Dronedarone-Induced Digoxin Toxicity

Vallakati, Ajay; Chandra, Preeti; Pednekar, Manali; Frankel, Robert; Shani, Jacob

doi:10.1097/mjt.0b013e31821106c9

Cited by 18 publications

(18 citation statements)

References 5 publications

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“…Transporter DDI for Glecaprevir and Pibrentasvir by renal excretion, and does not undergo significant enterohepatic circulation (Marcus et al, 1976;Lloyd et al, 1978). Thus, the digoxin AUC may only be increased a maximum of 25%-67% by inhibition of intestinal efflux, which affects bioavailability, not clearance-increases up to 150% have been reported upon coadministration with dronedarone and likely reflect additive inhibition of digoxin renal tubular secretion (Hori et al, 1993;Vallakati et al, 2013). The 48% increase in digoxin AUC observed with glecaprevir and pibrentasvir and accompanying modest impact on digoxin terminal elimination half-life in plasma are suggestive, but not conclusive, of an intestinal-based interaction.…”

Section: Discussionmentioning

confidence: 99%

Translation of In Vitro Transport Inhibition Studies to Clinical Drug-Drug Interactions for Glecaprevir and Pibrentasvir

Kosloski

Bow

Kikuchi

et al. 2019

J Pharmacol Exp Ther

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Glecaprevir and pibrentasvir are oral direct-acting antiviral agents approved in combination for treatment of chronic hepatitis C viral infection. In vitro studies identified the combination as potentially clinically relevant inhibitors of the efflux transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and the hepatic uptake transporters organic anion transporting polypeptide (OATP) 1B1 and OATP1B3. Glecaprevir inhibited P-gp, BCRP, OATP1B1, and OATP1B3 with IC 50 values of 0.33, 2.3, 0.017, and 0.064 mM, respectively. Pibrentasvir inhibited P-gp, BCRP, and OATP1B1 with IC 50 values of 0.036, 14, and 1.3 mM, respectively. Neither agent inhibited organic cation transporter (OCT) 1, OCT2, organic anion transporter (OAT) 1, OAT3, multidrug and toxin extrusion (MATE) 1, or MATE2K. Openlabel phase 1 clinical drug-drug interaction studies were conducted in healthy subjects to evaluate interaction potential of glecaprevir/ pibrentasvir and coadministered selective substrates for P-gp (digoxin, dabigatran etexilate, and sofosbuvir), BCRP (rosuvastatin and sofosbuvir), and OATP1B1/3 (pravastatin and rosuvastatin). The pharmacokinetic maximum plasma concentration (C max) and area under the concentration-time curve (AUC) parameters were evaluated for probe substrates alone and in combination with glecaprevir/ pibrentasvir. The C max central values increased by 72%, 105%, 123%, 462%, and 66% for digoxin, dabigatran, pravastatin, rosuvastatin, and sofosbuvir, respectively, and the AUC central values increased by 48%, 138%, 130%, 115%, and 125% for digoxin, dabigatran, pravastatin, rosuvastatin, and sofosbuvir, respectively. Exposure of sofosbuvir metabolite GS-331007 (nucleoside analog) was similar with or without glecaprevir/pibrentasvir. The outcomes of the clinical drug-drug interaction studies confirmed clinically relevant inhibition of P-gp, BCRP, and OATP1B1/3, and were used to provide dosing guidance for the concomitant use of glecaprevir/pibrentasvir with relevant transporter substrates.

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Section: Discussionmentioning

confidence: 99%

Translation of In Vitro Transport Inhibition Studies to Clinical Drug-Drug Interactions for Glecaprevir and Pibrentasvir

Kosloski

Bow

Kikuchi

et al. 2019

J Pharmacol Exp Ther

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“…Amiodarone was also found to increase the oral bioavailability of the anticoagulants, dabigatran, rivaroxaban and apixaban by ~10% through inhibition of intestinal Pgp (60, 63). In contrast, dronedarone showed even stronger DDIs with digoxin than amiodarone (59). The AUC of digoxin was almost 2-fold higher with dronedarone and there was a 60% decrease in renal clearance (59).…”

Section: In Vitro Ion Channel Inhibitor Ddis With Pgp and The Corrmentioning

confidence: 97%

“…In contrast, dronedarone showed even stronger DDIs with digoxin than amiodarone (59). The AUC of digoxin was almost 2-fold higher with dronedarone and there was a 60% decrease in renal clearance (59).…”

Section: In Vitro Ion Channel Inhibitor Ddis With Pgp and The Corrmentioning

confidence: 97%

“…These potassium channel inhibitors are also known to exhibit a number of DDIs in the clinic (e.g. 58, 59, 60). The pharmacokinetic consequences of amiodarone-digoxin DDIs have been the most thoroughly evaluated (e.g.…”

Section: In Vitro Ion Channel Inhibitor Ddis With Pgp and The Corrmentioning

confidence: 99%

“…In the clinic, cardiovascular ion channel inhibitors show a large range of effects on digoxin pharmacokinetics. Large increases in digoxin exposure and drug plasma concentration are observed in the presence of dronedarone (59), while decreases in digoxin plasma concentration are observed in the presence of phenytoin (96). Unfortunately, in vitro Pgp-mediated inhibition of digoxin transport and the observed pharmacokinetics are not well correlated.…”

Section: Current Strategies For Overcoming Pgp-mediated Ddis In Thmentioning

confidence: 99%

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Cardiovascular Ion Channel Inhibitor Drug-Drug Interactions with P-glycoprotein

Ledwitch

Roberts

2016

AAPS J

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P-glycoprotein (Pgp) is an ATP-binding cassette (ABC) transporter that plays a major role in cardiovascular drug disposition by effluxing a chemically and structurally diverse range of cardiovascular therapeutics. Unfortunately, drug-drug interactions (DDIs) with the transporter have become a major roadblock to effective cardiovascular drug administration because they can cause adverse drug reactions (ADRs) or reduce the efficacy of drugs. Cardiovascular ion channel inhibitors are particularly susceptible to DDIs and ADRs with Pgp because they often have low therapeutic indexes and are commonly coadministered with other drugs that are also Pgp substrates. DDIs from cardiovascular ion channel inhibitors with the transporter occur because of inhibition or induction of the transporter and the transporter's tissue and cellular localization. Inhibiting Pgp can increase absorption and reduce excretion of drugs, leading to elevated drug plasma concentrations and drug toxicity. In contrast, inducing Pgp can have the opposite effect by reducing the drug plasma concentration and its efficacy. A number of in vitro and in vivo studies have already demonstrated DDIs from several cardiovascular ion channel inhibitors with human Pgp and its animal analogs, including verapamil, digoxin, and amiodarone. In this review, Pgp-mediated DDIs and their effects on pharmacokinetics for different categories of cardiovascular ion channel inhibitors are discussed. This information is essential for improving pharmacokinetic predictions of cardiovascular therapeutics, for safer cardiovascular drug administration and for mitigating ADRs emanating from Pgp.

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