Effect of meal and antisecretory agents on the pharmacokinetics of danoprevir/ritonavir in healthy volunteers

Morcos, Peter N.; Moreira, Sebastian; Navarro, Mercidita T.; Bech, Nuria; Quatkemeyer, Amanda; Smith, Patrick F.; Brennan, Barbara J.

doi:10.1111/jphp.12151

Cited by 9 publications

(3 citation statements)

References 24 publications

(29 reference statements)

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“…The similarities in PK parameters suggest that the differences in study protocol (i.e., the presence of nasal gastric tubes in the intestinal sampling study, and the positioning of the volunteers (alternating between supine and sitting up during the MRI study vs. semi-supine during the intestinal sampling study)) did not substantially affect ritonavir absorption. It should be noted that a systematic review by Béïque et al [ 22 ], as well as a study by Morcos et al [ 23 ], did not report an effect of another PPI (omeprazole) on plasma C max or AUC of ritonavir. Chiu et al [ 24 ] did observe a decreased ritonavir AUC when 40 mg omeprazole was dosed 2 h prior to an atazanavir/ritonavir tablet.…”

Section: Discussionmentioning

confidence: 99%

Exploring the Effect of Esomeprazole on Gastric and Duodenal Fluid Volumes and Absorption of Ritonavir

et al. 2020

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Proton-pump inhibitors (PPIs), frequently prescribed to lower gastric acid secretion, often exert an effect on the absorption of co-medicated drug products. A previous study showed decreased plasma levels of the lipophilic drug ritonavir after co-administration with the PPI Nexium (40 mg esomeprazole), even though duodenal concentrations were not affected. The present study explored if a PPI-induced decrease in gastrointestinal (GI) fluid volume might contribute to the reduced absorption of ritonavir. In an exploratory cross-over study, five volunteers were given a Norvir tablet (100 mg ritonavir) orally, once without PPI pre-treatment and once after a three-day pre-treatment with the PPI esomeprazole. Blood samples were collected for eight hours to assess ritonavir absorption and magnetic resonance imaging (MRI) was used to determine the gastric and duodenal fluid volumes during the first three hours after administration of the tablet. The results confirmed that PPI intake reduced ritonavir plasma concentrations by 40%. The gastric residual volume and gastric fluid volume decreased by 41% and 44% respectively, while the duodenal fluid volume was reduced by 33%. These data suggest that the PPI esomeprazole lowers the available fluid volume for dissolution, which may limit the amount of ritonavir that can be absorbed. Although additional factors may play a role, the effect of PPI intake on the GI fluid volume should be considered when simulating the absorption of poorly soluble drugs like ritonavir in real-life conditions.

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Section: Discussionmentioning

confidence: 99%

Exploring the Effect of Esomeprazole on Gastric and Duodenal Fluid Volumes and Absorption of Ritonavir

et al. 2020

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“…2158 studies did not address the research question or met the exclusion criteria. Of 94 studies that were assessed for eligibility, 7 were excluded for reasons as follows: drug other than antiretroviral being assessed [26][27][28], a study design that does not allow to resolve the impact of food on an antiretroviral drug [29,30], a study performed on hepatitis B patients [31], the impact of food being assessed for intravenously given antiretroviral drug [32].…”

Section: Eligible Studiesmentioning

confidence: 99%

Interactions of Antiretroviral Drugs with Food, Beverages, Dietary Supplements, and Alcohol: A Systematic Review and Meta-analyses

et al. 2022

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Multiple factors may affect combined antiretroviral therapy (cART). We investigated the impact of food, beverages, dietary supplements, and alcohol on the pharmacokinetic and pharmacodynamic parameters of 33 antiretroviral drugs. Systematic review in adherence to PRISMA guidelines was performed, with 109 reports of 120 studies included. For each drug, meta-analyses or qualitative analyses were conducted. We have found clinically significant interactions with food for more than half of antiretroviral agents. The following drugs should be taken with or immediately after the meal: tenofovir disoproxil, etravirine, rilpivirine, dolutegravir, elvitegravir, atazanavir, darunavir, lopinavir, nelfinavir, ritonavir, saquinavir. Didanosine, zalcitabine, zidovudine, efavirenz, amprenavir, fosamprenavir, and indinavir should be taken on an empty stomach for maximum patient benefit. Antiretroviral agents not mentioned above can be administered regardless of food. There is insufficient evidence available to make recommendations about consuming juice or alcohol with antiretroviral drugs. Resolving drug-food interactions may contribute to maximized cART effectiveness and safety.

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“…Unpublished data in the product label, and published pharmacokinetic studies, indicate that coadministration of ritonavir with food can cause a small increase, a small decrease, or have negligible effect on systemic availability, depending on the composition and timing of the meal . There is low probability that any of the variations attributable to coadministration with meals would alter or modify the CYP3A inhibitory effect of ritonavir.…”

Section: Comparison Of Ritonavir and Itraconazolementioning

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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Effect of meal and antisecretory agents on the pharmacokinetics of danoprevir/ritonavir in healthy volunteers

Abstract: The absence of clinically relevant effects of food, ranitidine or omeprazole on DNVr pharmacokinetics suggests that DNVr can be administered without regard to meals and in combination with H2 antagonists or proton pump inhibitors.

Cited by 9 publications

References 24 publications

Exploring the Effect of Esomeprazole on Gastric and Duodenal Fluid Volumes and Absorption of Ritonavir

Exploring the Effect of Esomeprazole on Gastric and Duodenal Fluid Volumes and Absorption of Ritonavir

Interactions of Antiretroviral Drugs with Food, Beverages, Dietary Supplements, and Alcohol: A Systematic Review and Meta-analyses

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

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