The steady-state disposition of indinavir is not altered by the concomitant administration of clarithromycin

Boruchoff, Susan E.; Sturgill, Marc G.; Grasing, Kenneth; Seibold, James R.; McCrea, Jackie; Winchell, Gregory A.; Kusma, Sandra E.; Deutsch, Paul

doi:10.1067/mcp.2000.105151

Cited by 17 publications

(8 citation statements)

References 18 publications

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“…A study with a similar design found a clinically non-significant effect of CLR on indinavir, i.e. , indinavir C max increase of 58% and AUC of 47% in a smaller group of 12 patients at steady state [165]. Co-administering a darunavir/ritonavir combination with CLR in a randomized open-label cross-over study in 18 healthy volunteers resulted in a small increase of darunavir AUC by 13% and C max by 17% [166].…”

Section: Resultsmentioning

confidence: 99%

Pharmacokinetic Drug Interactions of Antimicrobial Drugs: A Systematic Review on Oxazolidinones, Rifamycines, Macrolides, Fluoroquinolones, and Beta-Lactams

et al. 2011

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Like any other drug, antimicrobial drugs are prone to pharmacokinetic drug interactions. These drug interactions are a major concern in clinical practice as they may have an effect on efficacy and toxicity. This article provides an overview of all published pharmacokinetic studies on drug interactions of the commonly prescribed antimicrobial drugs oxazolidinones, rifamycines, macrolides, fluoroquinolones, and beta-lactams, focusing on systematic research. We describe drug-food and drug-drug interaction studies in humans, affecting antimicrobial drugs as well as concomitantly administered drugs. Since knowledge about mechanisms is of paramount importance for adequate management of drug interactions, the most plausible underlying mechanism of the drug interaction is provided when available. This overview can be used in daily practice to support the management of pharmacokinetic drug interactions of antimicrobial drugs.

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Section: Resultsmentioning

confidence: 99%

Pharmacokinetic Drug Interactions of Antimicrobial Drugs: A Systematic Review on Oxazolidinones, Rifamycines, Macrolides, Fluoroquinolones, and Beta-Lactams

et al. 2011

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“…Several antiretroviral agents and other drugs coadministered in AIDS patients can pharmacokinetically act as inhibitors or inducers. However, coadministration of clarithromycin, an inhibitor of CYP3A4 with indinavir, did not alter the blood levels of indinavir (Boruchoff et al 2000). Administration of antiretrovirals concurrently with other therapeutic agents may lead to increased absorption as a result of inhibition of P-gpmediated efflux and CYP-mediated metabolism leading to potential toxicity.…”

Section: Integrated Functions Of Efflux and Metabolismmentioning

confidence: 87%

MDR- and CYP3A4-Mediated Drug–Drug Interactions

Pal

Mitra

2006

Jrnl Neuroimmune Pharm

170

123

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P-glycoprotein (P-gp), multiple drug resistance associated proteins (MRPs), and cytochrome P450 3A4 together constitute a highly efficient barrier for many orally absorbed drugs. Multidrug regimens and corresponding drug-drug interactions are known to cause many adverse drug reactions and treatment failures. Available literature, clinical reports, and in vitro studies from our laboratory indicate that many drugs are substrates for both P-gp and CYP3A4. Our primary hypothesis is that transport and metabolism of protease inhibitors (PIs) and NNRTIs will be altered when administered in combination with azole antifungals, macrolide, fluroquinolone antibiotics, statins, cardiovascular agents, immune modulators, and recreational drugs [benzodiazepines, cocaine, lysergic acid dithylamide (LSD), marijuana, amphetamine (Meth), 3,4-methylenedioxymethamphetamine (MDMA), and opiates] due to efflux, and/or metabolism at cellular targets. Therefore, such drug combinations could be a reason for the unexpected and unexplainable therapeutic outcomes. A number of clinical reports on drug interaction between PIs and other classes (macrolide antibiotics, azole antifungals, cholesterol lowering statins, cardiovascular medicines, and immunomodulators) are discussed in this article. MDCKII-MDR1 was employed as an in vitro model to evaluate the effects of antiretrovirals, azole antifungals, macrolide, and fluroquinolone antibiotics on efflux transporters. Ketoconazole (50 muM) enhanced the intracellular concentration of (3)H ritonavir. The inhibitory effects of ketoconazole and MK 571 on the efflux of (3)H ritonavir were comparable. An additive effect was observed with simultaneous incorporation of ketoconazole and MK 571. Results of (3)H ritonavir uptake studies were confirmed with transcellular transport studies. Several fluroquinolones were also evaluated on P-gp-mediated efflux of (3)H cyclosporin and 14C erythromycin. These in vitro studies indicate that grepafloxacin, levofloxacin, and sparfloxacin are potent inhibitors of P-gp-mediated efflux of 14C erythromycin and (3)H cyclosporin. Simultaneous administration of fluoroquinolones and macrolides could minimize the efflux and metabolism of both of the drugs. Effects of erythromycin and ketoconazole on carbamazepine metabolism were examined. Formation of 10,11-epoxy carbamazepine, a major CBZ metabolite, was significantly inhibited by these agents. Therefore, drug efflux proteins (P-gp, MRPs) and metabolizing enzyme (CYP450) are major factors in drug interactions. Overlapping substrate specificities of these proteins result in complex and sometimes perplexing pharmacokinetic profiles of multidrug regimens. Drug-drug interactions with PIs and other coadministered agents for human immunodeficiency virus (HIV) positive population have been discussed in light of efflux transporters and metabolizing enzymes. This article provides an insight into low and variable oral bioavailability and related complications leading to loss of therapeutic activity of MDR and CYP 450 substrates.

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“…[17] Similar variations in the pharmacokinetics of clarithromycin have been reported when clarithromycin was administered in conjunction with other protease inhibitors, and these variations have had little effect upon clinical outcome. [36-38] Since it is unlikely that the observed changes in exposure will have clinical significance, no dose adjustment is required for darunavir or clarithromycin in patients with normal renal function. A 50% dose reduction is recommended for clarithromycin when coadministered with darunavir for individuals with creatinine clearance of 30–60 mL/min.…”

Section: Protease Inhibitorsmentioning

confidence: 99%

Drug Interactions with New and Investigational Antiretrovirals

Brown

Paul

Kashuba

2009

Clinical Pharmacokinetics

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More than 20 individual and fixed-dose combinations of antiretrovirals are approved for the treatment of human immunodeficiency virus (HIV) infection. However, owing to the ongoing limitations of drug resistance and adverse effects, new treatment options are still required. A number of promising new agents in existing or new drug classes are in development or have recently been approved by the US FDA. Since these agents will be used in combination with other new and existing antiretrovirals, understanding the potential for drug interactions between these compounds is critical to their appropriate use. This article summarizes the drug interaction potential of new and investigational protease inhibitors (darunavir), non-nucleoside reverse transcriptase inhibitors (etravirine and rilpivirine), chemokine receptor antagonists (maraviroc, vicriviroc and INCB 9471), integrase inhibitors (raltegravir and elvitegravir) and maturation inhibitors (bevirimat).Advances in the treatment of human immunodeficiency virus (HIV) infection include the discovery of new antiretroviral agents and an improved understanding of the optimal combination of these agents for therapeutic benefit. Currently, the most potent antiretroviral regimens are those that include a combination of medications targeting different stages of the HIV life cycle. In 2007, two new classes of antiretrovirals were approved by the US FDA, and a number of other novel antiretrovirals in new classes and existing classes are being developed. All of these drugs are promising options for treatment-experienced patients. However, each class has a unique drug-interaction profile, making the optimal combination of these drugs challenging. Encouragingly, some of these new agents are not substrates of either cytochrome P450 (CYP) enzymes or drug transport proteins. This increases their potential to be used in combination with currently available antiretroviral agents without concern for subtherapeutic or supratherapeutic exposures. This article reviews the drug-drug interaction data, as well as drug-drug interaction potential, for antiretrovirals that have recently become available or are currently undergoing later phase clinical study. New protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are featured, as are new agents in the chemokine receptor antagonist class, the integrase inhibitor class, and the maturation inhibitor class. A summary of interactions between antiretrovirals can be found in tables I-III, and a summary of interactions between these new antiretrovirals and concomitant medications is presented in table IV. DarunavirDarunavir is a new protease inhibitor recently approved for the treatment of HIV-1-infected patients. In the US, the approved dose of darunavir is 600 mg, administered in conjunction with 100 mg of ritonavir, every 12 hours with food. Darunavir is recommended for use in treatment-experienced (multiple protease inhibitor-resistant) adult patients (figure 1a).1.1.1 Pharmacology-The molecular weight of darun...

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The steady-state disposition of indinavir is not altered by the concomitant administration of clarithromycin

Abstract: The combination of indinavir sulfate and clarithromycin is generally well tolerated and can be coadministered without dose adjustment.

Cited by 17 publications

References 18 publications

Pharmacokinetic Drug Interactions of Antimicrobial Drugs: A Systematic Review on Oxazolidinones, Rifamycines, Macrolides, Fluoroquinolones, and Beta-Lactams

Pharmacokinetic Drug Interactions of Antimicrobial Drugs: A Systematic Review on Oxazolidinones, Rifamycines, Macrolides, Fluoroquinolones, and Beta-Lactams

MDR- and CYP3A4-Mediated Drug–Drug Interactions

Drug Interactions with New and Investigational Antiretrovirals

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