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A pharmacokinetic-pharmacodynamic model for the quantitative prediction of dofetilide clinical QT prolongation from human ether-a-go-go-related gene current inhibition data.
Clin Pharmacol Ther. 2005 Jun; 77(6):572-82.CP

Abstract

BACKGROUND

QT prolongation is an important biomarker of the arrhythmia torsades de pointes and appears to be related mainly to blockade of delayed inward cardiac rectifier potassium currents. The aim of this study was to quantify the relationship between in vitro human ether-a-go-go-related gene (hERG) potassium channel blockade and the magnitude of QT prolongation in humans for the class III antiarrhythmic dofetilide.

METHODS

The in vitro affinity and activity of dofetilide were determined in recombinant cell cultures expressing the hERG channel, and the QT-prolonging effect of dofetilide was assessed in 5 clinical studies (80 healthy volunteers and 17 patients with ischemic heart disease). A population pharmacokinetic-pharmacodynamic analysis of the in vitro and in vivo data was performed in NONMEM by use of the operational model of pharmacologic agonism to estimate the efficiency of transduction from ion channel binding to Fridericia-corrected QT response.

RESULTS

A 3-compartment pharmacokinetic model with first-order absorption characterized the time course of dofetilide concentrations. On the basis of an in vitro potency of 5.13 ng/mL for potassium current inhibition and predicted unbound dofetilide concentrations, the estimated transducer ratio (tau) of 6.2 suggests that the QT response plateaus before currents are fully blocked. In our study population, 10% hERG blockade corresponds to a QT prolongation of 20 ms (95% confidence interval, 12-32 ms). With long-term dofetilide administration, tolerance develops with a half-life of 4.7 days.

CONCLUSIONS

The current mechanism-based pharmacokinetic-pharmacodynamic model quantified the relationship between in vitro hERG channel blockade and clinical QT prolongation for dofetilide. This model may prove valuable for assessing the risk of QT prolongation in humans for other drugs that selectively block the hERG channel on the basis of in vitro assays and pharmacokinetic properties.

Authors+Show Affiliations

Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Faculty of Pharmacy, Uppsala University, Sweden. daniel.jonker@farmbio.uu.seNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15961988

Citation

Jonker, Daniël M., et al. "A Pharmacokinetic-pharmacodynamic Model for the Quantitative Prediction of Dofetilide Clinical QT Prolongation From Human Ether-a-go-go-related Gene Current Inhibition Data." Clinical Pharmacology and Therapeutics, vol. 77, no. 6, 2005, pp. 572-82.
Jonker DM, Kenna LA, Leishman D, et al. A pharmacokinetic-pharmacodynamic model for the quantitative prediction of dofetilide clinical QT prolongation from human ether-a-go-go-related gene current inhibition data. Clin Pharmacol Ther. 2005;77(6):572-82.
Jonker, D. M., Kenna, L. A., Leishman, D., Wallis, R., Milligan, P. A., & Jonsson, E. N. (2005). A pharmacokinetic-pharmacodynamic model for the quantitative prediction of dofetilide clinical QT prolongation from human ether-a-go-go-related gene current inhibition data. Clinical Pharmacology and Therapeutics, 77(6), 572-82.
Jonker DM, et al. A Pharmacokinetic-pharmacodynamic Model for the Quantitative Prediction of Dofetilide Clinical QT Prolongation From Human Ether-a-go-go-related Gene Current Inhibition Data. Clin Pharmacol Ther. 2005;77(6):572-82. PubMed PMID: 15961988.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A pharmacokinetic-pharmacodynamic model for the quantitative prediction of dofetilide clinical QT prolongation from human ether-a-go-go-related gene current inhibition data. AU - Jonker,Daniël M, AU - Kenna,Leslie A, AU - Leishman,Derek, AU - Wallis,Rob, AU - Milligan,Peter A, AU - Jonsson,E Niclas, PY - 2005/6/18/pubmed PY - 2005/7/20/medline PY - 2005/6/18/entrez SP - 572 EP - 82 JF - Clinical pharmacology and therapeutics JO - Clin. Pharmacol. Ther. VL - 77 IS - 6 N2 - BACKGROUND: QT prolongation is an important biomarker of the arrhythmia torsades de pointes and appears to be related mainly to blockade of delayed inward cardiac rectifier potassium currents. The aim of this study was to quantify the relationship between in vitro human ether-a-go-go-related gene (hERG) potassium channel blockade and the magnitude of QT prolongation in humans for the class III antiarrhythmic dofetilide. METHODS: The in vitro affinity and activity of dofetilide were determined in recombinant cell cultures expressing the hERG channel, and the QT-prolonging effect of dofetilide was assessed in 5 clinical studies (80 healthy volunteers and 17 patients with ischemic heart disease). A population pharmacokinetic-pharmacodynamic analysis of the in vitro and in vivo data was performed in NONMEM by use of the operational model of pharmacologic agonism to estimate the efficiency of transduction from ion channel binding to Fridericia-corrected QT response. RESULTS: A 3-compartment pharmacokinetic model with first-order absorption characterized the time course of dofetilide concentrations. On the basis of an in vitro potency of 5.13 ng/mL for potassium current inhibition and predicted unbound dofetilide concentrations, the estimated transducer ratio (tau) of 6.2 suggests that the QT response plateaus before currents are fully blocked. In our study population, 10% hERG blockade corresponds to a QT prolongation of 20 ms (95% confidence interval, 12-32 ms). With long-term dofetilide administration, tolerance develops with a half-life of 4.7 days. CONCLUSIONS: The current mechanism-based pharmacokinetic-pharmacodynamic model quantified the relationship between in vitro hERG channel blockade and clinical QT prolongation for dofetilide. This model may prove valuable for assessing the risk of QT prolongation in humans for other drugs that selectively block the hERG channel on the basis of in vitro assays and pharmacokinetic properties. SN - 0009-9236 UR - https://www.unboundmedicine.com/medline/citation/15961988/A_pharmacokinetic_pharmacodynamic_model_for_the_quantitative_prediction_of_dofetilide_clinical_QT_prolongation_from_human_ether_a_go_go_related_gene_current_inhibition_data_ L2 - https://doi.org/10.1016/j.clpt.2005.02.004 DB - PRIME DP - Unbound Medicine ER -