No clinically relevant drug–drug interactions when dalcetrapib is co-administered with atorvastatin

Derks, Michael; Abt, Markus; Parr, Graeme; Meneses-Lorente, Georgina; Young, Anne-Marie; Phelan, Mary C.

doi:10.1517/13543784.2010.509342

Cited by 17 publications

(12 citation statements)

References 23 publications

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“…While 900-mg dalcetrapib inhibited all CYP isoforms tested in vitro (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) [69], it did not result in clinically relevant inhibition in vivo when coadministered with a cocktail of five CYP substrates or rosiglitazone [69] or ketoconazole [68], as there was no significant increase in exposure to these agents. Furthermore, total exposure to dalcetrapib (900 mg) was modestly reduced by rosuvastatin, simvastatin [39] and atorvastatin [70]. These effects did not reduce the ability of dalcetrapib to raise HDL-C or inhibit CETP.…”

Section: Pharmacokinetics and Metabolismmentioning

confidence: 88%

An Update On the Clinical Development of Dalcetrapib (RO4607381), a Cholesteryl Ester Transfer Protein Modulator That Increases HDL Cholesterol Levels

et al. 2012

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CETP is the target of CETP inhibitors such as anacetrapib and the modulator dalcetrapib. Both molecules have entered Phase III clinical trials, with the ultimate goal of reducing cardiovascular events by raising HDL cholesterol. At the 600-mg dose selected for the dal-OUTCOMES study, dalcetrapib is expected to inhibit CETP activity by approximately 30% and raise HDL-C by approximately 30% with limited effects on LDL cholesterol. Importantly, dalcetrapib does not raise blood pressure or aldosterone levels, two effects previously associated with the CETP inhibitor torcetrapib. Dalcetrapib has been well tolerated at the 600-mg dose. In the dal-PLAQUE atherosclerosis imaging study, dalcetrapib reduced the enlargement of total vessel area over time. In May 2012, following the results of the second interim analysis of dal-OUTCOMES, the Data and Safety Monitoring Board recommended stopping the study owing to a lack of clinically significant benefit, which was followed by Roche's (Basel, Switzerland) decision to terminate the study and the dalcetrapib program (dal-HEART). Contrary to anacetrapib, a potent CETP inhibitor that markedly increases HDL cholesterol and significantly reduces LDL cholesterol, dalcetrapib has allowed us to test the hypothesis that an isolated, moderate elevation in HDL cholesterol prevents cardiovascular events.

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Section: Pharmacokinetics and Metabolismmentioning

confidence: 88%

An Update On the Clinical Development of Dalcetrapib (RO4607381), a Cholesteryl Ester Transfer Protein Modulator That Increases HDL Cholesterol Levels

et al. 2012

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“…Serious drug-drug interactions have led to the necessity of a drug manufacturer to withdraw or limit the use of marketed drugs which is a major cause of economic burden for pharmaceutical companies. A major mechanism of adverse drug-drug interactions is the inhibition of the metabolism of a drug by a co-administered drug, thereby elevating the systemic burden of the affected drug to a toxic level [111,112]. In general, CQ analogues are increasingly available over the counter (OTC) drug and on-line without prescription.…”

Section: Discussionmentioning

confidence: 99%

Clinically Significant Drug Interaction Profiles of Chloroquine Analogues with Adverse Consequences and Risk Management

Al‐Bari¹,

Islam²

2015

J. Sci. Res.

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The popularity of chloroquine (CQ) analogues, for malaria treatment in many countries emanates from it being cheap, widely available, relatively well tolerated, and having a rapid onset of action. Thus, CQ analogues are commonly sold as over-the-counter (OTC) medications. CQ analogues like hydroxychloroquine (HCQ) alone and/or other drugs in combination have been used as anti-inflammatory and immunomodulatory drugs in the treatment of various rheumatic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), sarcoidosis, dermatomyositis, Sjögren's syndrome, chronic juvenile arthritis, psoriatic arthritis, and have shown clinical benefits with an acceptable safety profile. As anti-inflammatory mechanism, CQ inhibits pro-inflammatory cytokine release, antigen processing and blocking the actions of histamine and phospholipase A 2 . CQ analogue has also been studied for its potential as an enhancing agent in cancer therapies in various clinical trials. In many cases, the lysosomotrophic property of CQ appears to be important for the increase in efficacy and specificity to inhibit inflammatory disorders. Moreover, it is indicated that the efficacy of conventional therapies can be dramatically enhanced if CQ analogues are given in combination. Although majority of CQ analogue in combination therapies improves overall the outcome, such treatments are often associated with serious toxicities leading to fatal.

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“…The change was not clinically significant. Co-administration did not decrease the efficacy of dalcetrapib or atorvastatin and was generally well tolerated [25].…”

Section: Drug Interaction Studies Between Dalcetrapib and Other Lipidmentioning

confidence: 91%

“…Two crossover studies, performed in healthy subjects established no clinically relevant interactions between dalcetrapib with atorvastatin when they were co-administered [25]. In the first study, atorvastatin was concurrently given with dalcetrapib 900 mg while in the second study; atorvastatin was given with dalcetrapib 600 mg either concurrently or 4 h after.…”

Section: Drug Interaction Studies Between Dalcetrapib and Other Lipidmentioning

confidence: 99%

Current Status of CETP Inhibitors in the Treatment of Hyperlipidemia: An Update

Ghosh

Ghosh²

2012

CCP

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Introduction: The inverse relationship between HDL-C and cardiovascular disease risk suggests that increasing HDL-C could potentially reduce the disease risk. Reverse cholesterol transport is considered to be the primary mechanism by which HDL-C exerts its anti-atherogenic effects. A key regulator of RCT is cholesteryl ester transfer protein (CETP).Areas Covered: Inhibition of CETP has been identified as a possible strategy for substantially increasing HDL-C levels and CETP inhibitors have demonstrated clinical efficacy in preliminary clinical trials. The development of this novel class suffered a major setback when the major phase 3 trial of torcetrapib, the first CETP inhibitior was prematurely terminated due to an increase in cardiovascular and noncardiovascular mortality. Subsequent animal and clinical studies have shown that the increase in cardiovascular mortality reported with torcetrapib was molecule specific and independent of its CETP inhibition effect. The other two CETP inhibitors i.e. dalcetrapib and anacetrapib were well tolerated in phase I and II clinical trials and unlike torcetrapib, did not affect blood pressure and aldosterone levels.In this review article the authors have discussed the lessons learned from torcetrapib failure and important preclinical and clinical developments of CETP inhibitors and their role in management of hyperlipidemia and cardiovascular risk reduction.

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No clinically relevant drug–drug interactions when dalcetrapib is co-administered with atorvastatin

Abstract: These results indicate no clinically relevant interactions for co-administration of dalcetrapib with atorvastatin.

Cited by 17 publications

References 23 publications

An Update On the Clinical Development of Dalcetrapib (RO4607381), a Cholesteryl Ester Transfer Protein Modulator That Increases HDL Cholesterol Levels

An Update On the Clinical Development of Dalcetrapib (RO4607381), a Cholesteryl Ester Transfer Protein Modulator That Increases HDL Cholesterol Levels

Clinically Significant Drug Interaction Profiles of Chloroquine Analogues with Adverse Consequences and Risk Management

Current Status of CETP Inhibitors in the Treatment of Hyperlipidemia: An Update

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