151:39. Abstract MoP21:W6. 9. Brown CDA, Windass A, Bleasby K, Lauffart B. Rosuvastatin is a high affinity substrate of hepatic organic anion transporter OATP-C. Atheroscler Suppl. 2001;2:90. Abstract P174. 10. McCormick AD, McKillop D, Butters CJ, et al. ZD4522—an HMG-CoA reductase inhibitor free of metabolically mediated drug interactions: Metabolic studies in human in vitro systems. J Clin Pharmacol. 2000;40:1055. Abstract 46. 11. Cooper KJ, Martin PD, Dane AL, et al. The effect of fluconazole on the pharmacokinetics of rosuvastatin. Eur J Clin Pharmacol. 2002;58:527–531. 12. Cooper KJ, Martin PD, Dane AL, et al. Lack of effect of ketoconazole on the pharmacokinetics of rosuvastatin in healthy subjects. Br J Clin Pharmacol. 2003;55:94–99. 13. Cooper KJ, Martin PD, Dane AL, et al. Effect of itraconazole on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther. 2003;73:322–329. 14. Cooper KJ, Martin PD, Dane AL, et al. The effect of erythromycin on the pharmacokinetics of rosuvastatin. Eur J Clin Pharmacol. 2003;59:51–56. 15. Martin PD, Dane AL, Nwose OM, et al. No effect of age or gender on the pharmacokinetics of rosuvastatin: A new HMG-CoA reductase inhibitor. J Clin Pharmacol. 2002; 42:1116–1121. 16. Martin PD, Mitchell PD, Schneck DW. Pharmacodynamic effects and pharmacokinetics of a new HMG-CoA reductase inhibitor, rosuvastatin, after morning or evening administration in healthy volunteers. Br J Clin Pharmacol. 2002;54:472–477. 17. Hull CK, Penman AD, Smith CK, Martin PD. Quantification of rosuvastatin in human plasma by automated solid-phase extraction using tandem mass spectrometric detection. J Chromatogr B Analyt Technol Biomed Life Sci. 2002;772:219–228. 18. Ludden TM, Beal SL, Sheiner LB. Comparison of the Akaike Information Criterion, the Schwarz criterion and the F test as guides to model selection. J Pharmacokinet Biopharm. 1994;22:431–445. 19. Rowland M, Tozer TN. Elimination. In: Clinical Pharmacokinetics: Concepts and Applications. Philadelphia: Lea and Febiger; 1996:157–183. 20. Singhvi SM, Pan HY, Morrison RA, Willard DA. Disposition of pravastatin sodium, a tissue-selective HMG-CoA reductase inhibitor, in healthy subjects. Br J Clin Pharmacol. 1990;29:239–243. 21. Tse FL, Jaffe JM, Troendle A. Pharmacokinetics of fluvastatin after single and multiple doses in normal volunteers. J Clin Pharmacol. 1992;32:630–638. 22. Gibson DM, Stern RH, Abel RB, Whitfield LR. Absolute bioavailability of atorvastatin in man. Pharm Res. 1997;14(Suppl):S253. Abstract 2107. 2562
P.D. Martin et al.
23. Muck W, Ritter W, Ochmann K, et al. Absolute and relative bioavailability of the HMG-CoA reductase inhibitor cerivastatin. Int J Clin Pharmacol Ther. 1997;35:255– 260. 24. Mauro VF. Clinical pharmacokinetics and practical applications of simvastatin. Clin Pharmacokinet. 1993;24:195–202.
Address correspondence to: Paul D. Martin, PhD, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom. E-mail: paul. [email protected] 2563
Absolute Oral Bioavailability of Rosuvastatin in Healthy White Adult Male Volunteers Paul D. Martin, PhD,1 Mike J. Warwick, PhD,1 Aaron L. Dane, MSc,1 Charlie Brindley, PhD,2 and Tracy Short, BSc2 1AstraZeneca,
Alderley Park, Macclesfield, Cheshire, and 2Quintiles Ltd., Riccarton, Edinburgh, United Kingdom
ABSTRACT
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 ≥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 ~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. Accepted for publication August 6, 2003. Printed in the USA. Reproduction in whole or part is not permitted. Copyright © 2003 Excerpta Medica, Inc.
0149-2918/03/$19.00
2553
CLINICAL THERAPEUTICS®
Conclusions: The absolute oral bioavailability of rosuvastatin in these 10 healthy volunteers was ~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. (Clin Ther. 2003;25:2553– 2563) Copyright © 2003 Excerpta Medica, Inc. Key words: rosuvastatin, HMG-CoA–reductase inhibitor, absolute bioavailability, pharmacokinetics.
INTRODUCTION
The 3-hydroxy-3-methylglutaryl coenzyme A–reductase inhibitor rosuvastatin* was developed for the treatment of dyslipidemia.1 The results of clinical trials suggest that it is effective and well tolerated.2–6 Rosuvastatin is a hepatoselective drug that is taken up into the liver by an active transport process known to involve the liver-specific organic anion transport protein C.7–9 In vitro, the drug has been shown to undergo extremely slow metabolism (5%–50% over 3 days) in human hepatocytes; cytochrome P450 (CYP) 2C9 was the primary isozyme involved.10 In pharmacokinetic trials in healthy volunteers, the time to the maximum plasma concentration (Tmax) ranged from 3 to 5 hours after administration of doses of rosuvastatin 10 to 80 mg PO, and the elimination half-life (t1/2) was ~20 hours.11–16 The pharmacokinetic properties of rosuvastatin did not appear to be affected by age, sex, or the time of day that the drug was administered.15,16 The results of rosuvastatin drug-interaction trials support the in vitro metabolic findings noted above. Coadministration of fluconazole, a potent CYP2C9 inhibitor, produced only small increases in systemic exposure to rosuvastatin—the area under the plasma concentration–time curve (AUC) and maximum observed plasma concentration (Cmax) increased by 14% and 9%, respectively.11 This finding supports limited metabolism of rosuvastatin via CYP2C9. Coadministration with the CYP3A4 inhibitor ketoconazole produced no change in rosuvastatin exposure.12 Itraconazole produced modest increases in rosuvastatin AUC and Cmax (≤39% and ≤36%, respectively) that were thought to be the result of inhibition by itraconazole of an as yet undefined rosuvastatin transport protein,13 and erythromycin reduced the rosuvastatin AUC and Cmax by a respective 20% and 31%, an effect probably associated with an increase in gastrointestinal motility induced by erythromycin.14 *Trademark:
2554
Crestor® (licensed by AstraZeneca, London, United Kingdom, from Shionogi & Co., Ltd., Osaka, Japan).
P.D. Martin et al.
The objectives of the present trial were to determine the absolute bioavailability of an oral dose of rosuvastatin and to describe the intravenous pharmacokinetics of rosuvastatin in healthy volunteers. SUBJECTS AND METHODS Inclusion and Exclusion Criteria
Healthy male volunteers aged 18 to 65 years with no clinically relevant conditions identified from the medical history, physical examination, or electrocardiography (ECG) were eligible for inclusion. Volunteers were excluded if any clinically relevant laboratory abnormality was identified on clinical chemistry tests (including tests of hepatic and renal biochemistry), hematology tests, or urinalysis, or if values for total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, or creatine kinase were outside the normal reference ranges at the start of the trial. Study Design
This randomized, open-label, crossover study (trial 4522/IL0010) was conducted at the AstraZeneca Clinical Pharmacology Unit (CPU) in Alderley Park, Macclesfield, Cheshire, United Kingdom. At the start of the trial, all eligible volunteers who satisfied the entry criteria were allocated to a treatment sequence (oral followed by intravenous rosuvastatin, or intravenous followed by oral rosuvastatin). The treatment sequence for each volunteer was determined through use of a randomization scheme prepared by the AstraZeneca Biostatistics Group, also in Alderley Park. The trial consisted of 2 trial days separated by a ≥7-day washout period. On each of the trial days, volunteers were given a single oral dose of rosuvastatin 40 mg (one 40-mg encapsulated tablet taken with 200 mL purified water) or an intravenous infusion of rosuvastatin 8 mg (40 mL of 0.2-mg/mL solution infused over 4 hours using a pilot anesthesia pump (Becton, Dickinson and Company, Plymouth, United Kingdom). The trial was designed and monitored in accordance with good clinical practice guidelines and the Declaration of Helsinki (South Africa, 1996). An ethics committee approved the protocol before initiation of the trial, and all volunteers gave written informed consent. Study Procedures
All doses of rosuvastatin were administered in the CPU. Volunteers fasted for 6 hours before dosing and remained in the CPU until 24 hours after dosing. Pharmacokinetic and tolerability assessments were conducted up to 96 hours after dosing. Strenuous exercise, alcohol and caffeine consumption, and smoking were restricted during the trial. Concomitant medications were not permitted unless 2555
CLINICAL THERAPEUTICS®
approved by the investigator. A final tolerability assessment took place within 14 days of trial completion. Blood Sampling and Analysis
Blood samples (7.5 mL of venous blood) were drawn for determination of rosuvastatin concentrations in plasma. For oral dosing, samples were obtained before dosing and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 30, 48, 54, 72, and 96 hours after dosing. For intravenous dosing, samples were obtained before dosing and at 1, 2, 3, and 4 hours; 4 hours 5 minutes, 4 hours 10 minutes, 4 hours 15 minutes, 4 hours 20 minutes, and 4 hours 30 minutes; and 5, 6, 7, 8, 10, 12, 14, 17, 20, 24, 30, 36, 48, and 54 hours after the start of the infusion. An intravenous cannula was inserted into a forearm vein to facilitate blood sampling. Samples were collected into tubes containing lithium heparin anticoagulant and centrifuged (1500g at 4°C for 10 minutes) within 30 minutes of collection. The plasma was harvested, mixed 1:1 with sodium acetate buffer 0.1 mol/L (pH 4.0), and stored at –70°C until assay. Urine samples were also collected for determination of rosuvastatin concentrations. Samples were collected from 0 to 24 hours and from 24 to 48 hours after oral dosing, and from 0 to 12 hours, 12 to 24 hours, and 24 to 48 hours after intravenous dosing. Samples were collected into sealable plastic containers holding 100 mL sodium acetate buffer 0.5 mol/L (pH 4.0) and stored at –20°C until assay. Samples were prepared and analyzed at Quintiles Ltd., Edinburgh, United Kingdom. Plasma samples were prepared by automated solid-phase extraction on 96-well plates containing a hydrophobic-lipophilic balanced copolymer sorbent using a Tecan (Maennedorf, Switzerland) Genesis RSP100 robotic sample preparation system.17 Urine samples were diluted with aqueous acetic acid (0.5 mol/L) before analysis and were analyzed using high-performance liquid chromatography with tandem mass-spectrometric detection. Briefly, samples were chromatographed on a Phenomenex (Macclesfield, United Kingdom) Luna C18 column (2) 5 µm (4.6 mm i.d. × 150 mm) with a mobile phase consisting of methanol:formic acid (0.2%) in distilled water (70:30 v/v); the flow rate was 1 mL/min. Rosuvastatin was detected using a Sciex (Applied Biosystems, Foster City, California) API 365 triple quadrupole mass spectrometer fitted with a turboionspray source. The lower limit of quantification (LoQ) for rosuvastatin in plasma was 0.1 ng/mL; the LoQ for rosuvastatin in urine was 10 ng/mL. Correlation coefficients for rosuvastatin calibration curves (plasma and urine) were 0.996 to 1.00. Mean imprecision values and inaccuracy levels for quality control samples were <8% and ≤9%, respectively, at all concentrations. Pharmacokinetic Methods
The following noncompartmental pharmacokinetic parameters were derived using standard methods: AUC from time zero to infinity (AUC0–∞) and from time 2556
P.D. Martin et al.
zero to the time of the last measurable concentration (AUC0–t); Cmax; Tmax; and terminal t1/2. Pharmacokinetic parameters were also determined by fitting pharmacokinetic models to the plasma concentration–time profiles for each volunteer after intravenous dosing. A 3-compartment model with 1/y predicted weighting (iterative reweighting) was considered the most appropriate pharmacokinetic model (model 19, WinNonlin version 2.1, Pharsight Corporation, Mountain View, California). The choice of model was based on the Akaike criterion.18 The pattern of residuals was used to assign the appropriate weighting scheme. Absolute oral bioavailability (F) was calculated using the dose-normalized logtransformed AUC values for the 2 rosuvastatin formulations. The log-transformed values were analyzed using an analysis-of-variance model with factors fitted for the effects of volunteer, period, and formulation. The results are presented in terms of estimated F and 90% CI. The hepatic extraction ratio (EH) was calculated as CLb/QH, where CLb is hepatic blood clearance of rosuvastatin and QH is hepatic blood flow. CLb was estimated using the formula CLnr (Cp/Cb), with CLnr representing nonrenal plasma clearance (calculated as plasma clearance [CLp] – renal clearance [CLr]) and Cp/Cb representing the ratio of plasma to blood concentrations (taken as 1.45; study ZD4522 KPJ062, data on file, AstraZeneca, 2000). QH was taken as 1350 mL/min.19 Tolerability Assessments
Vital signs (blood pressure and heart rate) and 12-lead ECGs were monitored, physical examinations carried out, and adverse events recorded throughout the trial. In addition, the following clinical laboratory tests were performed: hematology (red and white blood cell and platelet counts, hemoglobin levels, hematocrit, and prothrombin parameters), urinalysis (urine pH, glucose, blood, ketones, protein, bilirubin, and specific gravity), and clinical chemistry (including hepatic and renal biochemistry). All tests were performed at an accredited laboratory. 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). Pharmacokinetic Profiles
After oral dosing of rosuvastatin, a geometric mean Cmax of 18.8 ng/mL was achieved at a median Tmax of 5.0 hours (Table, Figure). After this peak, rosuvastatin concentrations declined in a biexponential manner, with a terminal phase beginning at 18 to 24 hours after dosing, and a mean terminal t1/2 of 20.3 hours. Individual profiles showed late peaks suggestive of enterohepatic recirculation (data not shown). 2557
CLINICAL THERAPEUTICS®
Table. Plasma pharmacokinetic parameters and urinary excretion after administration of a single oral dose of rosuvastatin 40 mg and an intravenous infusion of rosuvastatin 8 mg in healthy male volunteers. Summary Statistic*
Rosuvastatin 40 mg PO (n = 10)
Rosuvastatin 8 mg IV (n = 10)
176 (32.3)†
NC‡
Plasma parameters AUC0–∞, ng•h/mL
gmean (CV%)
AUC0–t, ng•h/mL
gmean (CV%)
165 (35.9)
164 (21.7)
Cmax, ng/mL
gmean (CV%)
18.8 (33.9)
NR§
Tmax, h
Median (range)
5.0 (1–6)
NR§
t1/2, h
Arithmetic mean (SD)
20.3 (5.46)†
NC‡
Arithmetic mean (SD)
NR¶
0.08 (0.02)
Arithmetic mean (SD)
NR¶
2.01 (0.46)
Arithmetic mean (SD)
NR¶
NC
Cinf , ng/mL
gmean (CV%)
NR¶
37.1 (16.2)
Vss, L**
Arithmetic mean (SD)
NR¶
134 (40.10)
EH
Arithmetic mean (SD)
NR¶
0.63 (0.13)
CLp , L/h**
gmean (CV%)
NR¶
48.9 (21.7)
CLr, L/h
gmean (CV%)
11.9 (39.4)
13.6 (39.1)
fe, %
Arithmetic mean (SD)
5.09 (1.77)
29.5 (7.32)
t1/21,
h||
t1/22,
h||
t1/23 , h||#
Urinary excretion
AUC0–∞ = area under the plasma concentration–time curve from time zero to infinity; gmean = geometric mean; CV% = coefficient of variation expressed as a percentage of the geometric mean (derived from SDs calculated on the log scale and back-transformed); NC = not calculable (could not be determined for >50% of volunteers); AUC0–t = area under the plasma concentration–time curve from time zero to the time of the last measurable concentration; Cmax = maximum observed plasma concentration; NR = not relevant; Tmax = time to Cmax; t1/2 = terminal elimination half-life; t1/21–3 = half-life associated with the first, second, and third exponents of a multiexponential equation; Cinf = concentration at the end of the infusion; Vss = volume of distribution at steady state; EH = hepatic extraction ratio; CLp = plasma clearance; CLr = renal clearance; fe = fraction of drug excreted unchanged in urine. *SD calculated using untransformed data. †n = 8. ‡n = 2. §These parameters are not relevant to an intravenous dose. ||Estimated by compartmental analysis. ¶These parameters were not calculated because a model was not fitted to the oral data. #It was not possible to make reliable estimates of the terminal elimination phase (t 1/23) in the majority of volunteers because there were secondary concentration spikes, which meant that this parameter could not be estimated with adequate precision. **Estimated by noncompartmental analysis using AUC 0–t rather than AUC0–∞ (which was not determinable because of poor definition of t1/2) and AUMC0–t rather than AUMC0–∞ (area under the curve of a plot of the product of concentration and time versus time from zero to infinity).
2558
P.D. Martin et al. 40 mg PO 8 mg IV
Plasma Concentration (ng/mL)
A 100
10
1
0.1 0
20
40
60
80
Time (h)
Plasma Concentration (ng/mL)
B 100
10
1
0.1 0
5
10
15
20
25
Time (h)
Figure. Geometric mean (SD) plasma concentration–time profiles (A) up to 72 hours and (B) up to 24 hours after administration of a single oral dose of rosuvastatin 40 mg and an intravenous infusion of rosuvastatin 8 mg in healthy male volunteers.
After the end of the intravenous infusion, rosuvastatin concentrations declined in a triexponential manner, with a terminal phase beginning at approximately the same time as that after the oral dose (Figure). On observation, the terminal t1/2 appeared comparable to that after oral dosing in most individuals. Reliable estimates of terminal t1/2 were made in 2 volunteers; these were 14.6 and 16.6 hours. 2559
CLINICAL THERAPEUTICS®
After the intravenous infusion, the mean volume of distribution at steady state (Vss) was 134 L. The EH was estimated as 0.63. The mean CLp was 48.9 L/h (Table). CLr was ~28% of total CLp. The absolute oral bioavailability of rosuvastatin was estimated to be 20.1% (90% CI, 17.2–23.4). AUC0–t was used for determining pharmacokinetic parameters rather than AUC0–∞, because difficulty in estimating the t1/2 also made the latter parameter difficult to determine. An estimate of AUC0–∞ was available for 2 volunteers after both oral and intravenous dosing. For these volunteers, absolute bioavailability values estimated using AUC0–t were <0.3% different from those obtained using AUC0–∞. Tolerability
In this small number of healthy male volunteers, rosuvastatin was well tolerated both as a 40-mg oral dose and as an 8-mg IV infusion. There were no withdrawals from the trial and no serious adverse events. No adverse events were associated with liver or muscle symptoms. The adverse-event profile of rosuvastatin in this trial was as expected, with the emergence of no new safety concerns. DISCUSSION
The results of this trial provide information about the absorption of an oral dose of rosuvastatin. Rosuvastatin’s absolute oral bioavailability was estimated to be 20.1%, which, together with the estimated EH of 0.63, implies that absorption was appreciably >20%. A realistic value for absorption—based on F/(1 – EH)— is ~50%. The finding of a Vss of 134 L is consistent with extensive distribution of rosuvastatin to the tissues. By analogy with animal data,7 rosuvastatin is likely to be distributed principally to the liver. This is supported by rosuvastatin’s high proportion of CLnr (>70%) and the high EH. Rosuvastatin’s modest absolute oral bioavailability and high EH—indicating that absorption is much greater than bioavailability—are consistent with first-pass uptake into the liver after oral dosing. The CLr of rosuvastatin (13.6 L/h) after the intravenous infusion was ~28% of total plasma clearance (48.9 L/h, 815 mL/min), demonstrating renal as well as hepatic routes of elimination from the systemic circulation. Plasma protein binding of rosuvastatin is 88% (ZD4522 KPJ062, data on file, AstraZeneca, 2000). The expected contribution of glomerular filtration rate to the CLr of a drug with 10% free fraction is 12 mL/min,19 which is only ~5% of the CLr observed in the present trial. Net tubular secretion is therefore responsible for ≥90% of the CLr of rosuvastatin. The estimated absolute oral bioavailability of rosuvastatin in this study (20.1%) is similar to that of pravastatin (~18%20), fluvastatin (~29%21), and atorvastatin (~14%22), but much lower than that of cerivastatin (~60%23). In addition, the 2560
P.D. Martin et al.
CLp of rosuvastatin (48.9 L/h), pravastatin (~60 L/h20), fluvastatin (~70 L/h21), atorvastatin (37.5 L/h22), and simvastatin (31.8 L/h24) is higher than that of cerivastatin (12.9 L/h23). To our knowledge, CLr data have been published only for pravastatin (>400 mL/min), which, like rosuvastatin, is actively secreted by the kidney.20 The pharmacokinetics of rosuvastatin observed in this trial are consistent with those reported elsewhere.11–16 It should be noted that this trial was performed in healthy volunteers under carefully controlled conditions. The inclusion/exclusion criteria and dietary/lifestyle restrictions employed affect the ability to extrapolate the results to the general population. CONCLUSIONS
The absolute oral bioavailability of rosuvastatin was ~20%, and absorption was estimated to be 50%. The Vss was consistent with extensive distribution of rosuvastatin to the tissues. The modest absolute oral bioavailability and high EH of rosuvastatin are consistent with first-pass uptake into the liver after oral dosing. Rosuvastatin was also eliminated from the systemic circulation by CLr (which was ~28% of CLp); tubular secretion was the predominant renal process. ACKNOWLEDGMENT
The authors thank Elizabeth Eaton, PhD, for assistance with manuscript preparation. REFERENCES 1. Chapman MJ, McTaggart F. Optimizing the pharmacology of statins: Characteristics of rosuvastatin. Atheroscler Suppl. 2002;2:33–36. 2. Olsson AG, Pears J, McKellar J, et al. Effect of rosuvastatin on low-density lipoprotein cholesterol in patients with hypercholesterolemia. Am J Cardiol. 2001;88:504– 508. 3. Paoletti R, Fahmy M, Mahla G, et al. Rosuvastatin demonstrates greater reduction of low-density lipoprotein cholesterol compared with pravastatin and simvastatin in hypercholesterolaemic patients: A randomized, double-blind study. J Cardiovasc Risk. 2001;8:383–390. 4. Davidson M, Ma P, Stein EA, et al. Comparison of effects on low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with rosuvastatin versus atorvastatin in patients with type IIa or IIb hypercholesterolemia. Am J Cardiol. 2002;89:268–275. 5. Olsson AG, Istad H, Luurila O, et al. Effects of rosuvastatin and atorvastatin compared over 52 weeks of treatment in patients with hypercholesterolemia. Am Heart J. 2002; 144:1044–1051. 6. Brown WV, Bays HE, Hassman DR, et al. Efficacy and safety of rosuvastatin compared with pravastatin and simvastatin in patients with hypercholesterolemia: A randomized, double-blind, 52-week trial. Am Heart J. 2002;144:1036–1043. 2561
CLINICAL THERAPEUTICS®
7. Nezasa K, Higaki K, Matsumura T, et al. Liver-specific distribution of rosuvastatin in rats: Comparison with pravastatin and simvastatin. Drug Metab Dispos. 2002;30:1158– 1163. 8. Nezasa K, Higaki K, Hasegawa H, et al. Uptake of HMG-CoA reductase inhibitor ZD4522 into hepatocytes and distribution into liver and other tissues of the rat. Atherosclerosis. 2000;151:39. Abstract MoP21:W6. 9. Brown CDA, Windass A, Bleasby K, Lauffart B. Rosuvastatin is a high affinity substrate of hepatic organic anion transporter OATP-C. Atheroscler Suppl. 2001;2:90. Abstract P174. 10. McCormick AD, McKillop D, Butters CJ, et al. ZD4522—an HMG-CoA reductase inhibitor free of metabolically mediated drug interactions: Metabolic studies in human in vitro systems. J Clin Pharmacol. 2000;40:1055. Abstract 46. 11. Cooper KJ, Martin PD, Dane AL, et al. The effect of fluconazole on the pharmacokinetics of rosuvastatin. Eur J Clin Pharmacol. 2002;58:527–531. 12. Cooper KJ, Martin PD, Dane AL, et al. Lack of effect of ketoconazole on the pharmacokinetics of rosuvastatin in healthy subjects. Br J Clin Pharmacol. 2003;55:94–99. 13. Cooper KJ, Martin PD, Dane AL, et al. Effect of itraconazole on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther. 2003;73:322–329. 14. Cooper KJ, Martin PD, Dane AL, et al. The effect of erythromycin on the pharmacokinetics of rosuvastatin. Eur J Clin Pharmacol. 2003;59:51–56. 15. Martin PD, Dane AL, Nwose OM, et al. No effect of age or gender on the pharmacokinetics of rosuvastatin: A new HMG-CoA reductase inhibitor. J Clin Pharmacol. 2002; 42:1116–1121. 16. Martin PD, Mitchell PD, Schneck DW. Pharmacodynamic effects and pharmacokinetics of a new HMG-CoA reductase inhibitor, rosuvastatin, after morning or evening administration in healthy volunteers. Br J Clin Pharmacol. 2002;54:472–477. 17. Hull CK, Penman AD, Smith CK, Martin PD. Quantification of rosuvastatin in human plasma by automated solid-phase extraction using tandem mass spectrometric detection. J Chromatogr B Analyt Technol Biomed Life Sci. 2002;772:219–228. 18. Ludden TM, Beal SL, Sheiner LB. Comparison of the Akaike Information Criterion, the Schwarz criterion and the F test as guides to model selection. J Pharmacokinet Biopharm. 1994;22:431–445. 19. Rowland M, Tozer TN. Elimination. In: Clinical Pharmacokinetics: Concepts and Applications. Philadelphia: Lea and Febiger; 1996:157–183. 20. Singhvi SM, Pan HY, Morrison RA, Willard DA. Disposition of pravastatin sodium, a tissue-selective HMG-CoA reductase inhibitor, in healthy subjects. Br J Clin Pharmacol. 1990;29:239–243. 21. Tse FL, Jaffe JM, Troendle A. Pharmacokinetics of fluvastatin after single and multiple doses in normal volunteers. J Clin Pharmacol. 1992;32:630–638. 22. Gibson DM, Stern RH, Abel RB, Whitfield LR. Absolute bioavailability of atorvastatin in man. Pharm Res. 1997;14(Suppl):S253. Abstract 2107. 2562
P.D. Martin et al.
23. Muck W, Ritter W, Ochmann K, et al. Absolute and relative bioavailability of the HMG-CoA reductase inhibitor cerivastatin. Int J Clin Pharmacol Ther. 1997;35:255– 260. 24. Mauro VF. Clinical pharmacokinetics and practical applications of simvastatin. Clin Pharmacokinet. 1993;24:195–202.
Address correspondence to: Paul D. Martin, PhD, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom. E-mail: paul. [email protected] 2563