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Population pharmacokinetics of lopinavir and ritonavir in combination with rifampicin-based antitubercular treatment in HIV-infected children
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2012 (English)In: Antiviral Therapy, ISSN 1359-6535, Vol. 17, no 1, 25-33 p.Article in journal (Refereed) Published
Abstract [en]

Background: The preferred antiretroviral regimen for young children previously exposed to non-nucleoside reverse transcriptase inhibitors is lopinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors. Rifampicin-based antitubercular treatment reduces lopinavir concentrations. Adding extra ritonavir to lopinavir/ritonavir overcomes the effect of rifampicin, however this approach is not feasible in many settings.

Methods: We developed an integrated population model describing lopinavir and ritonavir pharmacokinetics to predict lopinavir/ritonavir (4:1) doses achieving target lopinavir exposures in children treated for tuberculosis. The model included data from 15 children given 'superboosted' lopinavir (lopinavir/ritonavir = 1:1) and 20 children given twice the standard dose of lopinavir/ritonavir every 12 h during antitubercular treatment, and from children given standard lopinavir/ritonavir doses every 12 h (39 without tuberculosis and 11 sampled again after antitubercular treatment).

Results: A one-compartment model with first-order absorption and elimination best described the pharmacokinetics of lopinavir and a one-compartment model with transit absorption compartments described ritonavir pharmacokinetics. The dynamic influence of ritonavir concentration on lopinavir oral clearance was modelled as direct inhibition with an E-max model. Antitubercular treatment reduced the oral bioavailability of lopinavir by 77% in children receiving twice usual lopinavir/ritonavir doses and increased ritonavir clearance by 50%. Simulations predicted that respective 27, 21, 20 and 18 mg/kg 8-hourly doses of lopinavir (in lopinavir/ritonavir, 4: 1) maintains lopinavir concentrations > 1 mg/l in at least 95% of children weighing 3-5.9, 6-9.9, 10-13.9 and 14-19.9 kg.

Conclusions: The model describing the interactions between lopinavir, ritonavir and rifampicin in young children predicted feasible 8-hourly doses of lopinavir/ritonavir resulting in therapeutic lopinavir concentrations during antitubercular treatment.

Place, publisher, year, edition, pages
2012. Vol. 17, no 1, 25-33 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-175511DOI: 10.3851/IMP1915ISI: 000303652200004OAI: oai:DiVA.org:uu-175511DiVA: diva2:531950
Available from: 2012-06-08 Created: 2012-06-08 Last updated: 2012-06-08Bibliographically approved

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Karlsson, Mats OSimonsson, Ulrika S. H.
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