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Combinations of QTc-prolonging drugs: towards disentangling pharmacokinetic and pharmacodynamic effects in their potentially additive nature.
Meid, Andreas D; Bighelli, Irene; Mächler, Sarah; Mikus, Gerd; Carrà, Giuseppe; Castellazzi, Mariasole; Lucii, Claudio; Martinotti, Giovanni; Nosè, Michela; Ostuzzi, Giovanni; Barbui, Corrado; Haefeli, Walter E.
Affiliation
  • Meid AD; Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
  • Bighelli I; WHO Collaborating Center for Research and Training in Mental Health and Service Evaluation, University of Verona, Verona, Italy.
  • Mächler S; Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
  • Mikus G; Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
  • Carrà G; Division of Psychiatry, University College of London, UK Department of Medicine and Surgery, University of Milano Bicocca, Milan, Italy.
  • Castellazzi M; WHO Collaborating Center for Research and Training in Mental Health and Service Evaluation, University of Verona, Verona, Italy.
  • Lucii C; Department of Mental Health, Company Health-ULS7-Siena, Siena, Italy.
  • Martinotti G; Department of Neuroscience, Imaging and Clinical Sciences, University of Chieti, Chieti, Italy.
  • Nosè M; WHO Collaborating Center for Research and Training in Mental Health and Service Evaluation, University of Verona, Verona, Italy.
  • Ostuzzi G; WHO Collaborating Center for Research and Training in Mental Health and Service Evaluation, University of Verona, Verona, Italy.
  • Barbui C; WHO Collaborating Center for Research and Training in Mental Health and Service Evaluation, University of Verona, Verona, Italy.
  • Haefeli WE; Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
Ther Adv Psychopharmacol ; 7(12): 251-264, 2017 Dec.
Article in En | MEDLINE | ID: mdl-29201344
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Type of study: Prognostic_studies / Risk_factors_studies Language: En Journal: Ther Adv Psychopharmacol Year: 2017 Document type: Article Affiliation country: Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Type of study: Prognostic_studies / Risk_factors_studies Language: En Journal: Ther Adv Psychopharmacol Year: 2017 Document type: Article Affiliation country: Country of publication: