groups of six healthy volunteers received either 100 mg ciprofibrate/day followed by 200 mg fenofibrate 'high bioavailability' (HB)/day, or vice versa (group A), ...
atherosclerosis Atherosclerosis 124 Suppl. (1996) $65-$73
ELSEVIER
Pharmacodynamic activity of lipoprotein lipase and hepatic lipase, and pharmacokinetic parameters measured in normolipidaemic subjects receiving ciprofibrate (100 or 200 mg/day) or micronised fenofibrate (200 mg/day) therapy for 23 days Jean-Pierre Desager*, Y. Horsmans, C. Vandenplas, C. Harvengt Pharmacotherapy Laboratory, Catholic University of Louvain, 53, Avenue E. Mounier, BI200 Brussels, Belgium
Abstract
The activities of lipoprotein lipase (LPL) and hepatic lipase (HL) were investigated after 23 days of ciprofibrate (100 mg or 200 mg) therapy or fenofibrate (200 mg) therapy. In a double-blind, double-placebo, cross-over study, three groups of six healthy volunteers received either 100 mg ciprofibrate/day followed by 200 mg fenofibrate 'high bioavailability' (HB)/day, or vice versa (group A), 200 mg ciprofibrate/day followed by 200 mg fenofibrate HB/day, or vice versa (group B), or 100 mg ciprofibrate/day followed by 200 mg ciprofibrate/day, or vice versa (group C). Fasting plasma lipid levels and safety parameters were evaluated before and after treatment. One hundred milligrams ciprofibrate/day therapy was found to be approximately as effective as 200 mg fenofibrate HB/day therapy in altering the lipid profile. The highest activation of LPL was obtained after treatment with 200 mg ciprofibrate/day. A modest, but statistically significant, increase in HL activity was found after 100 or 200 mg ciprofibrate treatment. Investigation of the pharmacokinetics of ciprofibrate and fenofibric acid revealed a shorter time to reach peak plasma levels, but a longer elimination half life for the ciprofibrate preparations in comparison with fenofibrate. A dose of 200 mg ciprofibrate/day is more effective than 100 mg ciprofibrate/day at increasing LPL and HL activity; however, 200 mg ciprofibrate/day is also associated with a potentially detrimental change in safety parameters. Two hundred milligrams fenofibrate HB/day therapy may represent an alternative therapy to 100 mg ciprofibrate/day for hyperlipidaemic patients. Keywords: Ciprofibrate; Fenofibrate HB; Lipoprotein lipase (LPL); Hepatic lipase (HL); Normolipidaemic
1. Introduction
Ciprofibrate and fenofibrate belong to the second generation of fibric acid derivatives and are particularly effective in the treatment of hypertriglyceridaemia and combined hyperlipidaemia * Corresponding author. Tel.: +32 2 764 5349; Fax: +32 2 764 9322.
[1]. Administration of ciprofibrate or fenofibrate has been shown to reduce plasma triglycerides (TG), total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol, and to increase plasma levels of high-density lipoprotein (HDL) cholesterol [2-5]. These effects are believed to be secondary to a reduction in the production of very-low-density lipoprotein (VLDL) which is associated with enhanced lipoprotein lipase (LPL)
0021-9150/96/$15.00 © 1996 Elsevier Science Ireland Ltd. All rights reserved PH S0021-9150(96)05859-5
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activity [6,7]. LPL acts on chylomicrons from intestinal origin and on VLDL from hepatic origin, while another lipolytic enzyme, hepatic lipase (HL), catabolises the HDL particles in the liver. In hypertriglyceridaemia, large VLDL particles are produced by LPL and it has been demonstrated recently that ciprofibrate favours the formation of large LDL particles instead of small, dense, atherogenic LDL particles [8,9]. These dense LDL particle subspecies have a diminished oxidative resistance, potentiating their uptake by the scavenger receptors of macrophages and leading to cholesterol accumulation and foam cell formation [10]. Thus, ciprofibrate promotes the clearance of LDL particles from the plasma via the B 100 receptor and simultaneously reduces the production of the apolipoprotein in the slow cholesterol pool [8]. Fenofibrate regulates LDL metabolism in the same way as ciprofibrate [11]. In patients treated with ciprofibrate, HL is responsible for an increase in the cholesterol content of the HDL particles without an enhanced synthesis of protein [8]. Data on the influence of ciprofibrate on LPL and HL activity are sparse. However, the activity of plasma lipolytic enzymes in normolipidaemic subjects has been measured after short-term administration of 300 mg/day fenofibrate [12]. Recently, a micronised or 'high bioavailability' (HB) formulation of fenofibrate has been produced. Two hundred milligrams of fenofibrate HB is claimed to be equivalent to 300 mg of the previous fenofibrate formulation, but few data are available [13]. The aim of this study was to evaluate the effect of 23 days of treatment with 100 mg or 200 mg ciprofibrate/day, and 200 mg fenofibrate HB/day, on the post-heparin lipolytic activity of LPL and HL in normolipidaemic subjects. Plasma pharmacokinetics of the two drugs were also investigated during this short-term study.
2. Subjects and methods 2.1. Subjects
Eighteen male, normolipidaemic, non-smoking, non-obese subjects participated in the study. The subjects' mean body mass index was 21.5 ± 1.8 kg/m 2 and the mean age was 22.1 4- 1.5 years. The study protocol was approved by the ethical
committee of the School of Medicine of the Catholic University of Louvain. 2.2. Treatment protocol
The cross-over study was designed to be doubleblind. As the different drug capsules could be easily identified, the blind nature of the trial was ensured by supplying each study participant with two boxes of capsules; one box consisted of capsules containing the study drug to be taken, while the other box consisted of capsules, identical in form to one of the other capsules not being taken, but containing lactose instead of drug. All subjects were drug-free at study entry and were recommended to maintain their usual diet with a reduced level of physical activity. The study participants were subdivided into three groups (n = 6). Each group was randomised to initial drug therapy internally and the two 23 day periods of treatment were separated by a wash-out period of 24 days. Subjects in group A received 100 mg ciprofibrate/day for the first treatment period, followed by 200 mg fenofibrate HB/day in the second period, or vice versa. Group B subjects received 200 mg ciprofibrate/day followed by 200 mg fenofibrate HB/day, or vice versa, and subjects in group C received 100 mg ciprofibrate/day followed by 200 mg ciprofibrate/day, or vice versa. The daily dose was taken at breakfast time and consisted of one capsule containing the appropriate drug and one capsule containing placebo. 2. 3. Effectiveness and safety parameters
Blood samples were taken before and at the end of each treatment periods following a 12 h fast. At each visit, TC and TG levels were measured by an automated enzymatic method (Boehringer Mannheim, Germany). HDL cholesterol levels were determined by sodium phosphotungstate/magnesium chloride precipitation, while LDL cholesterol levels were calculated according to the Friedewald formula (LDL cholesterol = TC - HDL cholesterol - (TG/5)). Plasma apo A-I, A-II and B levels were measured by laser immunonephelometry using polyclonal antibodies. LPL and HL activities were assayed according to the NilssonEhle and Eckman method on post-heparin, venous
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plasma taken 10 min after heparin injection, 100 IU/kg [14]. One milli-unit of enzyme activity represents the release of 1.0 nmol of fatty acid. The samples from each subject were analysed simultaneously to avoid inter-assay variations. The coefficients of variation were 4% for LPL and 12.7% for HL. Lecithin:cholesterol acyltransferase activity (LCAT), expressed as the fractional esterification rate (LCAT-FER) and as the molar esterification rate (LCAT-MER), was determined by a radioenzymatic method [15]. Lipoprotein (Lp)(a) plasma levels were measured with an enzyme-linked immunosorbant assay (ELISA) kit (Innogenetics) [16] and uric acid and fibrinogen were measured using routine biochemical methods. The levels of the safety parameters, serum creatine phosphokinase (CPK), aspartate aminotransferase (ASAT; also known as glutamate-oxaloacetate transaminase, GOT), alanine aminotransferase (ALAT; also known as glutamate-pyruvate transaminase, GPT), 7-glutamyltransferase (7-GT) and alkaline phosphatase (ALP), were determined by routine clinical laboratory methods at each visit. 2.4. Pharmacokinetics
At the end of the first treatment period, a single dose of 100 mg or 200 mg ciprofibrate, or 200 mg fenofibrate HB, was administered to allow investigation of the respective pharmacokinetics under steady-state conditions. Blood samples were taken at 2, 3, 4, 6, 8, 10, 24, 30, 48, 72, 96, 144, 168 and 576 h after drug administration. Plasma levels of ciprofibrate or of fenofibric acid (the active circulating metabolite of fenofibrate) were measured by high performance liquid chromatography after hexane extraction of acidified plasma. The coefficients of variation were 8.5% (low) and 5.4% (high) for ciprofibrate and 7.9% (low) and 8.0% (high) for fenofibric acid. Data were processed with the extended least squares fit (ELSFIT) computer program [17]. 2.5. Compliance
Compliance with the drug regime was assessed by capsule counts. For each period, the subject received one box containing 25 active capsules and
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one box with 25 placebo capsules. At the end of the treatment periods, each box should contain two capsules. In addition, the plasma levels of ciprofibrate and fenofibric acid were determined at the end of each treatment period. 2.6. Statistical analys&
Statistical analysis of the data was performed using the computer program Stat 2 (Graph Pad Software Inc., San Diego, CA). To evaluate the effects of each drug separately, a paired Student's t-test was applied to the absolute values. When the correlation coefficient was poor, an unpaired Student's t-test was used to confirm the results. To compare the three treatments, the percentage of variation was calculated for each parameter in each treatment group, and then analysed by analysis of variance (ANOVA), the result being confirmed by the Bartlett and Tukey-Kramer tests. Non-parametric data were processed using the Kruskal-Wallis test, followed by the Dunn test. A paired Student's t-test on the percentage of variation was used to estimate the difference between 100 mg ciprofibrate/day and 200 mg ciprofibrate/day in the six subjects allocated to this sequence. 3. Results 3.1. Study population
One subject was excluded from the study, at the end of the first treatment period with 200 mg fenofibrate HB/day, due to a hepatic cytolytic reaction. Thus, data are available for 11 subjects receiving 100 mg ciprofibrate, for 12 subjects receiving 200 mg ciprofibrate and for 12 subjects receiving 200 mg fenofibrate HB/day. 3.2. Efficacy parameters
Examination of the main lipid parameters (Table 1) revealed that 100 mg ciprofibrate/day is approximately equipotent to 200 mg fenofibrate HB/day in changing the lipid profle; however, HDL cholesterol levels were increased to a greater extent after administration of 100 mg ciprofibrate or 200 mg ciprofibrate than after 200 mg
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Table 1 Mean ( ± S.D.) percentage change in the lipid profile of normolipidaemic subjects after 23 days of treatment with 100 mg ciprofibrate/day (n = 11), 200 mg ciprofibrate/day (n = 12) and 200 mg fenofibrate HB/day (n = 12) Parameter
100 mg Ciprofibrate (n = 1 I)
200 mg Ciprofibrate (n = 12)
200 mg Fenofibrate HB (n = 12)
! Triglycerides 2 Total cholesterol 3 LDL cholesterol 4 HDL cholesterol 5 Apo A-I 6 Apo A-II 7 Apo B 8 LPL activity 9 HL activity 10 LCAT-FER 11 LCAT-MER 12 Fibrinogen 13 Uric acid 14 Alkaline phosphatase 15 ASAT/GOT 16 ALAT/GPT 17 CPK
-24.4* - 13.4" -22.6* + 11.9* +0.5 +21.6" -24.3* +25.0* +8.7* +10.5 +1.2 -9.7** +5.4 -9.0" -5.4** - 12.2 -1.8
-35.4* - 12.6' - 19.4" + i 1.7"* +2.4 +36.8* -21.8" +36.1' +3.7* +17.2"* +3.3 -4.6 +11.9" - 13.1 * +39.5* +82.0** +80.8**
-21.1"* - 11.2' - 17.8* +6.0** +1.5 +20.3* -17.3" + 13.9* +2.7 +6.1 -5.4 -2.7** -19.1" - ! 2.2" +21.4 +60.4 -1.7
ALAT/GPT, alanine aminotransferase/glutamate-pyruvate transaminase; Apo, apolipoprotein; ASAT/GOT, aspartate aminotransferase/glutamate-oxaloacetate transaminase; CPK, creatine phosphokinase; HDL, high-density lipoprotein; HL, hepatic lipase; LCAT-FER, lecithin:cholesterol acyltransferase, fractional esterification rate; LCAT-MER, lecithin:cholesterol acyltransferase, molar esterification rate; LDL, low-density lipoprotein; LPL, lipoprotein lipase. *P < 0.01, **P ",: 0.05; statistical significance calculated by performing Student's t-test on the data before and after drug intake.
fenofibrate HB (+11.9%, +11.7% and +6.0%, respectively). Further reduction of TG and increase of apo A-II levels were obtained after 200 mg ciprofibrate as compared with 100 mg ciprofibrate or 200 mg fenofibrate HB. Comparison by ANOVA of the percentages of variation for the three treatments revealed that the level of apo A-II was significantly higher after treatment with 200 mg ciprofibrate/day as compared with the level observed after 100 mg ciprofibrate/day and 200 mg fenofibrate HB/day treatment(P < 0.05). The activities of LPL and HL were significantly enhanced after treatment with 100 mg ciprofibrate/day and 200 mg ciprofibrate/day (P < 0.01; Table 1, Figs. 1 and 2). After 200 mg fenofibrate HB/day therapy, only LPL activity was significantly enhanced (P _< 0.01; Table 1, Figs. 1 and 2). Analysis of the data by ANOVA revealed that the potency of 200 mg fenofibrate HB/day therapy to enhance LPL activity was significantly
Ciprofibrate ~ 100mg E
400
Ciprofibrate [ ~ Fenofibrate 200mg HB200mg i
E 300
200
1
8o_ m
100
B A
i
B A
B A
Fig. 1. Lipoprotein lipase activity (mean ± S.D.) in normolipidaemic subjects before, B, and after, A, 23 days of treatment with 100 nag ciprofibrate/day ( n = l l ) , 200 mg ciprofibrate/day ( n = 1 2 ) or 200 mg fenofibrate 'high bioavailability' (HB)/day (n = 12). *P < 0.003.
J.-P. Desager et aL / Atherosclerosis 124 Suppl. (1996) $65-$73 Ciprofibrate 100 mg
~ n l Ciprofibrate 200 mg
[~
Fenofibrate HB 200 mg
1000
E
750
.~
500
v :>,
.=o -r
250
A
B
A
Fig. 2. Hepatic lipase activity (mean 4-S.D.) in normolipidaemic subjects before, B, and after, A, 23 days of treatment with 100 mg ciprofibrate/day (n= 11), 200 mg ciprofibrate/day (n=12) or 200 mg fenofibrate 'high bioavailability' (HB)/day (n = 12). *P < 0.02.
lower than that observed for 200 mg ciprofibrate/day (P < 0.01). Moreover, for HL activity, 200 mg fenofibrate HB/day therapy was less effective than 100 mg ciprofibrate/day therapy (P < 0.05). In the six subjects who received both doses of ciprofibrate, the effect of 200 mg ciprofibrate/day therapy on LPL activity was superior to the effect of 100 mg ciprofibrate/day (P ___ 0.05). The activity of LCAT (Table 1) was only increased significantly after 200 mg ciprofibrate/day treatment when expressed as the fractional esterification rate (P --- 0.05). Plasma fibrinogen levels (Table 1) were reduced by each treatment; however, the greatest effect was observed after 100 mg ciprofibrate/day therapy. The potent uricosuric effect of 200 mg fenofibrate HB/day was confirmed in this study (P -< 0.01) (Table 1), whereas 200 mg ciprofibrate/day therapy raised the uric acid plasma levels significantly (P _< 0.01).
3.3. Safety parameters A significant reduction in ALP activity was observed in each treatment group (P _< 0.01 after
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each treatment, Table 1). The ALAT/GPT and ASAT/GOT activities were increased particularly after 200 mg ciprofibrate/day treatment (P ___ 0.05 and P _< 0.01, respectively, Table 1). In group C, ASAT/GOT (P < 0.015) and ALAT/GPT (P < 0.03) activities were significantly higher after 200 mg ciprofibrate/day therapy than after 100 mg ciprofibrate/day and 200 mg fenofibrate HB/day (Fig. 3). One hepatic cytolytic reaction was observed after 200 mg fenofibrate HB/day administration; after discontinuation of drug intake, ASAT/GOT and ALAT/GPT activities increased steadily for 2 weeks and the subject recovered 7 weeks later. CPK activity (Table 1, Fig. 4) was significantly enhanced after 200 mg ciprofibrate/day treatment (P < 0.05).
3.4. Compliance At the end of each treatment period, compliance was found to be approximately 100% by capsule counting and by the determination of ciprofibrate or fenofibric acid trough plasma levels. Mean plasma levels of 51.6 ± 9.9 #g/ml (range, 31.7-64.0; coefficient of variation (CV), 19.2%) after 100 mg ciprofibrate/day treatment, 97.8 4-24.9 #g/ml (range, 58.4-150.2; CV, 25.5%) after 200 mg ciprofibrate/day treatment and 9.2 4- 6.1 #g/ml (range, 1.8-24.1; CV, 66.3%) after 200 mg fenofibrate HB/day treatment were observed.
3.5. Pharmacokinetics The mean plasma curves obtained after 100 mg or 200 mg ciprofibrate treatment are shown in Fig. 5, while the curve obtained after 200 mg fenofibrate HB treatment is shown in Fig. 6. A one-compartment, open model was used to obtain the best curve fit. The calculated pharmacokinetic parameters are given in Table 2. Significantly higher peak values and area-under-the-curve (AUC) values, during a dose interval (0-r), were observed after 200 mg ciprofibrate treatment compared with 100 mg ciprofibrate treatment (P < 0.0001 and P < 0.0005, respectively). The group receiving 200 mg fenofibrate HB therapy was characterised by a large variation in the individual data.
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J.-P. Desager et al./ Atherosclerosis 124 SuppL (1996) $65-$73 ASAT/GOT
+200 -
ALAT/GPT
CPK
._= oo~.~
+100
>.>
> S
E -100 I
I
I
I
I
I
100 mg
200 mg
100 mg
200 rng
100 mg
200 mg
Dose of Ciprofibrate
Fig. 3. Individual variation in the activities of the enzymes, aspartate aminotransferase/glutamate-oxaloacetate transaminase (ASAT/GOT), alanine aminotransferase/glutamate-pyruvate transaminase (ALAT/GPT) and serum creatine phosphokinase (CPK), in six normolipidaemic subjects receiving 100 mg ciprofibrate/day and 200 mg ciprofibrate/day.
4. Discussion In hyperlipidaemic patients, it has been reported that transferring from 100 mg to 200 mg of ciprofibrate treatment results in a greater degree of 200
._>
-
150
13.. (..) ._=
g
loo
g
5o
T
normalisation of the lipid profile; this effect is maintained in the long-term [4]. In the present study, there was no major difference between the lipid levels observed in normolipidaemic subjects in each treatment group. For some parameters, the highest dose of ciprofibrate induced a greater reduction in TG levels accompanied by an increase in apo A-II levels and in LPL and LCAT activities. Investigations explaining why the variation in some lipid parameters is not proportional to the dose of ciprofibrate administered have recently been published [8,9,18]. Indeed, the magnitude of
"5 ~
150~1 ~
l°°L "~ =~
-50
Ciprofibrate 100 mg
Ciprofibrate 200 mg
Fenofibrate HB 200 mg
Fig. 4. Mean (± S.D.) percentage of variation in serum creatine phosphokinase (CPK) activity in normolipidaemic subjects after 23 days of treatment with 100 mg ciprofibrate/day (n = 11), 200 mg ciprofibrate/day (n = 12) or 200 nag fenofibrate 'high bioavailability' (HB)/day (n = 12).
~i~
T - ~
T
T
Ciprofibrate
5
~o Time after ~astdose (hours)
Fig. 5. Mean (± S.D.) plasma levels of ciprofibrate measured in normolipidaemic subjects after the 24th daily dose of 100 mg ciprofibrate/day (n = 7) and of 200 mg ciprofibrate/day (n = 6).
£-P. Desager et al. / Atherosclerosis 124 Suppl. (1996) $65-$73
69 _~.__. ¢o o • c
Fenofibrate
48
72
95
144
168
Time after last dose (hours)
Fig. 6. Mean ( ± S.D.) plasma levels of fenofibric acid measured in normolipidaemic subjects after the 24th daily dose of 200 mg fenofibrate 'high bioavailability' (HB) (n = 6).
the variation in these lipid parameters is directly dependent on the fasting TG level before drug administration [18]. When TG levels are low, as is observed in normolipidaemic subjects, the production of VLDL particles is lower. This affects the number of LDL particles, as shown by the equivalent decrease in LDL cholesterol and apo B levels for the three drug preparations. These results have been corroborated in studies involving both normolipidaemic and hyperlipidaemic subjects [8,9]. Consequently, HDL cholesterol levels are regulated in part by the number of VLDL and LDL particles formed [18].
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These catabolic transformations are modulated by the activities of LPL and HL. However, whereas LPL activity is dose-related, HL activity is not. A slight, but statistically significant, increase of HL activity after 100 mg or 200 mg ciprofibrate therapy must be considered as beneficial; an increased activity of HL corresponds to an increased cholesterol content of the HDL3 fraction, which improves the reverse cholesterol transport mechanism [19,20]. The increase in apo A-II levels is dose-related, and it has been shown recently that the fasting TG level and the activity ratio of LPL:HL are the major correlates of the HDL cholesterol:apo A-I plus apo A-II ratio [21]. The role of LCAT in the regulation of plasma HDL levels in normolipidaemic individuals remains unclear [20]. The dose-related effect of ciprofibrate on LCAT activity seems to be linked to the increased levels of apo A-II. The small effect on fibrinogen levels is also beneficial in terms of coronary heart disease (CHD) prevention. It should be noted that gemfibrozil, administered at three times the normal dose, was unable to demonstrate a dose-effect relationship in normolipidaemic subjects [22]. The new preparation of fenofibrate is approximately equipotent to 100 mg of ciprofibrate. However, compared with 300 mg of the older formulation, the new fenofibrate preparation does not produce the same degree of activation of LPL
Table 2 Mean ( ± S.D.) pharmacokinetic parameters of ciprofibrate and fenofibric acid, measured under steady-state conditions in normolipidaemic subjects after administration of 100 mg ciprofibrate, 200 mg ciprofibrate or 200 nag fenofibrate HB Parameter
Peak concentration (#g/ml) Time to peak (h) AUC for one dose interval (/~g x h per ml) Accumulation (%)b Elimination half-life (h) Total body clearance (ml/min per kg)
100 mg Ciprofibrate (n = 7) a
200 mg Ciprofibrate (n = 6)
200 mg Fenofibrate HB (n = 6)
66 ± 11.7 2.4 ± 0.9 1666 ± 269
111 ± 16.8 2.1 ± 1.2 2832 ± 364
23 ± 12.2 5.4 ± 1.4 431 ± 274
522 ± 180 104 ± 27.5 0.016 ± 0.020
476 ± 245 96 ± 36.0 0.018 ± 0.004
90.5 ± 29.0 20.7 ± 6.5 0.161 ± 0.101
AUC, area under the curve. aln one subject, blood samples for pharmacokinetic analysis were obtained after each treatment period. bCalculated as (AUC,_®/AUC0_¢) x 100.
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[12] or of LCAT [12,23] in normolipidaemic subjects. The potent uricosuric property of fenofibrate is, however, present in the new formulation. The incidence of side effects was low with 100 mg ciprofibrate/day treatment; however, the incidence was increased significantly after treatment with 200 mg ciprofibrate/day. Two hundred milligrams fenofibrate HB/day treatment caused a non-significant enhancement in ASAT and ALAT activities, although one case of a hepatic cytolytic reaction was detected at the end of the first treatment period. The increase in CPK activity, above the upper level of the normal range, as observed after 200 mg ciprofibrate/day in 58% of subjects is a matter of concern. Although the muscular cramps reported by two subjects cannot be considered objectively, the trend observed with 200 mg ciprofibrate/day treatment is noteworthy. The increase in plasma uric acid levels observed after 200 mg ciprofibrate/day treatment highlights the fact that this dosage should possibly be contraindicated in patients with hyperuricaemia or gout. Ciprofibrate is a free acid, active per se, which is extensively absorbed after oral administration [241. Its high bioavailability (approximately 90%) is responsible for the elevated circulating plasma levels observed after treatment with ciprofibrate. Excretion of ciprofibrate occurs mainly by the renal route either as conjugates, as minor amounts of three metabolites or as unchanged drug [24]. Faecal elimination of ciprofibrate is low (< 5%) [24]. Fenofibrate is a pro-drug (ester) which immediately after absorption is hydrolysed by tissue and plasma esterases to its active, major metabolite, fenofibric acid [25]. A low circulating concentration of the reduced fenofibric acid metabolite, a benzhydrol derivative, has also been detected [25]. These metabolites of fenofibrate, in the form of conjugates, are excreted mainly by the renal route [25]. Faecal excretion of fenofibrate occurs in varying proportions, depending on the extent of intestinal absorption [25]. These major metabolic differences explain the lower systemic plasma levels of fenofibric acid compared with ciprofibrate observed in this study, and the longer time taken to reach peak plasma levels in fenofibrate- versus ciprofibrate-treated subjects. The trough plasma levels of ciprofibrate, after administration of 100
mg and 200 mg ciprofibrate, observed in this study, are similar to those reported by Or6 et al. [4]. The long elimination half-life and high accumulation factor for ciprofibrate have no effect at the clinical level. Moreover, the AUC and peak values are dose-related for this drug. The pharmacokinetics of 200 mg fenofibrate HB are similar to those observed in an earlier study with the original 300 mg formulation [25]. The bioequivalence of 67 mg of the fenofibrate HB formulation versus 100 mg of the classical fenofibrate formulation has been demonstrated in a single-dose study involving 24 subjects [26]. A repeated-dose study in 18 subjects comparing 200 mg fenofibrate HB with 300 mg of the classical formulation has been performed to evaluate the variability of the pharmacokinetic parameters at therapeutic conditions (data on file; Fournier, unpublished observation). The coefficients of variation in AUC values and in peak and trough levels are reduced by 60%, 50% and 48%, respectively, after 200 mg fenofibrate HB when compared with the 300 mg classical formulation of this drug. The data collected in the study reported herein (n = 6) reveal higher absolute values for the same parameters, but a greater variability persists (S.D. = 50%) after 200 mg fenofibrate HB administration. This variability can be attributed to the presence of one subject who also had the highest peak plasma value after 200 mg ciprofibrate/day therapy. The high individual variability makes comparison between groups difficult. Nevertheless, this study confirms the good pharmacokinetic profile of ciprofibrate and highlights the possibility that a therapeutic failure in some individuals could be attributed to a poor resorption of the 200 mg fenofibrate HB dose. 5. Conclusion
A dose-response relationship for all the parameters could not be demonstrated in our normolipidaemic subjects receiving 100 mg and/or 200 mg ciprofibrate/day treatment. Appreciable effects on the lipid profile were seen with the lower dose of ciprofibrate; however, further improvements in the lipid profile could be obtained with the higher dose. An increased level of supervision should be undertaken in those subjects transferring from 100
J.-P. Desager et al./ Atherosclerosis 124 Suppl. (1996) $65-$73
mg ciprofibrate/day to 200 mg ciprofibrate/day therapy. The new once-a-day 200 mg fenofibrate HB therapy may represent an alternative to 100 mg ciprofibrate/day therapy; however, a lower bioavailability with the former may exist in some patients.
[13]
Acknowledgements
[14]
We wish to thank Dr. R. Hulhoven for the calculation of the pharmacokinetic parameters and Mr. J. Costermans for technical assistance and artwork. We are indebted to Mrs. N. Bouve for typing the manuscript.
[15]
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[26]
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