Additional file 1: of Effects of repurposed drug candidates nitroxoline and nelfinavir as single agents or in combination with erlotinib in pancreatic cancer cells
Serena VeschiLaura De LellisRosalba FlorioPaola LanutiAlberto MassucciNicola TinariMichele De TursiPierluigi Di SebastianoMarco MarchisioClara NatoliAlessandro Cama
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Table S1. Effects of erlotinib, nelfinavir and nitroxoline as single agents versus drug combinations on cell viability. (XLSX 12 kb)Keywords:
Nelfinavir
We studied the pharmacokinetics and pharmacodynamics of nelfinavir administered 2 or 3 times per day to human immunodeficiency virus type 1 (HIV-1)-infected children receiving highly active antiretroviral therapy containing nelfinavir. The geometric mean trough concentrations of nelfinavir for the thrice- and twice-daily regimens were 1.55 mg/L and 1.11 mg/L, respectively (P=not significant). Nelfinavir concentrations did not correlate with total daily dose, dose per kilogram of weight, age, weight, previous protease inhibitor (PI) experience, or CD4(+) cell percentage. In the 25 PI-naive children, the virus load reductions at 24 weeks of treatment with the twice- and thrice-daily regimens were comparable. A significantly higher percentage of children in the twice-daily group had a trough concentration of nelfinavir of less than the inhibitory concentration of 95% (P=.042). The decrease in the virus load at 24 weeks of treatment was not correlated with the trough concentration of nelfinavir. The variability of trough concentrations was extremely high, particularly among recipients of the twice-daily regimen, resulting in a higher number of patients with subinhibitory concentrations of nelfinavir in this group.
Nelfinavir
Pharmacodynamics
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Protease inhibitor (pharmacology)
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Nelfinavir
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Nelfinavir
Protease inhibitor (pharmacology)
Saquinavir
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Nelfinavir
Stavudine
Indinavir
Saquinavir
Protease inhibitor (pharmacology)
Regimen
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To review the clinical pharmacology, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage guidelines of nelfinavir mesylate.A MEDLINE search restricted to English-language literature from January 1966 to February 1998 and an extensive review of journals was conducted to prepare this article. MeSH headings included protease inhibitors, nelfinavir mesylate, and AG1343. Abstracts presented at meetings and data submitted to the Food and Drug Administration (FDA) were also reviewed.The data on efficacy, pharmacokinetics, adverse effects, and drug interactions were obtained from in vitro studies, as well as open-label and controlled trials.Nelfinavir inhibits HIV protease enzyme resulting in formation of immature and noninfectious virions. In combination with nucleoside reverse transcriptase inhibitors, nelfinavir is effective in reducing the viral load below the quantifiable limit (< 500 copies/mL) and increasing the mean CD4+ cell count. This antiviral effect is sustained at least over 21 months. The bioavailability of nelfinavir ranges from 20% to 80%, and it increases when nelfinavir is administered with food. Following multiple dosing of nelfinavir 750 mg three times daily, maximum concentration at steady-state was 3-4 micrograms/mL and minimum concentration was 1-3 micrograms/mL. The elimination half-life for nelfinavir ranges from three to five hours. Nelfinavir is primarily metabolized in the liver by the cytochrome P450 isoenzymes and excreted in the feces. Current dosing recommendations are 750 mg three times daily for adults and adolescents and 20-30 mg/kg/dose three times daily for children aged 2-13 years. Studies of twice-daily regimens in adults are being conducted and are promising. Use of nelfinavir as salvage therapy is also being studied. Some of the commonly reported adverse events of nelfinavir are diarrhea, nausea, vomiting, and abdominal pain.Despite the limited published data, the FDA has approved nelfinavir in combination therapy for the treatment of HIV infection. The choice of antiretroviral (ARV) regimens should be made based on the risk of disease progression as indicated by HIV RNA concentrations and CD4+ cell counts, patients' previous ARV experiences and responses, concomitant drug therapy, compliance history, underlying disease states, and adverse reaction history.
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Nelfinavir is an inhibitor of the HIV-1 and HIV-2 protease, with good in vivo activity in HIV-infected patients. Nelfinavir is used in combination with other antiretroviral medications as part of a potent antiretroviral regimen. When used in this manner, 50 - 75% of patients who are naïve to antiretroviral therapy have plasma HIV RNA levels below the limit of detection (<< 400 copies) after 12 months of treatment. This use of nelfinavir in combination regimens is associated with an increase of almost 200/mm3 CD4+ lymphocytes at 12 months of therapy. Initial trials and clinical experience indicate that nelfinavir is equipotent to other potent protease inhibitors (PIs). The drug is well-tolerated, with mild diarrhoea being the most common side effect in 12 - 20% of patients. Virologic failure of nelfinavir is associated with genotypic and phenotypic changes that have a unique pattern that may retain susceptibility to other PIs. The results of small, non-controlled trials suggest these failures can be rescued with a second protease-based regimen. Due to the above characteristics, nelfinavir has become the most frequently prescribed first line PI.
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Indinavir
Saquinavir
Lopinavir
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HIV-seronegative subjects with hepatic impairment (6 mild, 6 moderate) and 12 matched healthy controls received nelfinavir 1250 mg every 12 hours with food for 2 weeks. Mild impairment did not significantly change nelfinavir or major metabolite (M8) steady-state exposures compared with controls. In subjects with moderate impairment, steady-state area under the plasma concentration time-curve over the dosing interval and maximum observed plasma concentrations were 62% and 22% higher for nelfinavir than for controls, and for M8 were 46% and 35% of control values. With increasing degree of impairment, no trend toward increase in unbound nelfinavir was observed, but there was an increase in unbound M8 levels. Nelfinavir was safe and well tolerated. One subject with moderate impairment was discontinued because of transient leucopenia. Observed changes are unlikely to affect nelfinavir efficacy or markedly influence safety. Dose reduction of nelfinavir does not appear necessary for subjects with mild/moderate impairment. Further long-term evaluations of nelfinavir pharmacokinetics and safety in HIV-seropositive subjects with hepatic impairment may be useful.
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Virological failure to protease inhibitor (PI)-based antiretroviral regimens is often not explained by the selection of PI resistance mutations. The role of low PI plasma levels in treatment failure was assessed in 30 patients failing nelfinavir-containing triple combinations. Approximately a third of the patients showed sub-therapeutic nelfinavir plasma levels. More than two-thirds of them had no drug resistance mutations, suggesting that insufficient nelfinavir levels contributed to treatment failure. Virological failure to highly active antiretroviral therapy has been associated with low drug potency, the selection of drug-resistant variants, poor adherence to medication, or low drug exposure [1–4]. Overall, up to 35% of patients taking protease inhibitors (PI) without ritonavir boosting might have inadequate drug concentrations [5]. In a previous study [6], we demonstrated that virological failure in drug-naive patients taking nelfinavir as part of a first PI-based triple combination was associated with primary PI resistance mutations in only 27% of patients. In order to assess whether their virological failure could be related to low nelfinavir exposure, nelfinavir plasma trough concentrations were determined in samples collected at the time of viral rebound. Thirty patients were included in the study. All patients were taking nelfinavir 1200 mg twice a day plus two nucleoside reverse transcriptase inhibitors. They were seen regularly in the outpatient clinic every 3 months. Blood samples were drawn before the morning dose intake (trough concentration). Nelfinavir plasma concentrations were determined using a validated high-performance liquid chromatography method with ultraviolet detection [7]. Nelfinavir trough concentrations above 0.7 μg/ml were considered to be therapeutic, in accordance with previous reports [8]. HIV genotyping was performed using an automatic sequencer (ABI Prism 3100, Applied Biosystems, Foster City, CA, USA) for detecting drug resistance mutations. Treatment failure occurred at a median time of 13 months (4–32) after initiating nelfinavir, and the median plasma HIV-RNA level at the time of viral rebound was 4180 copies/ml. The results of the study are summarized in Table 1. Out of 20 patients for whom both nelfinavir plasma levels and HIV genotyping were available, seven (35%) were found to have sub-therapeutic nelfinavir plasma levels. Of note is the fact that in six patients those levels were undetectable, and in one were 0.5 μg/ml. Primary PI-associated resistance mutations were found in only one of the seven individuals (14%) with sub-therapeutic nelfinavir concentrations, whereas they were found in four out of 13 patients (30%) with adequate nelfinavir concentrations. It should be pointed out that drug resistance mutations were absent either in the protease or the reverse transcriptase genes in five out of seven patients with sub-therapeutic nelfinavir concentrations.Table 1: Resistance mutations and nelfinavir plasma concentrations.In line with other recent studies [9,10], our results highlight the importance of keeping adequate PI plasma levels in order to maintain a maximal HIV suppression. Sub-therapeutic nelfinavir plasma levels could explain the virological failure in approximately a third of our patients. Given that the majority of these individuals had undetectable nelfinavir plasma concentrations, a lack of adherence to the medication was the most likely cause of their sub-therapeutic drug levels. This hypothesis was supported by the lack of recognition of nelfinavir-associated resistance mutations in these individuals. Although other causes such as impaired gut absorption or drug interactions could also been involved, the lack of recognition of any nelfinavir trace in our patients strongly suggests that they were not taking the prescribed medication. Whereas low nelfinavir plasma levels represented the only identified factor involved in treatment failure in 20% of our patients, the presence of nucleoside reverse transcriptase inhibitor resistance mutations probably contributed to failure in another 10% of cases. It has been well established that the interplay between low plasma drug levels and resistance mutations may finally lead to virological failure. Incomplete HIV suppression in individuals with sub-therapeutic PI levels sets the ground for the selection of mutations. In a small subset of our patients neither nelfinavir resistance nor insufficient nelfinavir plasma levels could explain virological failure. In this situation, however, it may be argued that a single determination of nelfinavir plasma levels could be not enough to ascertain a good compliance for a long period of time. In summary, our results support the usefulness of measuring drug levels in patients on virological failure taking nelfinavir-based regimens. The utility of therapeutic drug monitoring (TDM) has previously been reported in the ATHENA study [11], a trial in which the use of TDM as a part of clinical care provided a better virological outcome as well as fewer treatment discontinuations as a result of toxicity. When integrating the information of TDM with that of HIV genotyping, drug regimens might be modified in a more rational fashion.
Nelfinavir
Lopinavir
Saquinavir
Protease inhibitor (pharmacology)
Ritonavir
Indinavir
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Nelfinavir is a novel protease inhibitor that exhibits good inhibitory activity against human immunodeficiency virus type 1 (HIV-1) and is currently used in combination with reverse transcriptase inhibitors for the management of HIV infection. In this study we analysed the pharmacokinetic profile of nelfinavir after multiple oral doses in 18 HIV-infected patients during a combination regimen of nelfinavir plus efavirenz and stavudine. Patients who received the study drug for ≥4 weeks were considered for pharmacokinetic evaluation. Blood samples were obtained at the following times: 0 (before nelfinavir administration), 1, 2, 3, 4, 6 and 8 h after administration. Nelfinavir plasma concentrations were analysed by a specific and validated HPLC assay with ultraviolet detection. Nelfinavir concentration–time data were analysed by compartmental and non-compartmental techniques and the pharmacokinetic parameters of nelfinavir were determined according to a one-compartment model. We found a high variability between individuals in nelfinavir plasma concentrations. The mean average drug plasma concentration was 2.22 ± 1.25 mg/L and the mean AUC during the dosing interval was 17.7 ± 10.0 mg•h/L. The mean nelfinavir trough plasma concentration was 1.58 ± 1.0 mg/L. A good relationship was found between AUC0–8h and the plasma concentrations measured at 6 h, and the trough plasma concentrations made total body exposure for nelfinavir less predictable. Alternatively, a 2 h abbreviated AUC provides a good estimate of the full AUC0–8h. Comparing the pharmacokinetic parameters obtained in our patients with those reported for patients receiving nelfinavir monotherapy or nelfinavir combined with nucleoside analogues, one observes substantial overlap with nelfinavir concentrations achieved without efavirenz.
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Efavirenz
Stavudine
Therapeutic Drug Monitoring
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