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A model based assessment of the CYP2B6 and CYP2C19 inductive properties by artemisinin antimalarials: implications for combination regimens
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy. (Farmakometri)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy. (Farmakometri)
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2008 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 35, no 2, 203-217 p.Article in journal (Refereed) Published
Abstract [en]

The study aim was to assess the inductive properties of artemisinin antimalarials using mephenytoin as a probe for CYP2B6 and CYP2C19 enzymatic activity. The population pharmacokinetics of S-mephenytoin and its metabolites S-nirvanol and S-4'-hydroxymephenytoin, including enzyme turn-over models for induction, were described by nonlinear mixed effects modeling. Rich data (8-16 samples/occasion/subject) were collected from 14 healthy volunteers who received mephenytoin before and during ten days of artemisinin administration. Sparse data (3 samples/occasion/subject) were collected from 74 healthy volunteers who received mephenytoin before, during and after five days administration of artemisinin, dihydroartemisinin, arteether, artemether or artesunate. The production rate of CYP2B6 was increased 79.7% by artemisinin, 61.5% by arteether, 76.1% by artemether, 19.9% by dihydroartemisinin and 16.9% by artesunate. The production rate of CYP2C19 increased 51.2% by artemisinin, 14.8% by arteether and 24.9% by artemether. In conclusion, all studied artemisinin derivatives induced CYP2B6. CYP2C19 induction by arteether and artemether as well as CYP2B6 and CYP2C19 induction by artemisinin was confirmed. The inductive capacity is different among the artemisinin drugs, which is of importance when selecting drugs to be used in antimalarial combination therapy such that the potential for drug-drug interactions is minimized.

Place, publisher, year, edition, pages
2008. Vol. 35, no 2, 203-217 p.
Keyword [en]
artemisinin, cytochrome P450, induction, malaria, pharmacokinetics
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-96697DOI: 10.1007/s10928-008-9084-6ISI: 000256013500004PubMedID: 18350255OAI: oai:DiVA.org:uu-96697DiVA: diva2:171356
Available from: 2008-02-06 Created: 2008-02-06 Last updated: 2011-11-30Bibliographically approved
In thesis
1. Pharmacokinetic drug-drug interactions in the management of malaria, HIV and tuberculosis
Open this publication in new window or tab >>Pharmacokinetic drug-drug interactions in the management of malaria, HIV and tuberculosis
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Malaria, Human Immunodeficiency Virus (HIV) and tuberculosis (TB) are global health problems having their worst situation in sub-Saharan Africa. Consequently, concomitant use of antimalarial, antiretroviral and antitubercular drugs may be needed, resulting in a potential risk of drug-drug interactions.

Cytochrome P-450 (CYP) enzyme induction/inhibition may lead to drug-drug interactions and can be detected by probe drugs. An analytical method was developed for the quantitation of mephenytoin, CYP2B6 and CYP2C19 probe, and its metabolites.

Induction/inhibition of principal CYP enzymes by the antimalarials; artemisinin, dihydroartemisinin, arteether, artemether and artesunate, was evaluated using the 4-hour plasma concentration ratios of probe drugs and their metabolites along with modelling the population pharmacokinetics of S-mephenytoin and its metabolites. The extent of change in enzymatic activities was different among the antimalarials, with artemisinin having strongest capacity for induction and inhibition, consequently, the strongest potential risk for drug-drug interactions.

Drug-drug interactions between the antitubercular rifampicin and the antiretrovirals nevirapine and lopinavir were assessed, in TB/HIV patients, by developing population pharmacokinetic models. Rifampicin increased nevirapine oral clearance. Simulations suggested that increasing the nevirapine dose to 300 mg twice daily when co-administered with rifampicin, would result in nevirapine concentrations above subtherapeutic levels, with minimum exposure above the recommended maximum concentration. Lopinavir is co-formulated with ritonavir in the ratio of 4:1. In children, increasing ritonavir dose four times did not completely compensate the enhancement of lopinavir oral clearance caused by rifampicin. However, the predicted lopinavir trough concentration was above the recommended minimum therapeutic concentration.

The work presented in this thesis followed an investigation line though not done for a particular drug. First the CYP enzymes involved in the interaction are identified. Afterwards, the expected drug-drug interaction is investigated where the potentially interacting drugs are concomitantly administered and an adjustment in the dose regimen is proposed that is subsequently evaluated.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 64 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 68
Keyword
Pharmacokinetics/Pharmacotherapy, Pharmacokinetics, Drug-drug interactions, Cytochrome P-450, Artemisinin antimalarials, Nevirapine, Lopinavir, Rifampicin, NONMEM, Farmakokinetik/Farmakoterapi
Identifiers
urn:nbn:se:uu:diva-8426 (URN)978-91-554-7080-7 (ISBN)
Public defence
2008-02-28, B22, BMC, Uppsala, 09:15
Opponent
Supervisors
Available from: 2008-02-06 Created: 2008-02-06Bibliographically approved

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Karlsson, Mats O.Simonsson, Ulrika S. H.

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