Lopinavir/ritonavir exposure in treatment-naive HIV-infected children following twice or once daily administration

Malaria and HIV infection are coendemic in a large portion of the world and remain a major cause of morbidity and mortality. Growing resistance of Plasmodium species to existing therapies has increased the need for new therapeutic approaches. The Plasmodium glucose transporter PfHT is known to be essential for parasite growth and survival. We have previously shown that HIV protease inhibitors (PIs) act as antagonists of mammalian glucose transporters. While the PI lopinavir is known to have antimalarial activity, the mechanism of action is unknown. We report here that lopinavir blocks glucose uptake into isolated malaria parasites at therapeutically relevant drug levels. Malaria parasites depend on a constant supply of glucose as their primary source of energy, and decreasing the available concentration of glucose leads to parasite death. We identified the malarial glucose transporter PfHT as a target for inhibition by lopinavir that leads to parasite death. This discovery provides a mechanistic basis for the antimalarial effect of lopinavir and provides a direct target for novel drug design with utility beyond the HIV-infected population.

Section: Resultsmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

The Glucose Transporter PfHT1 Is an Antimalarial Target of the HIV Protease Inhibitor Lopinavir

Kraft

Armstrong

Heitmeier

et al. 2015

“…A second study was then conducted on treatment-naive children infected by HIV and showed equivalence of pharmacokinetics between the two dosing schedules. High variability and low trough concentrations (C trough ) for the QD regimen suggested that therapeutic drug monitoring (TDM) is necessary to ensure adequate concentrations (19).Lopinavir alone has a poor oral bioavailability and needs to be coadministered with subtherapeutic doses of ritonavir. The absolute bioavailability of LPV/r in humans remains unknown.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Pharmacokinetics and Virological Efficacy after Switch to Once-Daily Lopinavir-Ritonavir in Treatment-Experienced HIV-1-Infected Children

Foissac

Urien

Hirt

et al. 2011

Lopinavir-ritonavir (LPV/r) is a protease inhibitor that is used twice daily (BID) in the treatment of HIV infection in children.In the context of a single-center observational study, a switch to a once-a-day (QD) LPV/r regimen was proposed for considerations of convenience and to support adherence. The aims of this study were to compare the pharmacokinetics, viral loads, percentages of CD4 ؉ T cells, and lipid profiles after switching from a twice-daily to a once-daily regimen of LPV/r in experienced children. For this purpose, LPV concentrations, viral loads, CD4؉ T cells, and biochemistry data were measured in routine therapeutic drug monitoring procedures in 45 children and adolescents. Thirty-six children were switched to the QD regimen. Nine children on the BID or QD regimen were added for pharmacokinetic-study purposes only. The QD trough concentrations (C trough ) of lopinavir in plasma were significantly lower than those observed with the BID regimen (P < 0.0001), but the 24-h exposure levels were not significantly lower with the QD than with the BID regimen (P ‫؍‬ 0.09). Among 34 evaluable patients who switched from the BID to the QD regimen, the virological efficacy of LPV/r appeared to differ (P < 0.001), with 74% and 57% of viral loads, respectively, being <50 copies/ml (mean follow-up times, 33 and 20 months). Among 22 patients with stable virological control before the switch, 12 experienced either failure or blip (one observation of detectable viral load between two observations of undetectable viral load) after the switch. The change from the BID to the QD regimen did not result in significant differences in CD4 ؉ T cell percentages or total cholesterol, high-density lipoprotein (HDL) cholesterol, or triglyceride levels. The switch from the BID to the QD LPV/r regimen led to equivalent exposure and lower C trough values and resulted in lower levels of virological control in these antiretroviral-experienced children.Lopinavir-ritonavir (LPV/r) is the protease inhibitor that is most used in children today, administered twice daily (BID) and usually combined with two nucleoside analogues. The protease inhibitor LPV/r has been approved by the European Medicines Agency (EMEA) for children aged at least 2 years (8) and by the U.S. Food and Drug Administration (FDA) for children aged at least 14 days and older (1). LPV/r has demonstrated durable antiviral activity in antiretroviral (ARV)-naïve and protease inhibitor-experienced children, with viral suppression (HIV-1 RNA at Ͻ50 copies/ml) in more than 60% of the population treated (60 to 80% of adults demonstrated suppression in previous studies) (6,20). Since 2006, LPV/r has been available as an oral solution or tablet, 200/50 mg or 100/25 mg, respectively.There is a general trend toward the simplification of treatment with once-a-day (QD) administration to improve convenience and patient adherence (13). The simplification of LPV/r dosage from 400/100 mg BID to 800/200 mg QD was studied initially in ARV-naïve adults and recently in experienced adults ...

“…In children and adolescents, doses as high as 467 mg/m 2 have been administered twice daily (13) and doses of 460 mg/m 2 once daily (35,40) have been administered without undue toxicity.…”

mentioning

confidence: 99%

Pharmacokinetics of High-Dose Lopinavir-Ritonavir with and without Saquinavir or Nonnucleoside Reverse Transcriptase Inhibitors in Human Immunodeficiency Virus-Infected Pediatric and Adolescent Patients Previously Treated with Protease Inhibitors

Robbins

Capparelli

Chadwick

et al. 2008

Human immunodeficiency virus (HIV)-In 16 subjects with SQV added, the SQV median AUC was 33.7 (range, 4.4 to 76.5) g ⅐ h/ml and the median SQV C trough was 2.1 (range, 0.2 to 4.1) g/ml. At week 24, 18 of 26 (69%) subjects remained in the study. Between weeks 24 and 48, one subject withdrew for nonadherence and nine withdrew for persistently high virus load. In antiretroviral-experienced children and adolescents with HIV, high doses of LPV/r with or without SQV offer safe options for salvage therapy, but the modest virologic response and the challenge of adherence to a regimen with a high pill burden may limit the usefulness of this approach.