Increased Dose of Lopinavir/Ritonavir Compensates for Efavirenz-Induced Drug-Drug Interaction in HIV-1-Infected Children

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: 60%

Section: Discussionmentioning

confidence: 99%

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

Kraft

Armstrong

Heitmeier

et al. 2015

“…Other studies have suggested that the currently recommended dose of LPV/RTV might result in suboptimal exposure in HIV-infected children (4,10,24). Based on our PK model and the LPV pharmacodynamic models by Hsu et al and Podzamczer et al (13,21), we have shown that the majority of children are unlikely to achieve therapeutic plasma LPV concentrations against virus that is moderately resistant to LPV, at degrees far below the clinical cutoffs suggested by current phenotypic resistance testing.…”

Section: Discussionmentioning

confidence: 57%

“…The recommended doses for children who weigh more than 15 kg are 10 mg/kg of body weight or 230 mg/m 2 (body surface area) twice daily, with a maximum of 400 mg per dose unless it is combined with drugs affecting cytochrome (CYP) P450 metabolism, which require LPV dose adjustment (4,28). Introduced as a salvage agent (22), LPV/RTV has become one of the preferred PI choices for first-line regimens in children Ͼ6 months of age in the countries with access to the drug.…”

mentioning

confidence: 99%

Population Pharmacokinetics of Lopinavir Predict Suboptimal Therapeutic Concentrations in Treatment-Experienced Human Immunodeficiency Virus-Infected Children

Rakhmanina¹,

Anker

Baghdassarian³

et al. 2009

In adult protease inhibitor (PI)-experienced patients, a lopinavir (LPV) phenotypic inhibitory quotient (PIQ) of >15 has been associated with a higher likelihood of viral suppression. The aims of this study were to develop a population pharmacokinetic (PK) model of LPV in children and to estimate the probability of achieving a PIQ of >15. HIV-infected, PI-experienced children receiving LPV were intensively sampled for 12 h to measure plasma LPV. The data were fitted to candidate PK models (using MM-USCPACK software), and the final model was used to simulate 1,000 children to determine the probability of achieving an LPV PIQ of >15. In 50 patients (4 to 18 years old), the median LPV plasma 12-hour-postdose concentration was 5.9 mg/liter (range, 0.03 to 16.2 mg/liter) lower than that reported in adults. After a delay, LPV was absorbed linearly into a central compartment whose size was dependent on the weight and age of the patient. Elimination was dependent on weight. The regression line of observed versus predicted LPV had an R 2 of 0.99 and a slope of 1.0. Visual predictive checks against all available measured concentrations showed good predictive ability of the model. The probability of achieving an LPV PIQ of >15 was >90% for wild-type virus but <10% for even moderately resistant virus. The currently recommended dose of LPV/ritonavir appears to be adequate for children infected with wild-type virus but is unlikely to provide adequate inhibitory concentrations for even moderately resistant human immunodeficiency virus (HIV). PI-experienced HIV-infected children will likely benefit from longitudinal, repeated LPV measurement in plasma to ensure that drug exposure is most often near the maximal end of the observed safe range.Lopinavir/ritonavir (LPV/RTV) (Kaletra) is the first and only coformulated RTV-boosted protease inhibitor (PI) approved for use in children. The recommended doses for children who weigh more than 15 kg are 10 mg/kg of body weight or 230 mg/m 2 (body surface area) twice daily, with a maximum of 400 mg per dose unless it is combined with drugs affecting cytochrome (CYP) P450 metabolism, which require LPV dose adjustment (4, 28). Introduced as a salvage agent (22), LPV/RTV has become one of the preferred PI choices for first-line regimens in children Ͼ6 months of age in the countries with access to the drug.Despite evidence for good antiviral efficacy among children in a clinical trial setting (16,17,23), the standard dose may not be adequate for every child. Noncompartmental analysis has shown that the average LPV plasma 12-hour-postdose concentration (C trough ) in children given the currently recommended pediatric dose of LPV is 67% lower than in adults (24). Recently, Jullien et al. published a population pharmacokinetics (PK) model of LPV in children aged 0 to 18 years (15). The model was based on a retrospective analysis of LPV plasma measurements in 157 children, with a median of 3 samples (range, 1 to 14) per patient, obtained for monitoring purposes after self-reported LPV intake. In t...

“…The pharmacokinetic interactions between efavirenz and PIs have been studied (11,12). Efavirenz induces cytochrome P450 and reduces PI concentrations, necessitating dosage changes (2). The combination of lopinavir-ritonavir and efavirenz was compared with nucleoside-based therapies.…”

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confidence: 99%

Pharmacokinetics of Darunavir at 900 Milligrams and Ritonavir at 100 Milligrams Once Daily when Coadministered with Efavirenz at 600 Milligrams Once Daily in Healthy Volunteers

Soon¹,

Shen

Yong

et al. 2010

Ritonavir-boosted darunavir with efavirenz may be considered a nucleoside-sparing regimen for treatmentnaïve HIV-infected patients. However, the pharmacokinetics of this combination administered once daily have not been studied. We conducted a three-period interaction study with healthy volunteers. The subjects were given darunavir at 900 mg with ritonavir at 100 mg once daily for 10 days. Efavirenz at 600 mg once daily was added for 14 days. Darunavir-ritonavir was then stopped and efavirenz alone was given for 14 days. At the end of each period, blood was taken predosing and for up to 24 h postdosing to measure the drug concentrations. We recruited seven males and five females ages 24 to 49 years and weighing 50 to 83 kg. The darunavir trough concentrations were reduced after efavirenz administration (geometric mean ratio The efavirenz half-life was significantly longer when it was coadministered with darunavir-ritonavir than when it was given alone (GMR, 1.66; 90% CI, 1.24 to 2.23; P ‫؍‬ 0.01), but there were no differences in the efavirenz trough or peak concentration or AUC 0-24 when it was coadministered with darunavir-ritonavir. Efavirenz reduced the trough concentrations of darunavir significantly, but the concentrations remained above the EC 50 for the wild-type virus. This regimen should be evaluated with treatment-naïve patients with no preexisting resistance.The treatment of HIV infection has been revolutionized by the advent of combination antiretroviral therapy (ARV), which suppresses viral replication and preserves immunological function. Currently recommended first-line combination therapy consists of two nucleoside reverse transcriptase inhibitors with either efavirenz or a ritonavir-boosted protease inhibitor (PI) (9).Much interest in the study of nucleoside-sparing regimens has been generated, in view of the toxicities of nucleosides and the development of resistance. The pharmacokinetic interactions between efavirenz and PIs have been studied (11,12). Efavirenz induces cytochrome P450 and reduces PI concentrations, necessitating dosage changes (2). The combination of lopinavir-ritonavir and efavirenz was compared with nucleoside-based therapies. This nucleoside-sparing regimen was found to cause more hyperlipidemia and was not as effective in patients with viral loads of Ͼ100,000 (17). It is also a twicedaily regimen and is not as convenient as current first-line therapies, which are mostly taken once daily.Darunavir (TMC114) is a new-generation PI with activity against viruses resistant to other PIs (7). The FDA-approved dose of darunavir-ritonavir is 600/100 mg twice daily for treatment-experienced HIV-infected patients and 800/100 once daily for treatment-naïve patients (14). Darunavir is metabolized by cytochrome P450 3A4 (CYP3A4) and is used in combination with ritonavir, which is a potent inhibitor of CYP3A4. When darunavir is boosted with ritonavir, the darunavir halflife is 15 h, thus allowing once-daily administration to treatment-naïve patients.Compared to lopinavir-ritonavir, darun...