Combinations of QTc-prolonging drugs: towards disentangling pharmacokinetic and pharmacodynamic effects in their potentially additive nature
Autor: | A. D. Meid, I. Bighelli, S. Mächler, G. Mikus, G. Carrà, M. Castellazzi, C. Lucii, G. Martinotti, M. Nosè, G. Ostuzzi, T. Acciavatti, A. Adamo, A. Aguglia, C. Albanese, S. Baccaglini, F. Bardicchia, R. Barone, Y. Barone, F. Bartoli, C. Bergamini, F. Bertolini, S. Bolognesi, A. Bordone, P. Bortolaso, M. Bugliani, C. Calandra, S. Calò, G. Cardamone, M. Caroleo, E. Carra, D. Carretta, L. Chiocchi, E. Cinosi, M. Clerici, M. Corbo, E. Corsi, R. Costanzo, G. Costoloni, F. D’Arienzo, S. Debolini, A. De Capua, W. A. Di Napoli, M. Dinelli, E. Facchi, F. Fargnoli, F. Fiori, A. Franchi, F. Gardellin, C. Gastaldon, E. Gazzoletti, L. Ghio, M. Giacomin, M. Gregis, N. Iovieno, D. Koukouna, A. Lax, C. Lintas, A. Luca, M. Luca, M. Lussetti, M. Madrucci, N. Magnani, L. Magni, E. Manca, C. Martorelli, R. Mattafirri, C. Paladini, D. Papola, M. Percudani, G. Perini, P. Petrosemolo, M. Pezzullo, S. Piantanida, F. Pinna, K. Prato, D. Prestia, D. Quattrone, C. Reggianini, F. Restaino, M. Ribolsi, G. Rinosi, C. Rizzo, R. Rizzo, M. Roggi, G. Rossi, S. Rossi, S. Ruberto, M. Santi, R. Santoro, G. Sepede, M. S. Signorelli, F. Soscia, P. Staffa, M. Stilo, S. Strizzolo, F. Suraniti, N. Tavian, L. Tortelli, F. Tosoni, M. Valdagno, V. Zanobini, C. Barbui, W. E. Haefeli |
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Přispěvatelé: | Meid, A, Bighelli, I, Mächler, S, Mikus, G, Carrà, G, Castellazzi, M, Lucii, C, Martinotti, G, Nosè, M, Ostuzzi, G, Acciavatti, T, Adamo, A, Aguglia, A, Albanese, C, Baccaglini, S, Bardicchia, F, Barone, R, Barone, Y, Bartoli, F, Bergamini, C, Bertolini, F, Bolognesi, S, Bordone, A, Bortolaso, P, Bugliani, M, Calandra, C, Calò, S, Cardamone, G, Caroleo, M, Carra, E, Carretta, D, Chiocchi, L, Cinosi, E, Clerici, M, Corbo, M, Corsi, E, Costanzo, R, Costoloni, G, D’Arienzo, F, Debolini, S, De Capua, A, Di Napoli, W, Dinelli, M, Facchi, E, Fargnoli, F, Fiori, F, Franchi, A, Gardellin, F, Gastaldon, C, Gazzoletti, E, Ghio, L, Giacomin, M, Gregis, M, Iovieno, N, Koukouna, D, Lax, A, Lintas, C, Luca, A, Luca, M, Lussetti, M, Madrucci, M, Magnani, N, Magni, L, Manca, E, Martorelli, C, Mattafirri, R, Paladini, C, Papola, D, Percudani, M, Perini, G, Petrosemolo, P, Pezzullo, M, Piantanida, S, Pinna, F, Prato, K, Prestia, D, Quattrone, D, Reggianini, C, Restaino, F, Ribolsi, M, Rinosi, G, Rizzo, C, Rizzo, R, Roggi, M, Rossi, G, Rossi, S, Ruberto, S, Santi, M, Santoro, R, Sepede, G, Signorelli, M, Soscia, F, Staffa, P, Stilo, M, Strizzolo, S, Suraniti, F, Tavian, N, Tortelli, L, Tosoni, F, Valdagno, M, Zanobini, V, Barbui, C, Haefeli, W |
Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: |
QT interval
medicine.medical_specialty electrocardiography 030204 cardiovascular system & hematology 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Internal medicine medicine cohort study 030212 general & internal medicine drug–drug interaction Pharmacology Toxicology and Pharmaceutics (miscellaneous) Original Research drug–drug interactions psychiatry medicine.diagnostic_test business.industry Pharmacodynamics Cardiology Psychology (miscellaneous) business Electrocardiography cohort study drug–drug interactions electrocardiography psychiatry QT interval Cohort study |
Zdroj: | Therapeutic Advances in Psychopharmacology |
Popis: | Background:Whether arrhythmia risks will increase if drugs with electrocardiographic (ECG) QT-prolonging properties are combined is generally supposed but not well studied. Based on available evidence, the Arizona Center for Education and Research on Therapeutics (AZCERT) classification defines the risk of QT prolongation for exposure to single drugs. We aimed to investigate how combining AZCERT drug categories impacts QT duration and how relative drug exposure affects the extent of pharmacodynamic drug–drug interactions.Methods:In a cohort of 2558 psychiatric inpatients and outpatients, we modeled whether AZCERT class and number of coprescribed QT-prolonging drugs correlates with observed rate-corrected QT duration (QTc) while also considering age, sex, inpatient status, and other QTc-prolonging risk factors. We concurrently considered administered drug doses and pharmacokinetic interactions modulating drug clearance to calculate individual weights of relative exposure with AZCERT drugs. Because QTc duration is concentration-dependent, we estimated individual drug exposure with these drugs and included this information as weights in weighted regression analyses.Results:Drugs attributing a ‘known’ risk for clinical consequences were associated with the largest QTc prolongations. However, the presence of at least two versus one QTc-prolonging drug yielded nonsignificant prolongations [exposure-weighted parameter estimates with 95% confidence intervals for ‘known’ risk drugs + 0.93 ms (–8.88;10.75)]. Estimates for the ‘conditional’ risk class increased upon refinement with relative drug exposure and co-administration of a ‘known’ risk drug as a further risk factor.Conclusions:These observations indicate that indiscriminate combinations of QTc-prolonging drugs do not necessarily result in additive QTc prolongation and suggest that QT prolongation caused by drug combinations strongly depends on the nature of the combination partners and individual drug exposure. Concurrently, it stresses the value of the AZCERT classification also for the risk prediction of combination therapies with QT-prolonging drugs. |
Databáze: | OpenAIRE |
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