Antiretroviral boosting by cobicistat, a structural analog of ritonavir

Greenblatt, David J.

doi:10.1002/cpdd.159

Cited by 16 publications

(29 citation statements)

References 26 publications

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“…Ritonavir is the most potent of clinically available CYP3A inhibitors and also is a strong inhibitor of transport via P‐gp . Cobicistat is an alternative enhancer that was first approved in 2012 as part of a combination product, and approved as a single entity in 2014 . Ritonavir and cobicistat are very similar in structure (Figure ) and similar or identical in pharmacologic properties and clinical efficacy as enhancing agents …”

Section: Clinical Importance Of Drug Interactions: the Concept Of Boomentioning

confidence: 99%

“…[48][49][50] Cobicistat is an alternative enhancer that was first approved in 2012 as part of a combination product, and approved as a single entity in 2014. [51][52][53] Ritonavir and cobicistat are very similar in structure ( Figure 2) and similar or identical in pharmacologic properties and clinical efficacy as enhancing agents. [54][55][56]…”

Section: Clinical Importance Of Drug Interactions: the Concept Of Boomentioning

confidence: 99%

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Mechanisms and Consequences of Drug‐Drug Interactions

Greenblatt

2017

Clinical Pharm in Drug Dev

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Medications used to treat human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections present a special challenge with respect to the management of potential and actual drug-drug interactions (DDIs). The HIV and HCV treatments may interact with each other, and also interact with drugs of abuse and/or with medications used to treat substance abuse. Possible mechanisms of these DDIs generally include induction or inhibition of activity/expression of human cytochromes P450, glucuronosyl transferases, or energy-dependent transport proteins. These DDIs can be complex and time-dependent in nature. Because time and resources available for new drug development are necessarily limited, not all potential DDIs can be evaluated via clinical pharmacokinetic studies in the course of development of HIV, HCV, and substance abuse treatments. Strategies are needed to refine existing in vitro models and screening techniques to allow more efficient targeting of resources to those clinical studies having the highest impact in terms of enhancing medication effectiveness and patient safety.

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Section: Clinical Importance Of Drug Interactions: the Concept Of Boomentioning

confidence: 99%

Section: Clinical Importance Of Drug Interactions: the Concept Of Boomentioning

confidence: 99%

Mechanisms and Consequences of Drug‐Drug Interactions

Greenblatt

2017

Clinical Pharm in Drug Dev

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“…Similar to ritonavir in structure and pharmacologic properties, cobicistat is available as a single entity for purposes of pharmacokinetic boosting . The extent of CYP3A inhibition by cobicistat in vitro is similar to that produced by ritonavir .…”

Section: Summary and Guidelines For The Use Of Ritonavirmentioning

confidence: 99%

Evidence‐based choice of ritonavir as index CYP3A inhibitor in drug‐drug interaction studies

Greenblatt

2015

The Journal of Clinical Pharma

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The "index" cytochrome P450-3A (CYP3A) inhibitor has become a critical research tool for the process of drug development.1,2 If a candidate drug under development is suspected of being dependent on CYP3A for its clearance, coadministration of this candidate with a strong or maximal in vivo CYP3A inhibitor can validate the relative contribution of CYP3A to net clearance, and map out the "worst possible" drug-drug interaction (DDI) scenario when CYP3A activity is essentially nullified. If the candidate itself is suspected of being a CYP3A inhibitor, its quantitative in vivo inhibitory potency can be compared to the "worst possible" extreme if the index inhibitor is used as a positive control in a DDI study involving a sensitive CYP3A substrate.The azole antifungal agent ketoconazole has served as the prototype index CYP3A inhibitor in this context for many years. 2,3 Ketoconazole has the following specific favorable attributes: (1) usual clinical doses (400 mg per day) will produce the maximum possible CYP3A inhibition in vivo; (2) these doses carry minimal risk of adverse events in healthy volunteers; (3) less than 24 hours of preexposure to ketoconazole is needed to produce maximal CYP3A inhibition, and a loading dose is not required; (4) inhibition is relatively (although not absolutely) specific for CYP3A; (5) ketoconazole does not have active metabolites of clinical importance; and (6) CYP3A inhibition is rapidly reversible when ketoconazole is discontinued.Warnings against the use of ketoconazole based on an alleged risk of liver injury, issued by the Food and Drug Administration (FDA) and the European Medicines Agency in 2013, are not supported by medical or scientific evidence.2-5 Specifically, there is no indication of substantive risk to healthy volunteers who receive ketoconazole as an index CYP3A inhibitor in DDI studies. Still, the regulatory warnings compel the clinical pharmacology and drug development communities to evaluate alternatives to ketoconazole. Proposed alternatives have included: ritonavir, cobicistat, itraconazole, posaconazole, and clarithromycin.2-7 A review of the available published evidence clearly indicates that ritonavir is the best choice as an alternative index inhibitor. Comparison of Ritonavir and Itraconazole Maximum InhibitionBoth ritonavir and itraconazole are strong CYP3A inhibitors in vitro, with ritonavir having greater inhibitory potency.8 Inhibition by ritonavir has both reversible and mechanism-based (time-dependent) components, [9][10][11] whereas inhibition by itraconazole is largely reversible. An earlier review evaluated clinical DDI studies in which oral midazolam was the index CYP3A substrate (victim), and the inhibitor was either ritonavir or itraconazole.5 The principal outcome variable was the ratio (R AUC ) of total area under the curve (AUC) for midazolam with inhibitor coadministration divided by AUC in the control condition. In 13 studies with ritonavir as inhibitor, the mean (AESE) R AUC was 14.5 AE 2.0, compared to 11.5 AE 1.2 in 15 studies of ketoconaz...

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“…[58,59] The concept of pharmacokinetic augmentation or 'boosting' refers to the use of a coadministered inhibitor of metabolism and/or transport to reduce presystemic extraction of a specific substrate drug and increase its systemic exposure. [60][61][62] Boosting is commonly applied to the treatment of HIV and hepatitis infection, whereby a boosting agent such as ritonavir or cobicistatas inhibitors of CYP3Amediated metabolism or efflux transport by P-glycoprotein is given along with antiviral medications to enhance their systemic plasma concentrations and bring exposures to a clinically effective range. [60,61,63] In the case of resveratrol, pharmacokinetic boosting is most effectively directed towards the principal mechanism of clearance, which is glucuronide conjugation.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol glucuronidation in vitro: potential implications of inhibition by probenecid

Matin

Sherbini

Alam

et al. 2019

Journal of Pharmacy and Pharmacology

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Objectives Resveratrol is a naturally occurring antioxidant with therapeutic potential in prevention and treatment of neoplastic disease and other human disorders. However, net clearance of resveratrol in humans is very high, mainly due to glucuronide conjugation. This leads to extensive presystemic extraction and low plasma concentrations after oral dosage. The present study evaluated the effect of probenecid, an inhibitor of glucuronide conjugation, on resveratrol metabolism in vitro. Methods Biotransformation of resveratrol to its 3‐O‐glucuronide and 4′‐O‐glucuronide conjugates was studied in vitro using human liver microsomal preparations. The mechanism and inhibitory potency of probenecid were evaluated based on a mixed competitive‐noncompetitive inhibition model. Key findings Probenecid inhibition of resveratrol 3‐O‐glucuronidation was predominantly noncompetitive, with an inhibition constant (Ki) averaging 3.1 mm. Conclusions The ratio of in vivo maximum concentration of probenecid [I] during usual clinical use to the in vitro Ki value ([I]/Ki) exceeds the boundary value of 0.1, used by regulatory agencies to identify the possibility of clinical drug interactions. This finding, together with the known property of probenecid as an inhibitor of glucuronide conjugation in humans, suggests that probenecid could serve as a pharmacokinetic boosting agent to enhance systemic exposure to resveratrol in humans.

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Antiretroviral boosting by cobicistat, a structural analog of ritonavir

Cited by 16 publications

References 26 publications

Mechanisms and Consequences of Drug‐Drug Interactions

Mechanisms and Consequences of Drug‐Drug Interactions

Evidence‐based choice of ritonavir as index CYP3A inhibitor in drug‐drug interaction studies

Resveratrol glucuronidation in vitro: potential implications of inhibition by probenecid

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