Chronic pentamidine aerosol prophylaxis does not induce QT prolongation

Thalhammer, Christoph; Bogner, Johannes R.; Lohmöller, G

doi:10.1007/bf00184735

Cited by 10 publications

(5 citation statements)

References 15 publications

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“…The concentration‐dependent suppression of the expression level of the hERG channel by pentamidine observed in this study seems to also indicate a much milder effect at the n M level, which occurs when other routes of administration are used. Indeed, no major QT prolongation and cardiac arrhythmia have been reported in patients treated with inhaled pentamidine when exposures are often below 50 ng ml −1 or 0.15 μ M total, 0.045 μ M protein‐unbound (Thalhammer et al ., 1993; Cardoso et al ., 1997).…”

Section: Discussionmentioning

confidence: 99%

Pentamidine reduces hERG expression to prolong the QT interval

Cordes¹,

Sun²,

Lloyd³

et al. 2005

British J Pharmacology

126

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1 Pentamidine, an antiprotozoal agent, has been traditionally known to cause QT prolongation and arrhythmias; however, its ionic mechanism has not been illustrated. 2 In a stable HEK-293 cell line, we observed a concentration-dependent inhibition of the hERG current with an IC 50 of 252 mM. 3 In freshly isolated guinea-pig ventricular myocytes, pentamidine showed no effect on the L-type calcium current at concentrations up to 300 mM, with a slight prolongation of the action potential duration at this concentration. 4 Since the effective concentrations of pentamidine on the hERG channel and APD were much higher than clinically relevant exposures (B1 mM free or lower), we speculated that this drug might not prolong the QT interval through direct inhibition of I Kr channel. We therefore incubated hERG-HEK cells in 1 and 10 mM pentamidine-containing media (supplemented with 10% serum) for 48 h, and examined the hERG current densities in the vehicle control and pentamidine-treated cells. 5 In all, 36 and 85% reductions of the current densities were caused by 1-and 10-mM pentamidine treatment (Po0.001 vs control), respectively. A similar level of reduction of the hERG polypeptides and a reduced intensity of the hERG protein on the surface membrane in treated cells were observed by Western blot analysis and laser-scanning confocal microscopy, respectively. 6 Taken together, our data imply that chronic administration of pentamidine at clinically relevant exposure reduces the membrane expression of the hERG channel, which may most likely be the major mechanism of QT prolongation and torsade de pointes reported in man.

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Section: Discussionmentioning

confidence: 99%

Pentamidine reduces hERG expression to prolong the QT interval

Cordes¹,

Sun²,

Lloyd³

et al. 2005

British J Pharmacology

126

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“…177 However, in a study of 100 patients taking inhaled pentamidine twice/week, the authors found no QT prolongation for the duration of the patients' therapy. 178 Of interest, other authors describe a case of torsade de pointes in a patient who received one dose of inhaled pentamidine (hypokalemia and low ionized calcium present). 177 Various fluoroquinolones have been implicated as causing QT prolongation, with the greatest concern with sparfloxacin and grepafloxacin.…”

Section: Definite Associationmentioning

confidence: 99%

Clinical Relevance and Management of Drug‐Related QT Interval Prolongation

2003

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Much attention recently has focused on drugs that prolong the QT interval, potentially leading to fatal cardiac dysrhythmias (e.g., torsade de pointes). We provide a detailed review of the published evidence that supports or does not support an association between drugs and their risk of QT prolongation. The mechanism of drug-induced QT prolongation is reviewed briefly, followed by an extensive evaluation of drugs associated with QT prolongation, torsade de pointes, or both. Drugs associated with QT prolongation are identified as having definite, probable, or proposed associations. The role of the clinician in the prevention and management of QT prolongation, drug-drug interactions that may occur with agents known to affect the QT interval, and the impact of this adverse effect on the regulatory process are addressed.

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“…A stronger effect on FPD was observed at 3 μM, a concentration that also induced cytotoxic effects at 48 h post compound addition, consistent with previously reported in vitro data ( Cordes et al, 2005 ; Asahi et al, 2019 ). Interestingly, inhaled pentamidine (nasal spray formulations) exposures are often in the nM range and those have not been associated to either QT prolongation or TdP ( Thalhammer et al, 1993 ). Correspondingly, we demonstrated that the lowest doses used in the study (i.e.,: 0.3–0.1 µM) did not result in a significant prolongation of the FPD.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of chronic drug-induced electrophysiological and cytotoxic effects using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs)

et al. 2023

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Introduction: Cardiotoxicity is one of the leading causes of compound attrition during drug development. Most in vitro screening platforms aim at detecting acute cardio-electrophysiological changes and drug-induced chronic functional alterations are often not studied in the early stage of drug development. Therefore, we developed an assay using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) that evaluates both drug-induced acute and delayed electrophysiological and cytotoxic effects of reference compounds with clinically known cardiac outcomes.Methods: hiPSC-CMs were seeded in 48-well multielectrode array (MEA) plates and were treated with four doses of reference compounds (covering and exceeding clinical free plasma peak concentrations -fCmax values) and MEA recordings were conducted for 4 days. Functional-electrophysiological (field-potentials) and viability (impedance) parameters were recorded with a MEA machine.Results: To assess this platform, we tested tyrosine-kinase inhibitors with high-cardiac risk profile (sunitinib, vandetanib and nilotinib) and low-cardiac risk (erlotinib), as well as known classic cardiac toxic drugs (doxorubicin and BMS-986094), ion-channel trafficking inhibitors (pentamidine, probucol and arsenic trioxide) and compounds without known clinical cardiotoxicity (amoxicillin, cetirizine, captopril and aspirin). By evaluating the effects of these compounds on MEA parameters, the assay was mostly able to recapitulate different drug-induced cardiotoxicities, represented by a prolongation of the field potential, changes in beating rate and presence of arrhythmic events in acute (<2 h) or delayed phase ≥24 h, and/or reduction of impedance during the delayed phase (≥24 h). Furthermore, a few reference compounds were tested in hiPSC-CMs using fluorescence- and luminescence-based plate reader assays, confirming the presence or absence of cytotoxic effects, linked to changes of the impedance parameters measured in the MEA assay. Of note, some cardiotoxic effects could not be identified at acute time points (<2 h) but were clearly detected after 24 h, reinforcing the importance of chronic drug evaluation.Discussion: In conclusion, the evaluation of chronic drug-induced cardiotoxicity using a hiPSC-CMs in vitro assay can contribute to the early de-risking of compounds and help optimize the drug development process.

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Chronic pentamidine aerosol prophylaxis does not induce QT prolongation

Cited by 10 publications

References 15 publications

Pentamidine reduces hERG expression to prolong the QT interval

Pentamidine reduces hERG expression to prolong the QT interval

Clinical Relevance and Management of Drug‐Related QT Interval Prolongation

Evaluation of chronic drug-induced electrophysiological and cytotoxic effects using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs)

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