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The effect of grapefruit juice on plasma profiles of lovastatin, lovastatin acid, and lovastatin HMG-CoA reductase inhibitors
71st EAS Meeting Abstracts" accepted for presentation in the abstract book http://www.umd.necker.fr]. The analysis of the 525 point mutations in our .DLR database gives the following information: (I) 61% of the mutations ire missense, and 20% occur in CpG dinucleotides; (2) although widely listributed throughout the gene, there is an excess of mutations in 4 exons 4-6-7-9) and a deficit in 5 exons (13-15-16-17-18); (3) 48% of the small leletions occur between repeated sequences; (4) 69% of the mutations in the igand-binding domain affect a conserved amino-acid involved in calcium :age formation; (5) the functional data we have for 210 (40%) mutations ndicate that 33% and 29% of them are class 2B and class I mutations 'espectively; (6) finally, the investigation of genotype/phenotype correlations s difficult since the clinical data is usually incomplete in mutation reports. :)irect access to the database through the web site will facilitate the input )f high quality clinical information for each mutation and should overcome :his shortage. VARIETY OF MUTATIONS OF THE LDL RECEPTOR GENE IN IAPANESE FAMILIAL HYPERCHOLESTEROLEMIA
H. Hattori, M. Nagano, T. Egashira. M. Tsuji 1, T. Hirayama2, M. Emi 2, T. O~ada . Research Department, R & D Center, BML. Inc.. Kawagoe; I Hokkaido Central Hospital for Social Health Insurance, Sapporo; "Department of Molecular Biolog3; Institute of Gerontology, Nippon Medical School. Kawasaki; 3Department of Pediatrics. School of Medicine. Nihon UniuersiO, Tokyo, Japan Mutations in the low density lipoprotein (LDL)-receptor gene cause familial hypercholesterolemia (FH), an autosomal dominant disease associated to an increased risk of premature atherosclerosis. It has been identified more than 250 mutations of the LDL receptor gene so far. We analyzed the LDL receptor activity determined by a flow cytometric procedure using DiI-LDL in peripheral lymphocytes from 152 FH patients, including seven homozygtes and 30 families. Subsequently, genomic DNA from patients were screened for mutation of the LDL receptor gene by the DGGE or the SSCP technique. The mutations were further identified by DNA sequencing when an abnormal band pattern was detected by DGGE or SSCP analysis. We found eleven missense mutations, C74S, EI 19K, C317R, C317S, F382L, A410T, D412H° L547V, P664L, and V779M, three nonsense mutations, C74X, W512X, and K790X, eight frameshifi mutations, Fs98, Fsl06, Fs395, Fs542, Fs572, Fs 634, and Fs658, one splice site mutation, 1845 + 2 T/C, and three inframe mutations, x7200-206, A351-354/~ALN, and A 753759. Each mutation generally accounted for few FH patients. However the high number of mutations were found in patients with K790X, 1845 + 2 T/C, El 19K, and C317S (with the 25.0%, 20.1%, 7.29%, and 5.21% of total FH cases, respectively). These results suggested that these four mutations are commonly occurred in Japanese FH as described by Miyake et al. The other remaining samples are still under investigation. THE EFFECT OF GRAPEFRUIT JUICE ON PLASMA PROFILES OF LOVASTATIN, LOVASTATIN ACID, AND LOVASTATIN HMG-COA REDUCTASE INHIBITORS
J.D. Rogers, J.M. Vega, J. Zhao, R.D. Amin, K. Gagliano, M. Stepanavage, Wilson, R.A. Blum. Merck Res. Labs. West Point. PA; Rahway. NJ: Millard Fillmore Hosp.. Buffalo, NY, USA Lovastatin, an inactive lactone prodrug, is rapidly hydrolyzed in vivo to Iovastatin acid, a potent HMG-CoA reductase inhibitor (HMGRI) for the treatment of hypercholesterolemia. Lovastatin and Iovastatin acid are substrates of CYP 3A4 leading to the formation of several active metabolites and their inactive lactone precursors. Hence, measurement o f HMGRI activity is a more meaningful index of the systemic exposure to the drug. Plasma concentrations o f HMGRI activity, Iovastatin, and lovastatin acid were determined following a commonly prescribed dose of Iovastatin and grapefruit juice, an inhibitor o f CYP3A4. Healthy subjects (n = 15) received a single 40-rag oral dose of lovastatin in the evening after consuming an 8-ounce glass o f regular strength grapefruit juice or water with breakfast for 3 consecutive days. Area under the plasma concentration-time profile (AUC) and maximum plasma concentration (Cm~,O of HMGRI activity increased slightly (~30% for each) following grapefruit juice. Similar effects on AUC and Cmax (~40% increase each) were noted following analysis o f hydrolyzed plasma samples (converts potentially active lactones to active hydroxy acid species). AUC and Cmax for lovastatin approximately doubled in the presence of grapefruit juice while the same parameters for lovastatin acid increased 1.6 fold. These results are in contrast to those from a study (Clinical Pharmacology Therapeutics 63: 397, 1998) in which subjects drank unusual quantities of double-strength grapefruit juice (200 mL t.i.d.
183
with lovastatin given in the morning with grapefruit juice) and a 15-fold increase in Iovastatin AUC and a 4-fold increase in lovastatin acid AUC were observed. Extensive clinical safety data with Iovastatin in controlled long-term trials in over 7000 patients demonstrate the excellent safety profile of Iovastatin.
COMPARISON OF RISK FACTOR PROFILE AND OUTCOME OF WOMEN AND MEN IN CARDIAC REHABILITATION V. Suresh, N. Naqvi, M. Wallwork, L. Lee. Wigan and Leigh NHS Trust
Wigan WNI 2NN, UK Little data is available regarding the outcome of women in cardiac rehabilitation. To determine whether women differ from men in risk factors and outcome 978 patients under the age of 70 were retrospectively analysed from a computer data during a period of 3 yrs (1995-1997) in a district general hospital exercise based cardiac rehabilitation programme. Prevalence of risk factors revealed smoking (62%) hypercholestrolaemia (random cholesterol > 5 mmol/litre) (56.2%) hypertension (21.1%) diabetes (4.5%) family history of coronary artery disease (37.6) and obesity defined as Body Mass Index (BMI) > 30 (23.6%). Among 786 men and 192 women who attended the cardiac rehabilitation programme the mean age in males was (52+15) and in females was (56+ 14). Compared to men fewer women were employed (35.1% Vs 32.1%) and more women when compared to men had hypercholestrolaemia (64.5% Vs 54.8% p-0.015) hypertension (33.8% Vs 20.5% p- < 0.001 ) diabetes (9.3% Vs 3.3% p- < 0.001 ) and overweight - BMI 25-25.9 (26.1% Vs 20.5%). But more men when compared to women were smokers (63. 1% Vs 59.3%) and obese ( 19.6% Vs 14.1%). Exercise capacity in women was less when compared to men (28.8% Vs 47.1% p- < 0.001). Fewer women returned to work (45.1% Vs 49.6%), attended physiotherapy (51% Vs 56.6%) and completed the course o f physiotherapy (64.2% Vs 67.8%) when compared to men. Also more women had intervention-coronary artery bypass graft or angioplasty (47.9% Vs 24.1% p- < 0.001) and reinfarct (1% Vs 0.7%). However more men stopped smoking (60.6% Vs 57%) when compared to women. Also men had a higher mortality due to reinfarct (3.8% Vs 0% p-0.002) when compared to women. Thus we conclude that women had more risk factor profile and low exercise capacity and were less compliant and had less benefit from cardiac rehabilitation.
COMPARISON OF A NEW HIGH-DOSE MODIFIED-RELEASE VERSUS CONVENTIONAL-RELEASE FORMULATION OF FLUVASTATIN
J. McKenney. Virginia Commonwealth UniuersiO, Richmond, Virginia, USA Background: Sustained-release dosage forms are often used to extend a drug's systemic effects and allow once-daily administration. In the case o f HMG CoA reductase inhibitors (statins), most of which have short half-lives, the effect on circulating LDL-cholesterol is prolonged because o f the long half-life of this lipoprotein. Thus, sustained-release formulations of statins attempt to maintain the LDL-cholesterol lowering efficacy without raising, and potentially by reducing, total systemic exposure, and thereby reducing associated adverse events. Objective: To test this hypothesis, the safety, tolerability and efficacy o f a modified-release formulation o f fluvastatin (80 and 160 rag; matrix tablet [Lescol XL]) was compared to a conventional-release formulation of fluvastatin (40 rag) in a double-blind, observer-blind-to-lipids value, parallelgroup, multicentre trial. Methods: Following a 4-week placebo/dietary run-in phase, approximately 120 patients with primary hypercholesterolaemia (type IIa/IIb) and LDL-C > 160 mg/dl and triglycerides < 400 mg/dl have been randomised to receive modified-release fluvastatin 160 mg (2 x 80 mg tablets), modifiedrelease fluvastatin 80 mg or conventional fluvastatin 40 mg, administered at bedtime, for 6 weeks (40 patients/treatment group). Patients assigned to the 160 mg treatment arm will receive modified-release fluvastatin 80 mg at bedtime for the first 2 weeks followed by modified-release fluvastatin 160 mg for the final 4 weeks o f the study, in addition to changes in lipid parameters, comparative safety and tolerability of the modified-release formulation of fluvastatin is also being assessed. Conclusion: The data obtained from this study will not only address the comparable efficacy and improved safety hypothesis outlined above, but will also provide information on whether the plateau of the dose-response curve has been reached with fluvastatin.
71st EAS Congress and Satellite Symposia
H. Hattori, M. Nagano, T. Egashira. M. Tsuji 1, T. Hirayama2, M. Emi 2, T. O~ada . Research Department, R & D Center, BML. Inc.. Kawagoe; I Hokkaido Central Hospital for Social Health Insurance, Sapporo; "Department of Molecular Biolog3; Institute of Gerontology, Nippon Medical School. Kawasaki; 3Department of Pediatrics. School of Medicine. Nihon UniuersiO, Tokyo, Japan Mutations in the low density lipoprotein (LDL)-receptor gene cause familial hypercholesterolemia (FH), an autosomal dominant disease associated to an increased risk of premature atherosclerosis. It has been identified more than 250 mutations of the LDL receptor gene so far. We analyzed the LDL receptor activity determined by a flow cytometric procedure using DiI-LDL in peripheral lymphocytes from 152 FH patients, including seven homozygtes and 30 families. Subsequently, genomic DNA from patients were screened for mutation of the LDL receptor gene by the DGGE or the SSCP technique. The mutations were further identified by DNA sequencing when an abnormal band pattern was detected by DGGE or SSCP analysis. We found eleven missense mutations, C74S, EI 19K, C317R, C317S, F382L, A410T, D412H° L547V, P664L, and V779M, three nonsense mutations, C74X, W512X, and K790X, eight frameshifi mutations, Fs98, Fsl06, Fs395, Fs542, Fs572, Fs 634, and Fs658, one splice site mutation, 1845 + 2 T/C, and three inframe mutations, x7200-206, A351-354/~ALN, and A 753759. Each mutation generally accounted for few FH patients. However the high number of mutations were found in patients with K790X, 1845 + 2 T/C, El 19K, and C317S (with the 25.0%, 20.1%, 7.29%, and 5.21% of total FH cases, respectively). These results suggested that these four mutations are commonly occurred in Japanese FH as described by Miyake et al. The other remaining samples are still under investigation. THE EFFECT OF GRAPEFRUIT JUICE ON PLASMA PROFILES OF LOVASTATIN, LOVASTATIN ACID, AND LOVASTATIN HMG-COA REDUCTASE INHIBITORS
J.D. Rogers, J.M. Vega, J. Zhao, R.D. Amin, K. Gagliano, M. Stepanavage, Wilson, R.A. Blum. Merck Res. Labs. West Point. PA; Rahway. NJ: Millard Fillmore Hosp.. Buffalo, NY, USA Lovastatin, an inactive lactone prodrug, is rapidly hydrolyzed in vivo to Iovastatin acid, a potent HMG-CoA reductase inhibitor (HMGRI) for the treatment of hypercholesterolemia. Lovastatin and Iovastatin acid are substrates of CYP 3A4 leading to the formation of several active metabolites and their inactive lactone precursors. Hence, measurement o f HMGRI activity is a more meaningful index of the systemic exposure to the drug. Plasma concentrations o f HMGRI activity, Iovastatin, and lovastatin acid were determined following a commonly prescribed dose of Iovastatin and grapefruit juice, an inhibitor o f CYP3A4. Healthy subjects (n = 15) received a single 40-rag oral dose of lovastatin in the evening after consuming an 8-ounce glass o f regular strength grapefruit juice or water with breakfast for 3 consecutive days. Area under the plasma concentration-time profile (AUC) and maximum plasma concentration (Cm~,O of HMGRI activity increased slightly (~30% for each) following grapefruit juice. Similar effects on AUC and Cmax (~40% increase each) were noted following analysis o f hydrolyzed plasma samples (converts potentially active lactones to active hydroxy acid species). AUC and Cmax for lovastatin approximately doubled in the presence of grapefruit juice while the same parameters for lovastatin acid increased 1.6 fold. These results are in contrast to those from a study (Clinical Pharmacology Therapeutics 63: 397, 1998) in which subjects drank unusual quantities of double-strength grapefruit juice (200 mL t.i.d.
183
with lovastatin given in the morning with grapefruit juice) and a 15-fold increase in Iovastatin AUC and a 4-fold increase in lovastatin acid AUC were observed. Extensive clinical safety data with Iovastatin in controlled long-term trials in over 7000 patients demonstrate the excellent safety profile of Iovastatin.
COMPARISON OF RISK FACTOR PROFILE AND OUTCOME OF WOMEN AND MEN IN CARDIAC REHABILITATION V. Suresh, N. Naqvi, M. Wallwork, L. Lee. Wigan and Leigh NHS Trust
Wigan WNI 2NN, UK Little data is available regarding the outcome of women in cardiac rehabilitation. To determine whether women differ from men in risk factors and outcome 978 patients under the age of 70 were retrospectively analysed from a computer data during a period of 3 yrs (1995-1997) in a district general hospital exercise based cardiac rehabilitation programme. Prevalence of risk factors revealed smoking (62%) hypercholestrolaemia (random cholesterol > 5 mmol/litre) (56.2%) hypertension (21.1%) diabetes (4.5%) family history of coronary artery disease (37.6) and obesity defined as Body Mass Index (BMI) > 30 (23.6%). Among 786 men and 192 women who attended the cardiac rehabilitation programme the mean age in males was (52+15) and in females was (56+ 14). Compared to men fewer women were employed (35.1% Vs 32.1%) and more women when compared to men had hypercholestrolaemia (64.5% Vs 54.8% p-0.015) hypertension (33.8% Vs 20.5% p- < 0.001 ) diabetes (9.3% Vs 3.3% p- < 0.001 ) and overweight - BMI 25-25.9 (26.1% Vs 20.5%). But more men when compared to women were smokers (63. 1% Vs 59.3%) and obese ( 19.6% Vs 14.1%). Exercise capacity in women was less when compared to men (28.8% Vs 47.1% p- < 0.001). Fewer women returned to work (45.1% Vs 49.6%), attended physiotherapy (51% Vs 56.6%) and completed the course o f physiotherapy (64.2% Vs 67.8%) when compared to men. Also more women had intervention-coronary artery bypass graft or angioplasty (47.9% Vs 24.1% p- < 0.001) and reinfarct (1% Vs 0.7%). However more men stopped smoking (60.6% Vs 57%) when compared to women. Also men had a higher mortality due to reinfarct (3.8% Vs 0% p-0.002) when compared to women. Thus we conclude that women had more risk factor profile and low exercise capacity and were less compliant and had less benefit from cardiac rehabilitation.
COMPARISON OF A NEW HIGH-DOSE MODIFIED-RELEASE VERSUS CONVENTIONAL-RELEASE FORMULATION OF FLUVASTATIN
J. McKenney. Virginia Commonwealth UniuersiO, Richmond, Virginia, USA Background: Sustained-release dosage forms are often used to extend a drug's systemic effects and allow once-daily administration. In the case o f HMG CoA reductase inhibitors (statins), most of which have short half-lives, the effect on circulating LDL-cholesterol is prolonged because o f the long half-life of this lipoprotein. Thus, sustained-release formulations of statins attempt to maintain the LDL-cholesterol lowering efficacy without raising, and potentially by reducing, total systemic exposure, and thereby reducing associated adverse events. Objective: To test this hypothesis, the safety, tolerability and efficacy o f a modified-release formulation o f fluvastatin (80 and 160 rag; matrix tablet [Lescol XL]) was compared to a conventional-release formulation of fluvastatin (40 rag) in a double-blind, observer-blind-to-lipids value, parallelgroup, multicentre trial. Methods: Following a 4-week placebo/dietary run-in phase, approximately 120 patients with primary hypercholesterolaemia (type IIa/IIb) and LDL-C > 160 mg/dl and triglycerides < 400 mg/dl have been randomised to receive modified-release fluvastatin 160 mg (2 x 80 mg tablets), modifiedrelease fluvastatin 80 mg or conventional fluvastatin 40 mg, administered at bedtime, for 6 weeks (40 patients/treatment group). Patients assigned to the 160 mg treatment arm will receive modified-release fluvastatin 80 mg at bedtime for the first 2 weeks followed by modified-release fluvastatin 160 mg for the final 4 weeks o f the study, in addition to changes in lipid parameters, comparative safety and tolerability of the modified-release formulation of fluvastatin is also being assessed. Conclusion: The data obtained from this study will not only address the comparable efficacy and improved safety hypothesis outlined above, but will also provide information on whether the plateau of the dose-response curve has been reached with fluvastatin.
71st EAS Congress and Satellite Symposia