uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Population pharmacokinetics of lopinavir in combination with rifampicin-based antitubercular treatment in HIV-infected South African children
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Show others and affiliations
2010 (English)In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 66, no 10, 1017-1023 p.Article in journal (Refereed) Published
Abstract [en]

The population pharmacokinetics (PK) of lopinavir in tuberculosis (TB)/human immunodeficiency virus (HIV) co-infected South African children taking super-boosted lopinavir (lopinavir/ritonavir ratio 1:1) as part of antiretroviral treatment in the presence of rifampicin were compared with the population PK of lopinavir in HIV-infected South African children taking standard doses of lopinavir/ritonavir (ratio 4:1).

Lopinavir concentrations were measured in 15 TB/HIV-co-infected paediatric patients who were sampled during and after rifampicin-based TB treatment and in 15 HIV-infected children without TB. During TB therapy, the dose of ritonavir was increased to lopinavir/ritonavir 1:1 in order to compensate for the induction of rifampicin. The children received median (interquartile range=IQR) doses of lopinavir 292 mg/m(2) (274, 309) and ritonavir 301 mg/m(2) (286, 309) twice daily. After TB treatment completion the children received standard doses of lopinavir/ritonavir 4:1 (median [IQR] lopinavir dose 289 mg/m(2) [286, 303] twice daily) as did those without TB (median [IQR] lopinavir dose 265 mg/m(2) [249, 289] twice daily).

Lopinavir oral clearance (CL/F) was about 30% lower in children without TB than in co-infected children treated with super-boosted lopinavir. However, the predicted lopinavir C-min was above the recommended minimum therapeutic concentration during TB/HIV co-treatment in the 15 children. Lopinavir CL/F increased linearly during the dosing interval.

Increasing the ritonavir dose to achieve a lopinavir/ritonavir ratio of 1:1 when given in combination with rifampicin-based TB treatment did not completely compensate for the enhancement of lopinavir CL/F caused by rifampicin. The time-dependent lopinavir CL/F might be due to a time-dependent recovery from ritonavir inhibition of lopinavir metabolism during the dosing interval.

Place, publisher, year, edition, pages
2010. Vol. 66, no 10, 1017-1023 p.
Keyword [en]
Lopinavir, Ritonavir, Pharmacokinetics, HIV, Tuberculosis
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-96699DOI: 10.1007/s00228-010-0847-9ISI: 000281947300006PubMedID: 20552180OAI: oai:DiVA.org:uu-96699DiVA: diva2:171358
Uppdaterad från Manuskript till Artikel; 20101202Available from: 2008-02-06 Created: 2008-02-06 Last updated: 2011-03-01Bibliographically 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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 68
Pharmacokinetics/Pharmacotherapy, Pharmacokinetics, Drug-drug interactions, Cytochrome P-450, Artemisinin antimalarials, Nevirapine, Lopinavir, Rifampicin, NONMEM, Farmakokinetik/Farmakoterapi
urn:nbn:se:uu:diva-8426 (URN)978-91-554-7080-7 (ISBN)
Public defence
2008-02-28, B22, BMC, Uppsala, 09:15
Available from: 2008-02-06 Created: 2008-02-06Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Simonsson, Ulrika S H
By organisation
Department of Pharmaceutical Biosciences
In the same journal
European Journal of Clinical Pharmacology
Pharmaceutical Sciences

Search outside of DiVA

GoogleGoogle Scholar

Altmetric score

Total: 231 hits
ReferencesLink to record
Permanent link

Direct link