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Journal articles on the topic 'Nelfinavir'

Author: Grafiati

Published: 4 June 2021

Last updated: 8 February 2022

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1

Bergshoeff, Alina S., Tom FW Wolfs, Sibyl PM Geelen, and David M. Burger. "Ritonavir-Enhanced Pharmacokinetics of Nelfinavir/M8 during Rifampin Use." Annals of Pharmacotherapy 37, no. 4 (April 2003): 521–25. http://dx.doi.org/10.1345/aph.1c335.

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OBJECTIVE: To describe a case of successful protease inhibitor–based highly active antiretroviral therapy (HAART) concomitant with rifampin. CASE SUMMARY: In a 7-month-old male infant with tuberculosis and HIV-1 infection, tuberculosis therapy including rifampin and HAART containing the protease inhibitor nelfinavir 40 mg/kg every 8 hours was started. Intensive steady-state pharmacokinetic sampling from baseline to 8 hours revealed very low plasma concentrations of nelfinavir: area under the plasma concentration–time curve (AUC0–24) <10% of adult population values for 750 mg every 8 hours and nonquantifiable concentrations of nelfinavir's principal metabolite (M8). Nelfinavir 40 mg/kg every 8 hours was then substituted with nelfinavir 30 mg/kg twice daily plus ritonavir 400 mg/m2 twice daily. Intensive steady-state (0–12 h) pharmacokinetic sampling was repeated. Nelfinavir concentrations had improved, but remained low when compared with adult population values of 1250 mg every 12 hours: AUC0–24 21.9 versus 47.6 mg/L•h (46%) and 12-hour trough level (C12) 0.25 versus 0.85 mg/L (29%). However, concentrations of M8 considerably exceeded population values: AUC0–24 57.5 versus 13.6 mg/L•h (443%) and C12 1.35 versus 0.28 mg/L (482%). Since M8 concentrations were highly elevated, pharmacokinetic parameters for (nelfinavir + M8) were used rather than those for nelfinavir alone. Thus, AUC0–24 (nelfinavir + M8) and C12 (nelfinavir + M8) comprised 130% and 142%, respectively of the adult population values. This, in addition to good clinical response and tolerability, favored continuation of the regimen. CONCLUSIONS: In an infant, nelfinavir-containing HAART was successfully used with rifampin after the addition of ritonavir. Ritonavir resolved the pharmacokinetic interaction between rifampin and nelfinavir by boosting nelfinavir and, especially, M8 concentrations. More research is needed to confirm these results.

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2

&NA;. "Nelfinavir." Reactions Weekly &NA;, no. 1200 (May 2008): 25. http://dx.doi.org/10.2165/00128415-200812000-00070.

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3

Jarvis, Blair, and Diana Faulds. "Nelfinavir." Drugs 56, no. 1 (1998): 147–67. http://dx.doi.org/10.2165/00003495-199856010-00013.

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4

Bardsley-Elliot, Anne, and Greg L. Plosker. "Nelfinavir." Drugs 59, no. 3 (March 2000): 581–620. http://dx.doi.org/10.2165/00003495-200059030-00014.

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5

Perry, Caroline M., James E. Frampton, Paul L. McCormack, M. Asif A. Siddiqui, and Risto S. Cvetkovi?? "Nelfinavir." Drugs 65, no. 15 (2005): 2209–44. http://dx.doi.org/10.2165/00003495-200565150-00015.

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6

&NA;. "Nelfinavir." Reactions Weekly &NA;, no. 788 (February 2000): 9. http://dx.doi.org/10.2165/00128415-200007880-00028.

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7

&NA;. "Nelfinavir." Reactions Weekly &NA;, no. 804 (June 2000): 10. http://dx.doi.org/10.2165/00128415-200008040-00026.

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8

&NA;. "Nelfinavir." Reactions Weekly &NA;, no. 814 (August 2000): 10. http://dx.doi.org/10.2165/00128415-200008140-00027.

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9

&NA;. "Nelfinavir." Drugs & Therapy Perspectives 10, no. 12 (December 1997): 7–9. http://dx.doi.org/10.2165/00042310-199710120-00003.

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10

&NA;. "Nelfinavir." Reactions Weekly &NA;, no. 733 (January 1999): 10–11. http://dx.doi.org/10.2165/00128415-199907330-00026.

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11

&NA;. "Nelfinavir." Reactions Weekly &NA;, no. 734 (January 1999): 9. http://dx.doi.org/10.2165/00128415-199907340-00026.

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12

&NA;. "Nelfinavir." Reactions Weekly &NA;, no. 705 (June 1998): 9. http://dx.doi.org/10.2165/00128415-199807050-00033.

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13

&NA;. "Nelfinavir." Reactions Weekly &NA;, no. 715 (August 1998): 9. http://dx.doi.org/10.2165/00128415-199807150-00026.

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14

&NA;. "Nelfinavir." Reactions Weekly &NA;, no. 1294 (March 2010): 28. http://dx.doi.org/10.2165/00128415-201012940-00086.

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15

&NA;. "Nelfinavir." Reactions Weekly &NA;, no. 736 (January 1999): 10. http://dx.doi.org/10.2165/00128415-199907360-00033.

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16

&NA;. "Nelfinavir." Reactions Weekly &NA;, no. 767 (September 1999): 10. http://dx.doi.org/10.2165/00128415-199907670-00033.

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17

&NA;. "Nelfinavir." Reactions Weekly &NA;, no. 768 (September 1999): 9. http://dx.doi.org/10.2165/00128415-199907680-00029.

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18

&NA;. "Nelfinavir." Reactions Weekly &NA;, no. 888 (February 2002): 10. http://dx.doi.org/10.2165/00128415-200208880-00031.

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19

&NA;. "Nelfinavir." Reactions Weekly &NA;, no. 908 (June 2002): 10. http://dx.doi.org/10.2165/00128415-200209080-00024.

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20

&NA;. "Nelfinavir." Reactions Weekly &NA;, no. 681 (December 1997): 10. http://dx.doi.org/10.2165/00128415-199706810-00029.

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21

Perry, Caroline M., and Paul Benfield. "Nelfinavir." Drugs 54, no. 1 (July 1997): 81–87. http://dx.doi.org/10.2165/00003495-199754010-00007.

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22

Breckenridge, Alasdair. "Nelfinavir." Drugs 54, no. 1 (July 1997): 88. http://dx.doi.org/10.2165/00003495-199754010-00008.

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23

Gathe, Joseph C. "Nelfinavir." Drugs 54, no. 1 (July 1997): 88. http://dx.doi.org/10.2165/00003495-199754010-00009.

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24

&NA;. "Nelfinavir." Reactions Weekly &NA;, no. 1127 (November 2006): 19. http://dx.doi.org/10.2165/00128415-200611270-00064.

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25

&NA;. "Nelfinavir." Reactions Weekly &NA;, no. 1156 (June 2007): 19. http://dx.doi.org/10.2165/00128415-200711560-00060.

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26

&NA;. "Nelfinavir." Reactions Weekly &NA;, no. 865 (August 2001): 10. http://dx.doi.org/10.2165/00128415-200108650-00028.

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27

Peytavin, G., B. Lacarelle, and J. Barré. "Nelfinavir." EMC - Biologie médicale 2, no. 2 (January 2007): 1–2. http://dx.doi.org/10.1016/s2211-9698(07)71370-5.

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28

&NA;. "Nelfinavir." Reactions Weekly &NA;, no. 1429 (November 2012): 32. http://dx.doi.org/10.2165/00128415-201214290-00118.

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29

Castiglione, Brenda. "Nelfinavir:." Journal of Infectious Disease Pharmacotherapy 3, no. 4 (December 1, 1998): 33–59. http://dx.doi.org/10.1300/j100v03n04_03.

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30

Kovsan, Julia, Alexander Osnis, Adva Maissel, Livnat Mazor, Tanya Tarnovscki, Liat Hollander, Shira Ovadia, et al. "Depot-specific adipocyte cell lines reveal differential drug-induced responses of white adipocytes—relevance for partial lipodystrophy." American Journal of Physiology-Endocrinology and Metabolism 296, no. 2 (February 2009): E315—E322. http://dx.doi.org/10.1152/ajpendo.90486.2008.

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Intra-abdominal (IA) fat functionally differs from subcutaneous (SC) adipose tissue, likely contributing to its stronger association with obesity-induced morbidity and to differential response to medications. Drug-induced partial lipodystrophy, like in response to antiretroviral agents, is an extreme manifestation of the different response of different fat depots, with loss of SC but not IA. Investigating depot-specific adipocyte differences is limited by the low accessibility to IA fat and by the heterogenous cell population comprising adipose tissue. Here, we aimed at utilizing immortalized preadipocyte cell lines from IA (epididymal) or SC (inguinal) fat to investigate whether they differentially respond to the HIV protease inhibitor nelfinavir. Preadipocytes were readily amenable to adipogenesis, as evidenced by lipid accumulation, expression of adipose-specific genes, measurable lipolysis, and insulin responsiveness. Leptin secretion was higher by the SC line, consistent with known differences between IA and SC fat. As previously reported, nelfinavir inhibited adipogenesis downstream of C/EBPβ, but similarly in both cell lines. In contrast, nelfinavir's capacity to diminish insulin signaling, decrease leptin secretion, enhance basal lipolysis, and decrease expression of the lipid droplet-associated protein perilipin occurred more robustly and/or at lower nelfinavir concentrations in the SC line. This was despite similar intracellular concentrations of nelfinavir (23.8 ± 5.6 and 33.6 ± 12.2 μg/mg protein for inguinal and epididymal adipocytes, respectively, P = 0.46). The cell lines recapitulated depot-differential effects of nelfinavir observed in differentiated primary preadipocytes and with whole tissue explants. Thus, we report the use of fat depot-specific adipocyte cell lines for unraveling depot-differential responses to a drug causing partial lipodystrophy.

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31

Boffito, Marta, Anton Pozniak, Brian P. Kearney, Christopher Higgs, Anita Mathias, Lijie Zhong, and Jaymin Shah. "Lack of Pharmacokinetic Drug Interaction between Tenofovir Disoproxil Fumarate and Nelfinavir Mesylate." Antimicrobial Agents and Chemotherapy 49, no. 10 (October 2005): 4386–89. http://dx.doi.org/10.1128/aac.49.10.4386-4389.2005.

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ABSTRACT A study explored the pharmacokinetics of tenofovir (300 mg administered once daily) and nelfinavir (1,250 mg twice daily) when coadministered in 29 healthy volunteers. Tenofovir, nelfinavir, and M8 pharmacokinetics was unaltered when tenofovir and nelfinavir were coadministered, and tenofovir administration did not affect the M8/nelfinavir area under the concentration-versus-time curve over the dosing interval (AUCtau) ratio. No interaction between tenofovir and nelfinavir was observed.

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32

Fassmannová, Dominika, František Sedlák, Jindřich Sedláček, Ivan Špička, and Klára Grantz Šašková. "Nelfinavir Inhibits the TCF11/Nrf1-Mediated Proteasome Recovery Pathway in Multiple Myeloma." Cancers 12, no. 5 (April 25, 2020): 1065. http://dx.doi.org/10.3390/cancers12051065.

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Proteasome inhibitors are the backbone of multiple myeloma therapy. However, disease progression or early relapse occur due to development of resistance to the therapy. One important cause of resistance to proteasome inhibition is the so-called bounce-back response, a recovery pathway driven by the TCF11/Nrf1 transcription factor, which activates proteasome gene re-synthesis upon impairment of the proteasome function. Thus, inhibiting this recovery pathway potentiates the cytotoxic effect of proteasome inhibitors and could benefit treatment outcomes. DDI2 protease, the 3D structure of which resembles the HIV protease, serves as the key player in TCF11/Nrf1 activation. Previous work found that some HIV protease inhibitors block DDI2 in cell-based experiments. Nelfinavir, an oral anti-HIV drug, inhibits the proteasome and/or pAKT pathway and has shown promise for treatment of relapsed/refractory multiple myeloma. Here, we describe how nelfinavir inhibits the TCF11/Nrf1-driven recovery pathway by a dual mode of action. Nelfinavir decreases the total protein level of TCF11/Nrf1 and inhibits TCF11/Nrf1 proteolytic processing, likely by interfering with the DDI2 protease, and therefore reduces the TCF11/Nrf1 protein level in the nucleus. We propose an overall mechanism that explains nelfinavir’s effectiveness in the treatment of multiple myeloma.

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33

&NA;. "Nelfinavir/saquinavir." Reactions Weekly &NA;, no. 803 (May 2000): 10. http://dx.doi.org/10.2165/00128415-200008030-00026.

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34

&NA;. "Nelfinavir interaction." Reactions Weekly &NA;, no. 958 (July 2003): 9–10. http://dx.doi.org/10.2165/00128415-200309580-00022.

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35

&NA;. "Indinavir/nelfinavir." Reactions Weekly &NA;, no. 970 (September 2003): 12. http://dx.doi.org/10.2165/00128415-200309700-00039.

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36

&NA;. "Betamethasone/nelfinavir." Reactions Weekly &NA;, no. 1006 (June 2004): 7–8. http://dx.doi.org/10.2165/00128415-200410060-00015.

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37

&NA;. "Nelfinavir/saquinavir." Reactions Weekly &NA;, no. 747 (April 1999): 9. http://dx.doi.org/10.2165/00128415-199907470-00028.

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38

&NA;. "Indinavir/nelfinavir." Reactions Weekly &NA;, no. 872 (October 2001): 9–10. http://dx.doi.org/10.2165/00128415-200108720-00028.

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39

Abraham, Prasad E., Suellyn J. Sorensen, William H. Baker, and Herbert E. Cushing. "Nelfinavir Desensitization." Annals of Pharmacotherapy 35, no. 5 (May 2001): 553–56. http://dx.doi.org/10.1345/aph.10150.

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40

Tebas, Pablo, and William G. Powderly. "Nelfinavir mesylate." Expert Opinion on Pharmacotherapy 1, no. 7 (December 2000): 1429–40. http://dx.doi.org/10.1517/14656566.1.7.1429.

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41

Besse, Andrej, Lenka Besse, Sara C. Stolze, Amin Sobh, Esther A. Zaal, Alwin J. van der Ham, Mario Ruiz, et al. "Nelfinavir Overcomes Proteasome Inhibitor Resistance in Multiple Myeloma By Modulating Membrane Lipid Bilayer Composition and Fluidity." Blood 136, Supplement 1 (November 5, 2020): 11. http://dx.doi.org/10.1182/blood-2020-136253.

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INTRODUCTION Nelfinavir is a highly lipophilic, first generation HIV-protease inhibitor (HIV-PI) approved for HIV treatment. It has largely been replaced by next-generation HIV-PI with increased specificity and efficacy for HIV therapy, partly reflecting the significant rate of the off-target activity of nelfinavir. Increasing preclinical and clinical evidence shows that nelfinavir has broad anti-cancer activity as a single agent and in combination, potentially related to its off-target activity in mammalian cells. Nelfinavir is particularly effective in the treatment of proteasome inhibitor-refractory multiple myeloma (MM), where the combination of nelfinavir+bortezomib+dexamethasone yielded an overall response rate (ORR, PR or better) > 65% in a Phase II clinical trial. The targets and molecular mechanism of action of nelfinavir in MM are unknown. This hampers both, a rational clinical repositioning and development of nelfinavir as antineoplastic drug, as well as the design, synthesis and testing of next generation nelfinavir-like compounds with optimized antineoplastic activity and improved specificity or pharmacologic properties. We therefore aimed to take an unbiased target-identification approach to identify molecular targets of nelfinavir in human malignant cells and link them to cell biological processes and mechanisms that mediate sensitivity or resistance to nelfinavir treatment. METHODS Proteome-wide affinity-purification of targets binding the nelfinavir active site was combined with genome-wide CRISPR/Cas9-based screening to identify protein partners interacting with nelfinavir and candidate genetic contributors affecting nelfinavir cytotoxicity. Multiple intracellular reporter systems including RUSH system, ATP/ADP constructs; FRAP microscopy, Seahorse measurements, flow cytometry, qPCR, metabolic labelling, lipidomics and viability assays were used to dissect functional alterations in pathways related to nelfinavir targets. RESULTS We identified a common set of proteins interacting specifically with the active site of nelfinavir. These proteins are embedded in intracellular, lipid-rich membranes of mitochondria (VDAC1,2,3, ANT2), endoplasmic reticulum (BCAP31, CANX, SRPRB) and nuclear envelope (PGRMC2) and are consistent across multiple cancer cell types. ADIPOR2, a key regulator gene of membrane lipid fluidity, was identified as a key nelfinavir resistance gene, while genes involved in fatty acids (FAs) and cholesterol metabolism, vesicular trafficking and mitochondria biogenesis are candidate sensitivity genes. We further show that via binding to proteins in lipid-rich membranes nelfinavir affects membrane composition and reduces membrane fluidity, leading to induction of FAs synthesis and the unfolded protein response (UPR). Via its structural interference with membrane fluidity, nelfinavir impairs the function and mobility of a diverse set of membrane-associated proteins and processes, such as glucose flux and processing, mitochondria respiration, energy supply, transmembrane vesicular transport and ABCB1-mediated drug efflux, as we show in different reporter systems in live MM cells. These functional effects are prevented by addition of metabolically inert lipids to be incorporated in membranes, supporting a direct structural activity of nelfinavir. The adaptive biology of proteasome inhibitor (PI)-resistant myeloma relies on metabolic reprogramming and changes in lipid composition, drug export and down-modulation of the UPR. Modulation of membrane fluidity and depletion of FAs/cholesterol is synergistic with proteasome inhibitors in PI-resistant MM. Thus, the mechanism of action of nelfinavir perfectly matches with the biology of PI-resistant MM, serving as a molecular rational for its significant clinical activity. CONCLUSION We here demonstrate in vitro that the activity of nelfinavir against MM cells is triggered through changes in lipid metabolism and the fluidity of lipid-rich membranes. Pharmacologic targeting of membrane fluidity is a novel, potent mechanism to achieve anti-cancer activity, in particular against PI-refractory MM. This mechanism explains the clinical activity of nelfinavir in MM treatment as well as the key side effects of nelfinavir during antiretroviral therapy. Disclosures No relevant conflicts of interest to declare.

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42

Hirt, Déborah, Jean-Marc Treluyer, Vincent Jullien, Ghislaine Firtion, Hélène Chappuy, Elisabeth Rey, Gérard Pons, Laurent Mandelbrot, and Saïk Urien. "Pregnancy-Related Effects on Nelfinavir-M8 Pharmacokinetics: a Population Study with 133 Women." Antimicrobial Agents and Chemotherapy 50, no. 6 (June 2006): 2079–86. http://dx.doi.org/10.1128/aac.01596-05.

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ABSTRACT A relationship between nelfinavir antiretroviral efficacy and plasma concentrations has been previously established. As physiological changes associated with pregnancy have a large impact on the pharmacokinetics of many drugs, a nelfinavir population study with women was developed, and the large intersubject variability was analyzed in order to optimize individual treatment schedules for this drug during pregnancy. A population pharmacokinetic model was developed in order to describe the concentration time course of nelfinavir and its metabolite M8 in pregnant and nonpregnant women. Individual characteristics, such as age, body weight, and weeks of gestation or delivery, which may influence nelfinavir-M8 pharmacokinetics were investigated. Data from therapeutic drug monitoring in 133 women treated with nelfinavir were retrospectively analyzed with NONMEM. Nelfinavir pharmacokinetics was described by a one-compartment model with linear absorption and elimination and M8 produced from the nelfinavir central compartment. Mean pharmacokinetic estimates and the corresponding intersubject percent variabilities for a nonpregnant woman were the following: absorption rate, 0.83 h−1; absorption lag time, 0.85 h; apparent nelfinavir elimination clearance (CL10/F), 35.5 liters/h (50%); apparent volume of distribution (V/F), 596 liters (118%); apparent formation clearance to M8 (CL1M/F), 0.65 liters/h (69%); and M8 elimination rate constant (k M0), 3.3 h−1 (59%). During pregnancy, we observed significant increases in nelfinavir (44.4 liters/h) and M8 (5 h−1) elimination but unchanged nelfinavir transformation clearance to M8, suggesting an induction of CYP3A4 but no effect on CYP2C19. Apparent nelfinavir clearance and volume showed a twofold increase on the day of delivery, suggesting a decrease in bioavailability on this day. The M8 elimination rate was increased by concomitant administration of nonnucleoside reverse transcriptase inhibitors. A trough nelfinavir plasma concentration above 1 mg/liter was previously shown to improve the antiretroviral response. The Bayesian individual pharmacokinetic estimates suggested that the dosage should not be changed in pregnant women but may be doubled on the day of delivery.

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43

Driessen, Christoph, Dagmar Hess, Thomas Pabst, Sarah R. Haile, Markus Joerger, Roger von Moos, Catherine Berset, et al. "SAKK 65/08: A Phase I Trial of the HIV Protease Inhibitor Nelfinavir in Combination with Bortezomib Identifies Nelfinavir As FDA Approved, Oral Drug that Inhibits the Proteasome and Induces Proteotoxic Stress in Vivo and has Potential Antimyeloma Activity." Blood 120, no. 21 (November 16, 2012): 2956. http://dx.doi.org/10.1182/blood.v120.21.2956.2956.

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Abstract Abstract 2956 Introduction: The HIV protease inhibitor nelfinavir has anti-myeloma activity in mice; it is approved at the 1250 mg bid dose for oral treatment of HIV. We performed a phase I dose escalation trial of nelfinavir in combination with bortezomib in patients with advanced hematologic malignancies. Methods: During cycle 1 (28 days), trial treatment consisted of 1 week nelfinavir monotherapy, followed by nelfinavir in combination with standard dose bortezomib (1.3 mg/m2i.v. day 8, 11, 15, 18), while cycles 2 and 3 (21 days each) consisted of 2 weeks nelfinavir in combination with bortezomib (day 1, 4, 8, 11). Non-progressing patients could continue therapy for up to 4 additional cycles with the same regimen as cycles 2 and 3. Nelfinavir dose was escalated in a 3+3 design over 3 dose levels (1250, 1875, 2500 mg bid). Dose limiting toxicity (DLT), the primary endpoint, was grade 3–4 non-hematological toxicity (excluding grade 3 bilirubin/alanine aminotransferase (ALT) or hyperlipidemia reversible within 2 weeks) or severe hematologic toxicity unrelated to the underlying disease during cycle 1. Secondary endpoints included pharmacodynamic and pharmacokinetic assessments during cycle 1 at baseline, nelfinavir monotherapy and after application of nelfinavir and bortezomib in combination, as well as signals for activity. Results: Twelve evaluable patients were registered (median age 58 years; 8 male; performance status 0–1 in 10/12 patients); 8 had multiple myeloma, 2 leukemia (1 acute myeloid, 1 acute lymphoblastic) and 2 lymphoma (1 diffuse large B-cell lymphoma, 1 mantle-cell (MCL)). All myeloma patients failed both prior bortezomib and lenalidomide-containing therapy; 7/8 had progressed under prior bortezomib. One patient (2500 mg bid dose) experienced a transient grade 4 elevated ALT, categorized as DLT, which resolved within 2 weeks. The patient continued the same regimen off study without recurrent hepatic toxicity. No further DLTs occurred, thus nelfinavir 2500 mg bid was established to be safe in combination with standard dose bortezomib. One patient with highly aggressive lymphoma died from cerebral vein thrombosis; a myeloma patient experienced a non-fatal pulmonary embolism. Elevated ALT (2 patients) was the only additional non-hematological toxicity grade 3/4 observed in >1 patient. Grade 3 febrile neutropenia and grade 4 thrombocytopenia were seen in 1 and 4 patients, respectively. Best treatment response was evaluated for 11 patients (1 not evaluable). Partial response was achieved in 3 patients (2 myeloma, 1 MCL) and stable disease for at least 2 cycles of therapy in 5 patients. Overall, 4/12 patients completed >=3 cycles of treatment. Assessment of proteasome activity in peripheral blood mononuclear cells (PBMC) from treated patients after 1 week nelfinavir monotherapy revealed inhibition of total proteasome activity in vivo by nelfinavir compared to baseline (mean inhibition, as determined by specific, quantitative intracellular affinity labeling of active proteasome subunits: 14.9 %, 95% confidence interval (CI): 8.8–23.5%, p=<0.001), including inhibition of the bortezomib-insensitive tryptic (β2-type) proteasome activity (mean inhibition: 17.7%, 95% CI: 8.0–27.4%, p=0.008). In addition, inhibition of pAKT, induction of the unfolded protein response and accumulation of polyubiquitinated protein in vivo was observed in PBMC after nelfinavir monotherapy. Mean intracellular proteasome inhibition after combination treatment with bortezomib and nelfinavir was 26.6 % (95% CI: 11.5–42%). Maximum nelfinavir plasma levels were observed at the 1875 mg bid dose level (Cmax mean 12.10 mM, trough mean 6.97 mM), matching the nelfinavir concentrations that mediate anti-myeloma activity in vitro. Conclusion: This is the first trial to report on the use of nelfinavir as an anti-neoplastic agent in patients with hematologic malignancies. It identifies nelfinavir as FDA approved, orally available drug with pan-proteasome inhibiting activity in vivo. Nelfinavir treament up to 2500 mg bid is safe as monotherapy and in combination with standard dose bortezomib. Bortezomib in combination with nelfinavir shows signals for clinical activity in individual myeloma patients that have failed bortezomib and lenalidomide-containing therapies. Nelfinavir warrants further clinical investigation in multiple myeloma, in particular in combination with proteasome inhibitors. Disclosures: No relevant conflicts of interest to declare.

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44

Zhang, Kanyin E., Ellen Wu, Amy K. Patick, Bradley Kerr, Mark Zorbas, Angela Lankford, Takuo Kobayashi, Yuki Maeda, Bhasker Shetty, and Stephanie Webber. "Circulating Metabolites of the Human Immunodeficiency Virus Protease Inhibitor Nelfinavir in Humans: Structural Identification, Levels in Plasma, and Antiviral Activities." Antimicrobial Agents and Chemotherapy 45, no. 4 (April 1, 2001): 1086–93. http://dx.doi.org/10.1128/aac.45.4.1086-1093.2001.

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ABSTRACT Nelfinavir mesylate (Viracept, formally AG1343) is a potent and orally bioavailable human immunodeficiency virus (HIV) type 1 (HIV-1) protease inhibitor (K i = 2 nM) and is being widely prescribed in combination with HIV reverse transcriptase inhibitors for the treatment of HIV infection. The current studies evaluated the presence of metabolites circulating in plasma following the oral administration of nelfinavir to healthy volunteers and HIV-infected patients, as well as the levels in plasma and antiviral activities of these metabolites. The results showed that the parent drug was the major circulating chemical species, followed in decreasing abundance by its hydroxy-t-butylamide metabolite (M8) and 3′-methoxy-4′-hydroxynelfinavir (M1). Antiviral assays with HIV-1 strain RF-infected CEM-SS cells showed that the 50% effective concentrations (EC50) of nelfinavir, M8, and M1 were 30, 34, and 151 nM, respectively, and that the corresponding EC50 against another HIV-1 strain, IIIB, in MT-2 cells were 60, 86, and 653 nM. Therefore, apparently similar in vitro antiviral activities were demonstrated for nelfinavir and M8, whereas an approximately 5- to 11-fold-lower level of antiviral activity was observed for M1. The active metabolite, M8, showed a degree of binding to human plasma proteins similar to that of nelfinavir (ca. 98%). Concentrations in plasma of nelfinavir and its metabolites in 10 HIV-positive patients receiving nelfinavir therapy (750 mg three times per day) were determined by a liquid chromatography tandem mass spectrometry assay. At steady state (day 28), the mean plasma nelfinavir concentrations ranged from 1.73 to 4.96 μM and the M8 concentrations ranged from 0.55 to 1.96 μM, whereas the M1 concentrations were low and ranged from 0.09 to 0.19 μM. In conclusion, the findings from the current studies suggest that, in humans, nelfinavir forms an active metabolite circulating at appreciable levels in plasma. The active metabolite M8 may account for some of the antiviral activity associated with nelfinavir in the treatment of HIV disease.

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Chow, W. A., S. Guo, and F. Valdes-Albini. "HIV protease inhibitor (PI) therapy for liposarcoma." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 9564. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.9564.

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9564 Background: Liposarcomas are the second most common soft-tissue sarcoma. Highly-active anti-retroviral therapy (HAART) with HIV PIs results in “HIV-1 protease inhibitor associated lipodystrophy syndrome,” characterized by peripheral fat wasting, central fat accumulation, insulin resistance, and hyperlipidemia. Based upon this syndrome, we hypothesized that HIV PIs might represent a novel liposarcoma therapy. Methods: SW872, LiSa-2, and FU-DDLS-1 liposarcoma, and control 293 embryonic kidney and HT1080 fibrosarcoma cell lines were treated with HIV PIs and subjected to cellular and molecular assays. Results: Clonogenic assays with SW872 cells using HIV PIs (saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) were performed. Nelfinavir demonstrated the most potent clonogenic inhibition without affecting 293 and HT1080 clonogenicity, and was studied further. Nelfinavir inhibited SW872 and LiSa-2 proliferation dose-dependently, and HT1080 proliferation at the highest concentration, without affecting FU-DDLS-1 nor 293 proliferation. Nelfinavir induced a G1 cell cycle arrest in SW872 and HT1080, but not in 293 cells. It also induced dose-dependent apoptosis in SW872, but not in 293 nor HT1080 cells. Western analyses for sterol regulatory element binding protein-1 (SREBP-1) expression, a key transcriptional regulator of fatty acid and cholesterol synthesis, were performed. Nelfinavir induced expression of SREBP-1 in nelfinavir-sensitive SW872 and LiSa-2 cells, and modestly in HT1080 cells, but not in insensitive FU-DDLS-1 nor 293 cells. Additionally, nelfinavir reduced protein expression of proliferating cell nuclear antigen (PCNA) in sensitive SW872 and LiSa-2 cells, and induced expression of the anti-proliferative protein, p21, as well as pro-apoptotic proteins, Bax and Fas, in a dose-dependent manner. Finally, forced expression of SREBP-1 with a Tet-On inducible SW872 cell line, in the absence of nelfinavir, induced expression of p21, Bax, Fas, reduced expression of PCNA, and inhibited cell proliferation. Conclusions: These studies demonstrate that nelfinavir inhibits cellular proliferation, and induces apoptosis in sensitive-liposarcoma cells through upregulation of SREBP-1. These studies validate nelfinavir as a potential, novel targeted therapy for liposarcoma. No significant financial relationships to disclose.

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&NA;. "Lamivudine/nelfinavir/zalcitabine." Reactions Weekly &NA;, no. 1223 (October 2008): 19. http://dx.doi.org/10.2165/00128415-200812230-00059.

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&NA;. "Lamivudine/zidovudine/nelfinavir." Reactions Weekly &NA;, no. 1275 (October 2009): 21. http://dx.doi.org/10.2165/00128415-200912750-00058.

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&NA;. "Didanosine/nelfinavir/stavudine." Reactions Weekly &NA;, no. 1276 (October 2009): 12–13. http://dx.doi.org/10.2165/00128415-200912760-00036.

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&NA;. "Lamivudine/nelfinavir/stavudine." Reactions Weekly &NA;, no. 1087 (February 2006): 17. http://dx.doi.org/10.2165/00128415-200610870-00054.

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&NA;. "Efavirenz/nelfinavir/stavudine." Reactions Weekly &NA;, no. 1094 (March 2006): 9–10. http://dx.doi.org/10.2165/00128415-200610940-00026.

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