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The effects of dose staggering on metabolic drug-drug interactions
Academic Unit of Molecular Pharmacology & Pharmacogenetics, Division of Clinical Sciences (South), University of Sheffield.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)ORCID iD: 0000-0003-3531-9452
Academic Unit of Molecular Pharmacology & Pharmacogenetics, Division of Clinical Sciences (South), University of Sheffield.
Academic Unit of Molecular Pharmacology & Pharmacogenetics, Division of Clinical Sciences (South), University of Sheffield.
2003 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 20, no 2, 223-232 p.Article in journal (Refereed) Published
Abstract [en]

PURPOSE

To investigate the effect of dose staggering on metabolic drug-drug interactions (MDDI).

METHODS

Using Matlab, anatomical, physiological and biochemical data relating to human pharmacokinetics were integrated to create a representative virtual healthy subject relevant to in vivo studies. The effects of dose staggering on AUC and C(max) were investigated under various scenarios with respect to pharmacokinetic characteristics of the inhibitor and substrate drugs (e.g. hepatic extraction ratio). Specific cases were also simulated where MDDI had been studied experimentally for combinations of drugs (budesonide and ketoconazole; triazolam and itraconazole).

RESULTS

The decrease in the magnitude of the inhibitory effect of the 'perpetrator' drug (inhibitor) on the 'victim' drug (substrate) as a result of 'dose staggering' was greater when the 'perpetrator' was given after the 'victim'. There was reasonable agreement between the predicted extent of the interactions and the observed in vivo data (mean prediction errors of 25 and -14% for AUC and C(max) values, respectively (n=7)). The impact of dose staggering was minimal during continuous dosage of inhibitors with long elimination half-lives (e.g. itraconazole, >20 h).

CONCLUSIONS

Clinical trial simulations using physiological information may provide useful guidelines for optimal dose staggering when poly-pharmacy is inevitable.

Place, publisher, year, edition, pages
Elsevier, 2003. Vol. 20, no 2, 223-232 p.
Keyword [en]
Dose staggering, drug–drug interactions, enzyme inhibition, simulation, ketoconazole, itraconazole
National Category
Other Medical Sciences not elsewhere specified
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
URN: urn:nbn:se:uu:diva-168500DOI: 10.1016/S0928-0987(03)00200-8ISI: 000186221300008PubMedID: 14550889OAI: oai:DiVA.org:uu-168500DiVA: diva2:499031
Available from: 2012-02-13 Created: 2012-02-13 Last updated: 2017-12-07

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Kjellsson, Maria

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