Pharmacokinetic interaction between amprenavir and delavirdine: Evidence of induced clearance by amprenavir

Tran, Jonathan Q.

doi:10.1067/mcp.2002.128868

Cited by 24 publications

(6 citation statements)

References 29 publications

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“…Because delavirdine is used in anti-HIV therapy, its level of use can be regarded as exceptional. To maintain the plasma concentration of amprenavir, another antiviral drug metabolized by CYP3A4, at a sufficient level for anti-HIV therapy, amprenavir is often used in combination with delavirdine (Tran et al, 2002). Thus, this analysis shows that compounds located in zones 3 and 4 have strong in vivo DDI potential through their actions on CYP3A.…”

Section: Discussionmentioning

confidence: 99%

Risk Assessment for Drug-Drug Interaction Caused by Metabolism-Based Inhibition of CYP3A Using Automated in Vitro Assay Systems and Its Application in the Early Drug Discovery Process

Watanabe

Nakamura²,

Okudaira³

et al. 2007

Drug Metabolism and Disposition

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ABSTRACT:The CYP3A family is a major drug metabolism enzyme in humans. Metabolism-based inhibition of CYP3A might cause clinically significant drug-drug interactions (DDIs). To assess the risk of DDIs caused by metabolism-based inhibition (MBI) of CYP3A, we established an automated single time-and concentration-dependent inhibition assay. To create a diagram to assess DDI risk of compounds in the early discovery stage, we classified 171 marketed drugs by the possibility of the occurrence of in vivo DDI caused by MBI from the relationship between the inactivation activity determined in the MBI screening, the therapeutic blood or plasma concentration, and the in vivo DDI information. This analysis revealed that the DDI risk depends on both the MBI potential and the blood concentration of a compound, and provided the criteria of the DDI risk. In the assay, three compounds (midazolam, nifedipine, and testosterone) were compared as CYP3A probe substrates. The results show that the evaluation for MBI does not depend on the probe substrates used in the assay. In addition, we established an automated assay to distinguish quasi-irreversible and irreversible binding to CYP3A in which the quasi-irreversible inhibitors such as diltiazem, verapamil, and nicardipine were dissociated from CYP3A by the addition of potassium ferricyanide, whereas the irreversible inhibitors such as clozapine, delavirdine, and mibefradil were not. It provides useful information related to chemical structures likely to cause MBI. By using these MBI assays supported by an extensive database of marketed compounds, a systematic MBI evaluation paradigm was established and has been incorporated into our drug discovery process.The cytochrome P450 (P450) superfamily comprises many isozymes that metabolize xenobiotic chemicals, including drugs (Guengerich, 2001). CYP1A2, 2C9, 2C19, 2D6, and 3A participate in the metabolism of approximately 80% of therapeutic drugs, such that the majority of P450-mediated drug metabolism is mediated by the CYP3A family (Wienkers and Heath, 2005). CYP3A4 is a major isoform of CYP3A. It has been reported that CYP3A5 may also contribute to the metabolism of CYP3A4 substrates because of the overlapping substrate specificity with CYP3A4 . Drugs metabolized by P450s may also inhibit the metabolism of coadministered drugs, which results in an increased blood concentration of the coadministered drugs (Bertz and Granneman, 1997). As a result, a patient to whom two or more drugs are administered might suffer from adverse effects induced by such a drug-drug interaction (DDI). Drugs such as terfenadine, mibefradil, cisapride, and nefazodone have been withdrawn from the market because of P450-related DDIs (Wienkers and Heath, 2005). Consequently, pharmaceutical companies now investigate the P450 inhibitory potential of drug candidates in the early stage of development (Wienkers and Heath, 2005). P450 inhibition can be classified into three categories: reversible, quasi-irreversible, and irreversible inhibition (Murray, 1997;Lin and Lu,...

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Section: Discussionmentioning

confidence: 99%

Risk Assessment for Drug-Drug Interaction Caused by Metabolism-Based Inhibition of CYP3A Using Automated in Vitro Assay Systems and Its Application in the Early Drug Discovery Process

Watanabe

Nakamura²,

Okudaira³

et al. 2007

Drug Metabolism and Disposition

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“… No significant in vitro Cattaneo et al ( 2019 ), Sherman et al ( 2015 ), Tseng et al ( 2017 ) Ritonavir E: > 50% M: 3A4, 2D6 (minor) Strong 3A4 inhibitors ketoconazole (minor) Strong 3A4 inducers rifampicin (moderate) 3A4 (mechanism-based), 2D6, 2C9 3A4-, 2D6- and 2C9-substrates variable effects 1A2, 2B6, 2C8, 2C9, 2C19 in vitro; in vivo minor or moderate effects Cattaneo et al ( 2019 ), Cooper et al ( 2003 ), Tseng et al ( 2017 ) Protease inhibitors Atazanavir (+cobicistat) M: 3A4 Strong 3A4 inducers rifampicin (strong) Efavirenz (moderate) 3A4 (mechanism-based), 2C8 (weak) 3A4 substrates (from weak to strong) No effect in vitro or in vivo Tseng et al ( 2017 ) Darunavir (+ritonavir) M: 3A4, 2D6 3A4-inducers and inhibitors (variable observed or predicted effects) 3A4, 2D6 3A4 substrates (from weak to moderate) 2C9? warfarin Tseng et al ( 2017 ), Wagner et al ( 2017 ) Fosamprenavir (amprenavir) (+ritonavir) M: 3A4 3A4-inducers and inhibitors (variable observed or predicted effects) 3A4 3A4 substrates (from weak to moderate) 3A4; in vivo effect minor or moderate Justesen et al ( 2003 ), Sale et al ( 2002 ), Tran et al ( 2002 ) Lopinavir (+ritonavir) M: 3A4 3A4-inducers and inhibitors (variable observed or predicted effects) 3A4 3A4 substrates (from weak to moderate) …”

Section: Antiretroviral Hiv Drugsmentioning

confidence: 99%

Inhibition and induction of CYP enzymes in humans: an update

et al. 2020

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The cytochrome P450 (CYP) enzyme family is the most important enzyme system catalyzing the phase 1 metabolism of pharmaceuticals and other xenobiotics such as herbal remedies and toxic compounds in the environment. The inhibition and induction of CYPs are major mechanisms causing pharmacokinetic drug–drug interactions. This review presents a comprehensive update on the inhibitors and inducers of the specific CYP enzymes in humans. The focus is on the more recent human in vitro and in vivo findings since the publication of our previous review on this topic in 2008. In addition to the general presentation of inhibitory drugs and inducers of human CYP enzymes by drugs, herbal remedies, and toxic compounds, an in-depth view on tyrosine-kinase inhibitors and antiretroviral HIV medications as victims and perpetrators of drug–drug interactions is provided as examples of the current trends in the field. Also, a concise overview of the mechanisms of CYP induction is presented to aid the understanding of the induction phenomena.

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“…No clinical trial data are available that directly compare a DLV-based regimen with a PI-based regimen. Because DLV is an inhibitor of CYP3A4, it has been used with PIs to boost the plasma concentration of the latter (Shelton et al, 2003;Tran et al, 2002).…”

Section: Nevirapinementioning

confidence: 99%

Clinical Utility of Current NNRTIs and Perspectives of New Agents in This Class under Development

Zhang

Hamatake

Hong

2004

Antivir Chem Chemother

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Highly active antiretroviral therapy (HAART) has significantly reduced the number of deaths caused by AIDS. However, the antiviral efficacy of HAART comprising protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) is frequently accompanied by a decrease in patients' quality of life. PI-based therapies often fail due to poor adherence caused by heavy pill burden, complex dosing schedules and undesirable side effects. The current trend is to switch from PI-based to PI-sparing regimens consisting of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and NRTIs. Despite some encouraging results from NNRTI-containing therapies, two major concerns in using the currently available NNRTIs remain: 1) low genetic barrier to the emergence of resistance and 2) cross-resistance due to single mutations that often render the whole class of NNRTIs ineffective. Clearly, new and improved NNRTIs are needed to address these concerns.

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Pharmacokinetic interaction between amprenavir and delavirdine: Evidence of induced clearance by amprenavir

Cited by 24 publications

References 29 publications

Risk Assessment for Drug-Drug Interaction Caused by Metabolism-Based Inhibition of CYP3A Using Automated in Vitro Assay Systems and Its Application in the Early Drug Discovery Process

Risk Assessment for Drug-Drug Interaction Caused by Metabolism-Based Inhibition of CYP3A Using Automated in Vitro Assay Systems and Its Application in the Early Drug Discovery Process

Inhibition and induction of CYP enzymes in humans: an update

Clinical Utility of Current NNRTIs and Perspectives of New Agents in This Class under Development

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