Effect of Multiple Cilostazol Doses on Single Dose Lovastatin Pharmacokinetics in Healthy Volunteers

Bramer, Steven L.; Brisson, Jerry; Corey, A.; Mallikaarjun, Suresh

doi:10.2165/00003088-199937002-00008

Cited by 15 publications

(10 citation statements)

References 5 publications

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“…Thus, a reduction in the dose of cilostazol to 50 mg, twice a day, should be considered during coadministration of inhibitors of these cytochrome enzymes (64,65). No dosage adjustments are necessary for drugs metabolized by CYP3A4, such as lovastatin (3). Coadministration of a single 25-mg dose of warfarin with a twice daily 100-mg dose of cilostazol does not alter (R) and (S)-warfarin pharmacokinetics, prothrombin time, partial thromboplastin time, Ivy bleeding times, or cilostazol protein binding (36).…”

Section: Pharmacokineticsmentioning

confidence: 99%

Cilostazol (Pletal®): A Dual Inhibitor of Cyclic Nucleotide Phosphodiesterase Type 3 and Adenosine Uptake

Liu

Shakur

Yoshitake

et al. 2001

Cardiovascular Drug Reviews

181

162

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Cilostazol (Pletal ® ), a quinolinone derivative, has been approved in the U.S. for the treatment of symptoms of intermittent claudication (IC) since 1999 and for related indications since 1988 in Japan and other Asian countries. The vasodilatory and antiplatelet actions of cilostazol are due mainly to the inhibition of phosphodiesterase 3 (PDE3) and subsequent elevation of intracellular cAMP levels. Recent preclinical studies have demonstrated that cilostazol also possesses the ability to inhibit adenosine uptake, a property that may distinguish it from other PDE3 inhibitors, such as milrinone. Elevation of interstitial and circulating adenosine levels by cilostazol has been found to potentiate the cAMP-elevating effect of PDE3 inhibition in platelets and smooth muscle, thereby augmenting antiplatelet and vasodilatory effects of the drug. In contrast, elevation of interstitial adenosine by cilostazol in the heart has been shown to reduce increases in cAMP caused by the PDE3-inhibitory action of cilostazol, thus attenuating the cardiotonic effects. Cilostazol has also been reported to inhibit smooth muscle cell proliferation in vitro and has been demonstrated in a clinical study to favorably alter plasma lipids: to decrease triglyceride and to increase HDL-cholesterol levels. One, or a combination of several of these effects may contribute to the clinical benefits and safety of this drug in IC and other disease conditions secondary to atherosclerosis. In eight double-blind randomized placebo-controlled trials, cilostazol significantly increased maximal walking distance, or absolute claudication distance on a treadmill. In addition, cilostazol improved quality of life indices as assessed by patient questionnaire. One large randomized, double-blinded, placebo-con- 369

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Section: Pharmacokineticsmentioning

confidence: 99%

Cilostazol (Pletal®): A Dual Inhibitor of Cyclic Nucleotide Phosphodiesterase Type 3 and Adenosine Uptake

Liu

Shakur

Yoshitake

et al. 2001

Cardiovascular Drug Reviews

181

162

View full text Add to dashboard Cite

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“…In Italy, lovastatin was introduced in 2005, based on the present bioequivalence study. In view of the number of subjects enrolled for the present investigation, which is the highest among those available in literature for kinetic studies (11)(12)(13)(14)(15)(16)(17), and of the interesting aspects emerging in terms of lovastatin pharmacokinetics, we have decided to publish the present study. This work has evaluated the bioequivalence of an oral formulation of lovastatin 40 mg tablets (lovastatin generic or LVSG), in comparison with the reference MSD product Mevinacor ® 40 mg tablets by assessing plasma levels of lovastatin and lovastatin hydroxyacid.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Bioequivalence Study of Two Tablet Formulations of Lovastatin in Healthy Volunteers

Mignini¹,

Tomassoni²,

Streccioni³

et al. 2008

Clinical and Experimental Hypertension

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Lovastatin is a lipid-lowering agent indicated for primary hypercholesterolemia. This study has assessed single-dosing pharmacokinetics of lovastatin and of its main metabolite, lovastatin beta-hydroxyacid, and has compared the pharmacokinetics of two formulations of lovastatin, a test lovastatin generic (LVSG), and a reference (mevinacor 40 MSD) preparation. The pharmacokinetics and bioequivalence of the two formulations of lovastatin were evaluated by a two-way cross-over randomized double blinded study, in 36 healthy volunteers after a single oral dose of 2 x 40 mg per subject. On plasma samples, collected at given intervals of time (0-24h), lovastatin and its main active metabolite were assayed by high pressure liquid chromatography with positive turbo ion spray ionization tandem mass spectrometry detection. The pharmacokinetic parameters, area under the curve total (AUC(t)) and to infinity (AUC(inf)), peak plasma concentration (C(max)), time to attain peak (t(max)), and elimination half-life (t(1/2)) were determined and analyzed statistically. Only minor differences in the pharmacokinetics of lovastatin and lovastatin hydroxyacid between LVSG and mevinacor were found. Analysis of variance (ANOVA) did not show any significant difference between the two formulations, and 90% confidence intervals fell within the acceptable range for bioequivalence. The tolerability profile was good and comparable for the two formulations of lovastatin. Our study, which was performed with the largest number of subjects compared with those published in literature, indicates the bioequivalence of LVSG and mevinacor tablets. The high inter-subject variability of parameters investigated indicate the need of appropriate sample size in pharmacokinetics studies with lovastatin.

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“…Bramer et al . reported that the concentration of lovastatin and its β‐hydroxy acid metabolite, CYP3A substrate, was increased by up to twofold after multiple co‐administrations of cilostazol . This suggests that cilostazol or its metabolites might have a mild inhibitory effect on CYP3A.…”

Section: Discussionmentioning

confidence: 99%

The pharmacokinetic and pharmacodynamic interaction of clopidogrel and cilostazol in relation to CYP2C19 and CYP3A5 genotypes

Kim

Lim

et al. 2015

Brit J Clinical Pharma

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AIMThe primary objective of the present study was to evaluate the pharmacokinetic and pharmacodynamic interactions between clopidogrel and cilostazol in relation to the CYP2C19 and CYP3A5 genotypes. METHODSIn a randomized, three-way crossover study, 27 healthy subjects were administered clopidogrel (300 mg), cilostazol (100 mg) or clopidogrel + cilostazol orally. Plasma concentrations of clopidogrel, cilostazol and their active metabolites (clopidogrel thiol metabolite, 3,4-dehydrocilostazol and 4″-trans-hydroxycilostazol), and adenosine diphosphate-induced platelet aggregation were measured for pharmacokinetic and pharmacodynamic assessment. RESULTSThe area under the plasma concentration-time curve (AUC) of the active thiol metabolite of clopidogrel was highest in the CYP2C19 extensive metabolizers (EM) and lowest in the poor metabolizers (PM). Cilostazol decreased the thiol metabolite AUC by 29% in the CYP3A5*1/*3 genotype [geometric mean ratio (GMR) 0.71; 90% confidence interval (CI) 0.58, 0.86; P = 0.020] but not in the CYP3A5*3/*3 genotype (GMR 0.93; 90% CI 0.80, 1.10; P = 0.446). Known effects of the CYP2C19 and CYP3A5 genotypes on the exposure of cilostazol and its metabolites were observed but there was no significant difference in the AUC of cilostazol and 3,4-dehydrocilostazol between cilostazol and clopidogrel + cilostazol. The inhibition of platelet aggregation from 4 h to 24 h (IPA 4-24 ) following the administration of clopidogrel alone was highest in the CYP2C19 EM genotype and lowest in the CYP2C19 PM genotype (59.05 ± 18.95 vs. 36.74 ± 13.26, P = 0.023). However, the IPA of the CYP2C19 PM following co-administration of clopidogrel and cilostazol was comparable with that of the CYP2C19 EM and intermediate metabolizers (IM) only in CYP3A5*3/*3 subjects. CONCLUSIONSThe additive antiplatelet effect of cilostazol plus clopidogrel is maximized in subjects with both the CYP2C19 PM and CYP3A5*3/*3 genotypes because of a lack of change of clopidogrel thiol metabolite exposure in CYP3A5*3/*3 as well as the highest cilostazol IPA in CYP2C19 PM and CYP3A5*3/*3 subjects. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• CYP2C19 loss-of-function alleles produce less clopidogrel active metabolite, causing less platelet aggregation inhibition, but more cilostazol active metabolite, leading to enhanced antiplatelet effects.• Cilostazol is a possible inhibitor of CYP3A enzymes that contribute to the formation of clopidogrel active metabolite.• There is a possibility of a clopidogrelcilostazol drug interaction. WHAT THIS STUDY ADDS• Cilostazol decreased the formation of clopidogrel active metabolite in CYP3A5*1/*3 but not in CYP3A5*3/*3 subjects. The antiplatelet effects of CYP2C19 EM, IM and PM after co-administration of clopidogrel and cilostazol were similar in CYP3A5*3/*3 genotypes.• Antiplatelet therapy which includes cilostazol might overcome the clopidogrel resistance caused by CYP2C19 PM in subjects with the CYP3A5*3/*3 genotype.

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Effect of Multiple Cilostazol Doses on Single Dose Lovastatin Pharmacokinetics in Healthy Volunteers

Cited by 15 publications

References 5 publications

Cilostazol (Pletal®): A Dual Inhibitor of Cyclic Nucleotide Phosphodiesterase Type 3 and Adenosine Uptake

Cilostazol (Pletal®): A Dual Inhibitor of Cyclic Nucleotide Phosphodiesterase Type 3 and Adenosine Uptake

Pharmacokinetics and Bioequivalence Study of Two Tablet Formulations of Lovastatin in Healthy Volunteers

The pharmacokinetic and pharmacodynamic interaction of clopidogrel and cilostazol in relation to CYP2C19 and CYP3A5 genotypes

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