Pharmacokinetics of atorvastatin and its metabolites after single and multiple dosing in hypercholesterolaemic haemodialysis patients

Robert L. Lins1,, Katelijne E. Matthys2, Gert A. Verpooten3, Patrick C. Peeters4, Max Dratwa5, Jean-Claude Stolear6 and Norbert H. Lameire7

1 Nephrology–Hypertension, ACZA, Stuivenberg & SGS Biopharma, Antwerp, 2 Pfizer Pharmaceutical Group, Medical Department, Brussels, 3 Nephrology–Hypertension, University Hospital UIA, Antwerp, 4 Nephrology, University Hospital VUB, Brussels, 5 Nephrology, University Hospital Brugmann, Brussels, 6 Nephrology, IMCH Tournai and 7 Nephrology, University Hospital RUG, Ghent, Belgium



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Patients with chronic renal failure commonly suffer from a secondary form of complex dyslipidaemia, and may benefit from lipid-lowering treatment. Atorvastatin has been shown to reduce efficiently the levels of atherogenic lipoproteins also in patients with renal failure, but pharmacokinetic data in haemodialysis patients are lacking.

Methods. In this study, hypercholesterolaemic haemodialysis patients received 40 mg (n=12) or 80 mg (n=11) atorvastatin once daily, first as a single dose and then continuously for 2 weeks. Plasma levels of atorvastatin and its active and inactive metabolites were measured by LC/MS/MS, and pharmacokinetic parameters (Cmax, tmax, AUC, t1/2) compared between single and multiple dosing, and between the different doses.

Results. The pharmacokinetic parameters of the parent drug atorvastatin acid were not significantly different after single and 2-week multiple dosing; they showed dose-proportionality between the 40 and 80 mg dose, and were comparable to findings in healthy volunteers. Dose-proportionality and absence of accumulation was also observed for the major active metabolite ortho-hydroxy-atorvastatin and the inactive metabolites atorvastatin lactone and ortho-hydroxy-atorvastatin lactone, but the levels of the active metabolite were relatively lower, and the inactive metabolites higher, compared with healthy volunteers. The para-hydroxy-metabolites constituted only a minor pathway in atorvastatin's metabolic elimination. Haemodialysis did not cause enhanced clearance of atorvastatin or its metabolites, the drug was well tolerated and there were no serious adverse events.

Conclusion. While subtle differences may exist in the metabolic processing of atorvastatin in haemodialysis patients, active drug did not accumulate nor did it show enhanced elimination, and levels were comparable to those measured in healthy volunteers. Therefore there is no need to adapt atorvastatin dosage in this particular patient population.

Keywords: atorvastatin; haemodialysis; metabolites; pharmacokinetics; renal insufficiency; safety



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients with chronic renal disease often suffer from a secondary form of complex dyslipidaemia [1]. The most important abnormalities in the lipid profile are an increase in triglyceride levels, the presence of small, dense low-density lipoprotein (LDL) particles and low high-density lipoprotein (HDL) cholesterol levels. The increase in triglyceride levels is due to elevated levels of very-low-density lipoprotein (VLDL) remnants and intermediate-density lipoprotein (IDL). Each of these parameters has been associated with increased risk of cardiovascular disease [1].

The cardiovascular mortality of dialysis patients is 10–15 times higher compared with the general population [2]. The mortality rate during the first year of dialysis is over 19%, with more than half of the deaths related to cardiac disease [3]. Therefore, adequate therapeutic life-style changes and pharmacological treatment of all known cardiovascular risk factors, including dyslipidaemia, should be initiated. European [4] and American [5] associations have issued guidelines for the treatment of hyper- and dyslipidaemia. In high-risk patients, the goal of therapy is a reduction of LDL cholesterol to below 2.6 mmol/l [5]. Triglyceride levels are considered a secondary goal and should be reduced to below 2.3 mmol/l. Most renal patients exhibit higher levels and should be treated according to these recommendations, preferentially with a statin or gemfibrozil [1].

Atorvastatin is a 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase inhibitor that efficiently and dose-dependently lowers both cholesterol [6] and triglyceride [7] levels in hyperlipidaemic patients. Atorvastatin produces larger reductions of cholesterol and triglycerides compared with other drugs in this class [8]. It has also been shown to reduce the levels of small, dense LDL and IDL [9].

Atorvastatin is administered in its active acid form and undergoes extensive first-pass metabolism mainly by cytochrome P450 3A4 (CYP3A4) in the liver [10], the organ that is also its primary site of action. Liver metabolism produces two active hydroxy metabolites, ortho-hydroxy-atorvastatin (o-OH-atorvastatin) and para-hydroxy-atorvastatin (p-OH-atorvastatin), and three corresponding inactive lactone metabolites [11]. The active metabolites are equipotent to the parent drug in vitro. Elimination of the drug is mainly through the bile; renal excretion of radiolabelled drug and metabolites in urine is negligible [12]. In a study in subjects with different degrees of renal dysfunction, but excluding patients on dialysis, plasma atorvastatin equivalent concentrations were measured after 2-weeks' oral administration of atorvastatin 10 mg daily. No effect of decreasing creatinine clearance on active drug plasma levels could be detected [13]. Therefore, and in contrast to other statins, dosage adjustment to avoid accumulation in patients with renal impairment is not necessary [10].

Because of the complex and difficult-to-treat dyslipidaemia in dialysis patients, higher doses of atorvastatin (40 and 80 mg) might be of value in the treatment of hypercholesterolaemic patients on haemodialysis. Haemodialysis is not expected to enhance significantly the clearance of atorvastatin, since the drug is extensively bound to plasma proteins. However, it is known that renal dysfunction may hamper the hepatic metabolism of drugs [14,15], which could lead to accumulation of atorvastatin and/or its long-lived metabolites, in turn increasing the risk of clinically important adverse events such as rhabdomyolysis. This warrants the performance of supplemental pharmacokinetic studies in the renal patient population also for hepatically metabolized drugs, especially when higher doses of drug are considered.

In the present study, the pharmacokinetics and tolerance of higher doses of atorvastatin (40 and 80 mg) were evaluated in 23 haemodialysis patients with hypercholesterolaemia. The plasma concentrations of atorvastatin and its different metabolites were determined. To assess whether drug accumulation occurred in this patient population, pharmacokinetic parameters after single and 2 weeks' dosing were compared, and dose-proportionality of the drug was investigated.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Participants
This study was conducted in six haemodialysis centres, according to the principles of the Declaration of Helsinki and according to ICH/GCP. The protocol was approved by each of the hospital's ethics committees, and the participants gave written informed consent before participation in the study. The pharmacokinetic study reported here preceded a 12-week efficacy study of atorvastatin in hypercholesterolaemic patients on haemodialysis, which will be reported separately.

In total, 23 patients were enrolled in this study. To be eligible, patients had to meet the following criteria: chronic renal failure treated with haemodialysis for at least 3 months, haemodialysis sessions at least twice a week, hypercholesterolaemia (total cholesterol >=210 mg/dl) and triglycerides <=500 mg/dl. Patients had to be at least 18 years old. Women on contraceptive or hormone replacement therapy had to be on stable treatment for at least 3 months; pregnant and breastfeeding women were excluded. Also excluded were patients with non-stabilized diabetes mellitus (HbA1c>10%) or with hepatic dysfunction (based on transaminases >=3 times the upper limit of normal).

The following concomitant drugs were not permitted during this study: (i) other lipid-lowering drugs or preparations (acipimox, niacin, fibrates, bile sequestrants, other statins, soluble fibre preparations like psyllium and Metamucil); (ii) other drugs known to modulate lipid parameters (corticosteroids, isotretinoin); (iii) antioxidant vitamins; (iv) immunosuppressive drugs; (v) drugs known to be associated with myopathy in combination with HMG-CoA reductase inhibitors, due to competition for metabolic pathways (cyclosporin, macrolide antibiotics, azole antifungals). Permitted medications, e.g. antihypertensive drugs and phosphate-binding drugs, were to be kept constant throughout the study, both in dosage and time of intake. The occasional use of antacids was permitted. Any concurrent medications were to be taken at least 30 min after the study medication. Patients were asked not to change their eating habits during the course of the study.

Protocol of drug administration and blood sampling
The protocol is shown in Figure 1Go. Participants were randomized to one of the two treatment groups: 40 mg of atorvastatin (n=11) or 80 mg of atorvastatin (n=12). Drug intake had to be performed at 8.00 a.m. and started (day 1) one day prior to a dialysis session (day 2). In order to study single-dose pharmacokinetics, a placebo tablet was administered on days 2 and 3. From day 4 until day 20 (±2 days), patients received atorvastatin, followed by 4 days of placebo intake. On days of pharmacokinetic blood sampling, breakfast and concurrent medication was delayed at least 2 h after atorvastatin intake.



View larger version (12K):
[in this window]
[in a new window]
 
Fig. 1.  Protocol of drug administration and blood sampling. Dosing regimen, atorvastatin or placebo intake, dialysis sessions and blood sampling time points are indicated. Patients were dialysed three times per week. Only the dialysis (D) sessions taking place during the two phases of blood sampling are indicated. Dialysis started around 9.00 a.m. and lasted for a mean duration of 230 min. *Time of drug intake; blood sampling was performed just before drug intake. §Samples taken just before (bD), just after (aD), and 1 h after dialysis (D+1). $Dialysis session on one of these consecutive days.

 
For the evaluation of single-dose pharmacokinetics, blood samples were taken just before the first intake of atorvastatin (8.00 a.m., day 1) and 1, 2, 4, 6 and 24 h (8.00 a.m., day 2) after intake. The next day, which was a dialysis day (day 2), three additional samples were taken: one just before the start of the dialysis session, the second just after dialysis and the third 1 h after the end of the dialysis session. The last sample was obtained 48 h after drug intake (8.00 a.m., day 3).

For the evaluation of multiple-dose pharmacokinetics, blood samples were taken on day 20 (±2 days), which was the last day of atorvastatin intake, and day 21, which was a dialysis day, according to the schedule described above for day 1 and day 2. Additional samples were taken 48, 72 and 96 h after the last atorvastatin intake.

Blood sample collection and analysis
Seven millilitres of venous blood was drawn in vacuum blood collection tubes containing 100 USP units of heparin. Blood samples were centrifuged, and plasma was separated and stored frozen at -20°C until analysis of drug concentrations.

The dialysate was not analysed, as atorvastatin is highly lipophylic and protein-bound and therefore unlikely to be cleared by the dialysate.

Blood samples were analysed for the parent compound atorvastatin, its ortho- and para-hydroxy-metabolites, and their respective lactones, by a high-performance liquid chromatography/tandem mass spectrometry (LC/MS/MS) assay [16]. This assay has been shown to be specific and accurate, with high sensitivity allowing reliable and reproducible quantification of atorvastatin and its metabolites down to a level of 0.25 ng/ml.

Pharmacokinetic parameters
Data from six sampling times within 24 h after drug intake were used to obtain the mean peak plasma concentrations (Cmax, ng·ml-1) and time of Cmax (tmax, h) for each of the compounds. The area under the plasma concentration-time curve (AUC) was estimated by use of the linear trapezoidal method. For assessment of exposure after a single dose, AUC was extrapolated to infinity (AUC0->{infty}); after multiple dosing, the AUC value was calculated during the dose interval at steady state (AUC0->24). The terminal elimination half-life (t1/2, h) was calculated for atorvastatin and its major active metabolite o-OH-atorvastatin from the logarithmic concentration curve, from 24 to 48 h after drug intake, assuming one-compartmental elimination.

Statistical analysis
The pharmacokinetic parameters obtained for atorvastatin and its metabolites are expressed as means±SD. The 95% confidence intervals are also given. All statistical tests were performed two-tailed, at the 5% level of significance. Baseline characteristics of the two treatment groups were compared by the chi-square test (categorical variables) or the Mann–Whitney test (continuous variables). The pharmacokinetic parameters Cmax, tmax and t1/2 for single and multiple dosage regimens (within the same patient) were compared by the Wilcoxon test. To investigate dose-proportionality, Cmax and AUC were compared between the 40 mg and the 80 mg group after doubling the values obtained in the 40 mg group, using the Mann–Whitney test.

Adverse event assessment
Adverse events occurring during a dialysis session were recorded together with the other dialysis data. Adverse events that did not abate after dialysis and events occurring outside dialysis sessions were recorded separately. Liver enzymes and creatine phosphokinase plasma levels were not measured in this short-term pharmacokinetics study, but were monitored during the subsequent longer-lasting efficacy study, which will be reported separately.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patient characteristics and concomitant medication
Baseline patient characteristics are given in Table 1Go. There were no significant differences between the two dose groups.


View this table:
[in this window]
[in a new window]
 
Table 1.  Baseline patient characteristics

 
Most patients were on diverse chronic medications, including proton-pump inhibitors, diverse antihypertensives, antihistamines, hypnotics. Substrates or weak inhibitors of CYP3A4 such as benzodiazepines were taken by 11 of 23 patients. Occasional use of antacids occurred in five patients. Most patients (21 of 23) were taking phosphate-binding drugs.

Plasma levels, Cmax and tmax of atorvastatin and metabolites after single and multiple dosing
The cumulative mean plasma concentrations of atorvastatin and its active (o- and p-OH-atorvastatin) and inactive metabolites (3 lactone compounds) up to 6 h after drug administration are shown in Figure 2Go. Cumulative curves are constructed so as to visualize the relative contributions of the different compounds within this time frame: atorvastatin>atorvastatin lactone>o-OH-lactone>o-OH-atorvastatin>>p-OH-lactone>>p-OH-atorvastatin. Multiple dosing did not lead to higher peak plasma levels of atorvastatin. It did, however, result in higher peak cumulative levels of atorvastatin and its mixture of metabolites, and this seemed to be due mainly to slightly increased levels of the inactive atorvastatin lactone and o-OH-lactone compounds. Indeed, the mean Cmax value of these inactive metabolites was higher upon multiple dosing, however without reaching statistical significance (Table 2Go).



View larger version (63K):
[in this window]
[in a new window]
 
Fig. 2.  Plasma levels of atorvastatin and its metabolites during the first 6 h after single and multiple dosing of 40 and 80 mg atorvastatin. Cumulative curves are constructed to visualize the relative contributions of the different compounds.

 

View this table:
[in this window]
[in a new window]
 
Table 2.  Pharmacokinetic parameters for atorvastatin and its metabolites, following single and 2-week dosing in haemodialysis patients

 
The pharmacokinetic parameters Cmax and tmax of the individual analytes, and their plasma levels 24 h after drug intake are given in Table 2Go. For the three major compounds (atorvastatin itself and inactive atorvastatin lactone and o-OH-lactone), mean Cmax values after single dosing ranged between 20 and 30 ng/ml in patients who had received 40 mg atorvastatin, and between 40 and 70 ng/ml in the 80 mg group. For these compounds, Cmax was reached quickly and tmax tended to be even shorter upon multiple dosing of 80 mg. The major active metabolite o-OH-atorvastatin also appeared early in the blood, with a Cmax that was 2–3-fold lower than that of atorvastatin itself, and that was not significantly increased upon multiple dosing. The Cmax values of the minor active metabolite p-OH-atorvastatin and the inactive o-OH-lactone compound were much lower (Cmax of active p-OH-atorvastatin more than 50 times lower than Cmax of atorvastatin), and occurred much later after single dosing, especially in the 40 mg group. The Cmax was significantly increased and the tmax decreased upon multiple dosing, indicating accumulation of these metabolites. But even after multiple dosing, the plasma level of these minor metabolites remained very low.

Twenty-four hours after drug intake, mean levels of atorvastatin and its metabolites had dropped below 5 ng/ml in both dose groups and for all dosing protocols (Table 2Go).

At 48 h, individual maximal values did not exceed 2 ng/ml. After the last drug intake in the multiple-dosing protocol, the levels of atorvastatin and its metabolites had fallen below the detection limit 72 h later in almost all patients.

Evolution of plasma levels of atorvastatin and metabolites during haemodialysis
Figure 3Go shows the evolution of the plasma levels of atorvastatin and its metabolites before and after dialysis, exemplified for a single dose of atorvastatin 80 mg the day before dialysis. Within this short time frame, the plasma measurements fluctuated, but haemodialysis clearly did not wash out the compounds. The plasma levels of atorvastatin and its metabolites slightly decreased in most patients, but the difference usually did not reach statistical significance.



View larger version (34K):
[in this window]
[in a new window]
 
Fig. 3.  Plasma levels of atorvastatin and its metabolites during dialysis. The data presented are for 80 mg single dosing. The duration of dialysis was on average 230 min. Plasma levels were assessed at several time points after atorvastatin intake (1, 2, 4, 6 and 24 h), just before (bD, ±25 h) and just after dialysis (aD), and 1 h after dialysis (D+1h). Please note that the Y-axis has a logarithmic scale.

 

Systemic drug exposure and dose-proportionality of atorvastatin 40 and 80 mg/day
The AUC0->{infty} after single dosing and the AUC0->24 after multiple dosing were calculated for atorvastatin and its metabolites (Table 3Go). In general, the highest AUC values were detected for the major inactive lactones atorvastatin lactone and o-OH-lactone (40–100% higher than AUC of free atorvastatin acid). The AUC value of the major active metabolite o-OH-atorvastatin was 30–50% lower compared with atorvastatin itself. The total AUC of the minor metabolites p-OH-atorvastatin and p-OH-lactone constituted less than 10% of the total AUC of all analytes.


View this table:
[in this window]
[in a new window]
 
Table 3.  Total systemic drug exposure to atorvastatin and its metabolites, following single and 2-week dosing in haemodialysis patients

 
After intake of 40 or 80 mg/day atorvastatin, no more than a dose-proportional increase in Cmax or AUC values (Tables 2Go and 3Go) was observed for atorvastatin or its metabolites.

Elimination half-life of atorvastatin and its major active metabolite
The t1/2 value after a single dose of atorvastatin was about 11 h (Table 3Go). After multiple dosing, the values were not significantly different, although multiple dosing of atorvastatin 80 mg slightly prolonged the t1/2 to 14.7±6.8 h. For the ortho-hydroxy metabolite of atorvastatin, t1/2 was about 18 h for a single dose of atorvastatin 40 mg or 80 mg. Multiple dosing again seemed to slightly prolong the elimination half-life, but values were not significantly different between single and multiple dosing.

Inter-subject variability
The plasma levels of atorvastatin and its metabolites varied considerably between subjects. For instance, the Cmax values for atorvastatin varied between 26 and 161 ng/ml after a single dose of atorvastatin 80 mg. Four patients (2 in the 40 mg and 2 in the 80 mg group) had no detectable or only trace levels of atorvastatin 6 h after drug intake. In these subjects, also the metabolites of atorvastatin were barely detectable. One patient had undetectable levels of atorvastatin after repeated dosing of 40 mg during the first 72 h, but had developed significant plasma levels 96 h after drug intake (19 ng/ml). This may be due to severe impairment of gastric emptying, a problem often encountered in dialysis patients.

Also in the t1/2, there were large differences in individual values, e.g. ranging between 6.5 and 22.0 h after 40 mg single dosing of atorvastatin acid.

Adverse events
Two patients terminated the study prematurely: one on 40 mg/day due to adverse events (nausea, vomiting and back pain) and one on 80 mg/day because of kidney transplantation.

There were no serious adverse events. Adverse events were reported in five patients (45%) in the 40 mg group and in three patients (27%) in the 80 mg group (Table 4Go). These were mainly gastro-intestinal symptoms and/or hypotension. Most adverse events were reported during dialysis and resolved spontaneously at the end of the dialysis session, including one reported case of muscle cramps.


View this table:
[in this window]
[in a new window]
 
Table 4.  Adverse events during dialysis

 



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
While the need to treat lipid abnormalities complicating renal disease is largely unproven, it is reasonable to assume that well-established cardiovascular risk factors present the same health hazards to dialysis patients as they do to patients without renal disease. Several small, short-term trials of statins in patients with end-stage renal disease (ESRD) have shown that these drugs can be used safely in this patient population, and that they cause potentially beneficial changes in the lipoprotein profile [1719]. Atorvastatin 10–40 mg has been shown to correct hypercholesterolaemia and hypertriglyceridaemia in patients receiving peritoneal dialysis [20,21]. Recently the effectiveness of lipid lowering on the reduction of cardiovascular mortality in renal disease has been calculated, based on analysis of data of 3716 patients represented in the United States Renal Data System—Dialysis Morbidity and Mortality Study–2 [17]. Statin use was independently associated with a reduced risk of cardiovascular mortality (relative risk 0.64) as well as total mortality (relative risk 0.68). The use of fibrates was not associated with reduced mortality (relative risk 1.29).

For atorvastatin and other drugs of this class, the liver is the primary site of action. Therefore, dose administered, rather than plasma concentrations, predicts the pharmacological response. However, increased systemic availability of active drug or metabolites may increase the risk for clinically important adverse events such as rhabdomyolysis. Elevated active drug concentrations may result from the administration of usual doses of lovastatin, simvastatin and pravastatin to patients with renal impairment [10]. Daily intake of 10 mg atorvastatin in patients with renal impairment did not result in elevated plasma levels [13], but to date, pharmacokinetic studies in haemodialysis patients receiving higher doses of atorvastatin have not been published.

Renal failure has been shown to alter the hepatic cytochrome P450 system of drug-metabolizing enzymes [15], but the exact mechanisms of altered drug metabolism have not been well characterized. Hepatic levels of CYP3A4, the major enzyme involved in atorvastatin metabolism [10], have been shown to be reduced by more than 65% in a rat model of chronic renal failure [22]. However, in humans with renal failure, CYP3A4 isozyme may be spared [14].

In subjects without renal disease, pharmacokinetic studies involving 40 and 80 mg atorvastatin dosing showed that mean Cmax and AUC of atorvastatin increased proportionally with increasing dose [23]. With a high dose of 120 mg, Cmax and AUC of atorvastatin increased clearly more than expected from dose-proportionality, probably due to saturation of first-pass hepatic metabolism [24]. In this study in haemodialysis patients, Cmax plasma levels for single and multiple dosing of 40 mg atorvastatin were comparable, with mean values of 28–29 ng/ml. In addition, in patients taking 80 mg of atorvastatin, multiple dosing did not result in a higher Cmax than single dosing, with mean values of 66–68 ng/ml. While the measured plasma levels show clear dose-proportionality, also their absolute values are in the range found in healthy volunteers (Table 5Go), certainly when one considers that Cmax and AUC of atorvastatin and o-OH-atorvastatin are approximately 2-fold higher in the elderly than in the young [23]. Cmax values of the major active metabolite o-OH-atorvastatin were lower than Cmax values of the parent drug, in keeping with findings in healthy volunteers' studies (Table 5Go).


View this table:
[in this window]
[in a new window]
 
Table 5.  Pharmacokinetic parameters of atorvastatin and ortho-hydroxy-atorvastatin in healthy volunteers

 
AUC reflects the total systemic exposure during a longer time and is therefore a more reliable parameter of drug exposure and metabolism. Like Cmax, the AUC values for atorvastatin that we obtained in this patient group showed dose-proportionality and were comparable to values obtained in healthy volunteers (Table 5Go). While we observed dose-proportionality also for o-OH-atorvastatin, normal subjects show levels higher than expected from dose-proportionality for this active metabolite (Table 5Go). In addition, the AUC ratio of o-OH-atorvastatin to atorvastatin was between 0.5 and 0.7 in this study, compared with 1.2 to 1.6 in healthy volunteers receiving single or multiple doses of 40 mg atorvastatin and 2.6 for 80 mg repetitive dosing (Table 5Go). An explanation could be that the balance between (active) acid forms and (inactive) lactone forms is shifted towards the latter. This indeed seems to be the case: whereas the AUC ratio of atorvastatin lactone to atorvastatin is <=1 in normal subjects [2527], it is between 1.4 and 1.8 in our study. The AUC ratio of o-OH-lactone to o-OH-atorvastatin is about 2.1 in normal subjects [26,27], whereas it is 2.9 in this study. The presence of acidosis or other metabolic disturbances in these patients may explain the slightly higher conversion to the lactone forms.

For atorvastatin, mean Cmax was reached within 2 h, irrespective of the dosage used, as reported previously [12]. The mean tmax values of the major active and inactive metabolites were between 2 and 4 h, independent of the dose given and in keeping with previously published data [24,28,29].

In our haemodialysis setting, the average half-life of atorvastatin was 11–15 h. The half-life of the major active metabolite ortho-hydroxy-atorvastatin was longer (18–22 h). This corresponds with published values [12,23,28].

In most patients, drug levels after dialysis were slightly lower than before dialysis, as can be expected based on normal elimination. The differences in levels before and after dialysis were in most cases not statistically significant. Assessing whether there is a higher elimination during dialysis than right after dialysis can be performed theoretically by comparing the respective elimination rate constants. However the relatively short time frame of a dialysis session, the already low drug levels at the time of dialysis, the small number of blood sampling time points and the inherent variation in the measurement of drug plasma levels make it highly unlikely that differences in elimination rate constants can be detected. On the other hand, it is clear from the data that atorvastatin and its metabolites are not washed out.

The high inter-subject variability in pharmacokinetic parameters seen in this study is noteworthy. A high variability in atorvastatin kinetic parameters has also been observed in subjects without renal disease. Age, gender, food intake, and level of CYP3A4 expression and activity all influence the body's handling of atorvastatin [12]. An important characteristic of CYP3A4 is the large inter-individual variability in activity (about 5-fold), which reflects genetic polymorphism combined with modulation by environmental factors [30]. Intake of known strong inhibitors or inducers of CYP3A4 did not occur in this study. However, in haemodialysis patients, who are polymedicated and have complex metabolic disturbances, uncharacterized interactions with concomitant drugs and endogenous substances may have contributed to the large variation in atorvastatin pharmacokinetic parameters. Additional variation may have been introduced by co-morbid conditions existing in this patient population, like gastric paresis in diabetic patients. Although shown to decrease the levels of atorvastatin, occasional use of antacids was permitted and occurred in five patients.

In non-renal patients, atorvastatin 10–80 mg/day was well tolerated in clinical trials of up to 2 years involving over 2500 patients [31]. In a 16-weeks' study in CAPD patients [20], the rate of serious adverse events and the proportion of patients withdrawing due to adverse events was greater, but this was attributed to the generally worse condition of this specific patient population, since the overall adverse event profile for atorvastatin was similar to that observed with placebo. Also, in the present small-scale, short-term pharmacokinetic study, atorvastatin was well tolerated. One patient complained of muscle cramps during the haemodialysis session, which resolved thereafter. This event therefore appeared to be a typical symptom of haemodialysis intolerance.

There is still a pressing need for large, prospective randomized controlled trials with long-term follow-up to determine the effects of lipid-lowering therapy on cardiovascular morbidity and mortality. This is addressed in the 4D atorvastatin study (Die Deutsche Diabetes Dialyse study): long-term treatment with atorvastatin 20 mg will be compared with placebo in approximately 1200 type 2 diabetic patients receiving haemodialysis [32]. The results of this study are expected in 2003, and will hopefully lend more support to the safe use of statins in this specific and vulnerable patient group.

This study in hyperlipidaemic haemodialysis patients indicates that there is no need to adapt the dosage of atorvastatin in this particular patient population, since (i) atorvastatin 40 mg and 80 mg was well tolerated, (ii) there was no evidence of increased accumulation of atorvastatin or its major active metabolite upon multiple dosing, compared with healthy volunteers, (iii) plasma levels did not increase significantly more than expected from dose-proportionality, and (iv) plasma levels of atorvastatin and its metabolites remained sufficiently sustained during haemodialysis.

Overall, this study revealed subtle differences in the processing of atorvastatin in haemodialysis patients compared with normal subjects, but is reassuring with respect to levels of exposure to active compound.



   Acknowledgments
 
This study was funded by Pfizer. We thank Suzy Huijghebaert for her assistance in preparing the manuscript.



   Notes
 
Correspondence and offprint requests to: R. L. Lins, MD, PhD, Department of Nephrology–Hypertension, ACZA Stuivenberg & SGS Biopharma, Lange Beeldekensstraat 267, B-2060 Antwerpen, Belgium. Email: robert.lins{at}pro.tiscali.be Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Wanner C, Quaschning T. Dyslipidemia and renal disease: pathogenesis and clinical consequences. Curr Opin Nephrol Hypertens 2001; 10:195–201[CrossRef][ISI][Medline]
  2. Gradaus F, Ivens K, Peters AJ et al. Angiographic progression of coronary artery disease in patients with end-stage renal disease. Nephrol Dial Transplant 2001; 16:1198–1202[Abstract/Free Full Text]
  3. US Renal Data System Annual Data Report. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases 2000
  4. Wood D, De Backer G, Faergeman O et al. Prevention of coronary heart disease in clinical practice. Recommendations of the Second Joint Task Force of European and other Societies on coronary prevention. Eur Heart J 1998; 19:1434–1503[Free Full Text]
  5. Grundy SM. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001; 285:2486–2497[Free Full Text]
  6. Nawrocki JW, Weiss SR, Davidson MH et al. Reduction of LDL cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin, a new H MG-CoA reductase inhibitor. Arterioscler Thromb Vasc Biol 1995; 15:678–682[Abstract/Free Full Text]
  7. Bakker-Arkema RG, Davidson MH, Goldstein RJ et al. Efficacy and safety of a new H MG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia. JAMA 1996; 275:128–133[Abstract]
  8. Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 1998; 81:582–587[CrossRef][ISI][Medline]
  9. Guerin M, Egger P, Soudant C et al. Dose-dependent action of atorvastatin in type IIB hyperlipidemia: preferential and progressive reduction of atherogenic apoB-containing lipoprotein subclasses (VLDL-2, IDL, small dense LDL) and stimulation of cellular cholesterol efflux. Atherosclerosis 2002; 163:287–296[CrossRef][ISI][Medline]
  10. Chong PH, Seeger JD, Franklin C. Clinically relevant differences between the statins: implications for therapeutic selection. Am J Med 2001; 111:390–400[CrossRef][ISI][Medline]
  11. Jacobsen W, Kuhn B, Soldner A et al. Lactonization is the critical first step in the disposition of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor atorvastatin. Drug Metab Dispos 2000; 28:1369–1378[Abstract/Free Full Text]
  12. Lea AP, McTavish D. Atorvastatin. A review of its pharmacology and therapeutic potential in the management of hyperlipidaemias. Drugs 1997; 53:828–847[ISI][Medline]
  13. Stern RH, Yang BB, Horton M et al. Renal dysfunction does not alter the pharmacokinetics or LDL-cholesterol reduction of atorvastatin. J Clin Pharmacol 1997; 37:816–819[Abstract/Free Full Text]
  14. Touchette MA, Slaughter RL. The effect of renal failure on hepatic drug clearance. DICP 1991; 25:1214–1224[ISI][Medline]
  15. Yuan R, Venitz J. Effect of chronic renal failure on the disposition of highly hepatically metabolized drugs. Int J Clin Pharmacol Ther 2000; 38:245–253[ISI][Medline]
  16. Bullen WW, Miller RA, Hayes RN. Development and validation of a high-performance liquid chromatography tandem mass spectrometry assay for atorvastatin, ortho-hydroxy atorvastatin, and para-hydroxy atorvastatin in human, dog, and rat plasma. J Am Soc Mass Spectrom 1999; 10:55–66[CrossRef][ISI][Medline]
  17. Seliger SL, Weiss NS, Gillen DL et al. H MG-CoA reductase inhibitors are associated with reduced mortality in ESRD patients. Kidney Int 2002; 61:297–304[CrossRef][ISI][Medline]
  18. Saltissi D, Morgan C, Rigby RJ, Westhuyzen J. Safety and efficacy of simvastatin in hypercholesterolemic patients undergoing chronic renal dialysis. Am J Kidney Dis 2002; 39:283–290[ISI][Medline]
  19. Nishizawa Y, Shoji T, Tabata T, Inoue T, Morii H. Effects of lipid-lowering drugs on intermediate-density lipoprotein in uremic patients. Kidney Int Suppl 1999; 71:S134–S136[CrossRef][Medline]
  20. Harris KP, Wheeler DC, Chong CC. A placebo-controlled trial examining atorvastatin in dyslipidemic patients undergoing CAPD. Kidney Int 2002; 61:1469–1474[CrossRef][ISI][Medline]
  21. Hufnagel G, Michel C, Vrtovsnik F et al. Effects of atorvastatin on dyslipidaemia in uraemic patients on peritoneal dialysis. Nephrol Dial Transplant 2000; 15:684–688[Abstract/Free Full Text]
  22. Leblond F, Guevin C, Demers C et al. Downregulation of hepatic cytochrome P450 in chronic renal failure. J Am Soc Nephrol 2001; 12:326–332[Abstract/Free Full Text]
  23. Malhotra HS, Goa KL. Atorvastatin: an updated review of its pharmacological properties and use in dyslipidaemia. Drugs 2001; 61:1835–1881[ISI][Medline]
  24. Posvar EL, Radulovic LL, Cilla DD, Jr., Whitfield LR, Sedman AJ. Tolerance and pharmacokinetics of single-dose atorvastatin, a potent inhibitor of H MG-CoA reductase, in healthy subjects. J Clin Pharmacol 1996; 36:728–731[Abstract/Free Full Text]
  25. Mazzu AL, Lasseter KC, Shamblen EC et al. Itraconazole alters the pharmacokinetics of atorvastatin to a greater extent than either cerivastatin or pravastatin. Clin Pharmacol Ther 2000; 68:391–400[CrossRef][ISI][Medline]
  26. Kantola T, Kivisto KT, Neuvonen PJ. Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998; 64:58–65[ISI][Medline]
  27. Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin. Clin Pharmacol Ther 1999; 66:118–127[ISI][Medline]
  28. Stern RH, Yang BB, Hounslow NJ et al. Pharmacodynamics and pharmacokinetic-pharmacodynamic relationships of atorvastatin, an H MG-CoA reductase inhibitor. J Clin Pharmacol 2000; 40:616–623[Abstract/Free Full Text]
  29. Cilla DD, Jr., Whitfield LR, Gibson DM, Sedman AJ, Posvar EL. Multiple-dose pharmacokinetics, pharmacodynamics, and safety of atorvastatin, an inhibitor of H MG-CoA reductase, in healthy subjects. Clin Pharmacol Ther 1996; 60:687–695[ISI][Medline]
  30. Thummel KE, Wilkinson GR. In vitro and in vivo drug interactions involving human CYP3A. Annu Rev Pharmacol Toxicol 1998; 38:389–430[CrossRef][ISI][Medline]
  31. Black DM, Bakker-Arkema RG, Nawrocki JW. An overview of the clinical safety profile of atorvastatin (Lipitor), a new HMG-CoA reductase inhibitor. Arch Intern Med 1998; 158:577–584[Abstract/Free Full Text]
  32. Wanner C, Krane V, Ruf G, Marz W, Ritz E. Rationale and design of a trial improving outcome of type 2 diabetics on hemodialysis. Die Deutsche Diabetes Dialyse Studie Investigators. Kidney Int Suppl 1999; 71:S222–S226[Medline]
  33. Oishi S, Watanabe T, Higuchi S et al. Atorvastatin (CI-981) clinical pharmacokinetic study (II) – Pharmacokinetics of single dose atorvastatin in healthy male volunteers. Jpn Pharmacol Ther 1998; 26:79–92
  34. Fichtenbaum CJ, Gerber JG, Rosenkranz SL et al. Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047. AIDS 2002; 16:569–577[CrossRef][ISI][Medline]
Received for publication: 4. 2.02
Accepted in revised form: 5.12.02