Circulating Metabolites of the Human Immunodeficiency Virus Protease Inhibitor Nelfinavir in Humans: Structural Identification, Levels in Plasma, and Antiviral Activities

Zhang, Kanyin E.; Wu, Ellen; Patick, Amy K.; Kerr, Bradley M.; Zorbas, Mark; Lankford, Angela; Kobayashi, Takuo; Maeda, Yasuhiro; Shetty, Bhasker V.; Webber, Stephanie

doi:10.1128/aac.45.8.2405-2405.2001

Cited by 23 publications

(43 citation statements)

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“…No data are available for inhibition of SARS-CoV-2 replication by the M8 metabolite but if active, this could provide and advantage for nelfinavir over tipranavir for COVID-19. Conversely, While the analysis of pharmacokinetics relative to potency of these molecules against SARS-CoV-2 is encouraging, it should be noted that the reported in vitro activity for HIV [58,65] is far higher than that against SARS-CoV-2 and both drugs are highly protein bound [66,67]. While older HIV protease inhibitors like tipranavir and nelfinavir are associated with long-term toxicities [58,[68][69][70] these may be less of a concern over shorter term exposure if they prove to be successful for COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

Arshad

Pertinez

Box

et al. 2020

Preprint

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There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against SARS-CoV-2. However, this has not been accompanied by a comprehensive evaluation of the ability of these drugs to achieve target plasma and lung concentrations following approved dosing in humans. Moreover, most publications have focussed on 50% maximum effective concentrations (EC50), which may be an insufficiently robust indicator of antiviral activity because of marked differences in the slope of the concentration-response curve between drugs. Accordingly, in vitro anti-SARS-CoV-2 activity data was digitised from all available publications up to 13 th April 2020 and used to recalculate an EC90 value for each drug. EC90 values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug after administration of the approved dose to humans (Cmax/EC90 ratio). Only 14 of the 56 analysed drugs achieved a Cmax/EC90 ratio above 1 meaning that plasma Cmax concentrations exceeded those necessary to inhibit 90% of SARS-CoV-2 replication. A more in-depth assessment of the putative agents tested demonstrated that only nitazoxanide, nelfinavir, tipranavir (boosted with ritonavir) and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval at their approved human dose. For all drugs reported, the unbound lung to plasma tissue partition coefficient (KpUlung) was also simulated and used along with reported Cmax and fraction unbound in plasma to derive a lung Cmax/EC50 as a better indicator of potential human efficacy (lung Cmax/EC90 ratio was also calculable for a limited number of drugs). Using this parameter hydroxychloroquine, chloroquine, mefloquine, atazanavir (boosted with ritonavir), tipranavir (boosted with ritonavir), ivermectin, azithromycin and lopinavir (boosted with ritonavir) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50. This analysis was not possible for nelfinavir because insufficient data were available to calculate KpUlung but nitozoxanide and sulfadoxine were also predicted to exceed their reported EC50 by 3.1-and 1.5-fold in lung, respectively. The antiviral activity data reported to date have been acquired under different laboratory conditions across multiple groups, applying variable levels of stringency. However, this analysis may be used to select potential candidates for further clinical testing, while deprioritising compounds which are unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments such as the lung, in order to maximise the potential for success of proposed human clinical trials.

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Section: Discussionmentioning

confidence: 99%

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

Arshad

Pertinez

Box

et al. 2020

Preprint

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“…Preliminary data in animal studies have not demonstrated any fetal toxicity of this agent [6]. NFV is mainly metabolized by cytochromes P450 (CYP) 3A4 and 2C19 [7], whose metabolic activity has been shown to be altered during pregnancy, which, together with the physiological changes in gastrointestinal motility, volume of distribution and hepatic blood flow, may significantly affect the pharmacokinetics of the drug.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of nelfinavir in HIV‐1‐infected pregnant and nonpregnant women

Villani

Floridia

Pirillo

et al. 2006

Brit J Clinical Pharma

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AimsTo compare steady-state nelfinavir (NFV) pharmacokinetics in pregnant and nonpregnant HIV-infected women. MethodsTwenty-five pregnant HIV-infected women were selected from an ongoing observational study evaluating the pharmacokinetics of antiretroviral agents during pregnancy. Twenty of them were in the third and five in the second trimester. Data for the control group of 21 HIV-infected nonpregnant women were taken from a previous multicentre pharmacokinetic trial. All the participating women achieved steady-state plasma concentrations while on a highly active antiretroviral therapy (HA ART) regimen including NFV (1250 mg bid) and two nucleoside reverse transcriptase inhibitors (N RTIs). Blood samples for NFV measurement were collected predose ( C trough ) and at 0.5, 1, 2, 3, 4, 5, 6, 8 and 12 h post dose. ResultsDuring the third trimester of pregnancy NFV AUC 0 − 12 h median (range) values were 25.76 (12.61-42.74) µ g h − 1 ml − 1 , and were 32. 49 (19.16-63.81) µ g h − 1 ml − 1 in the control group [mean difference − 9.30 µ g h − 1 ml − 1 ; 95% confidence interval (CI) − 15.76, − 2.83; P < 0.05). Median oral clearance (CL/F) was significantly higher in pregnant women than in the control group (48.5 l h − 1 , range 29.3-99.1 l h − 1 vs. 38.5 l h − 1 , range 19.6-65.2 l h − 1 ; mean difference 12.6 l h − 1 ; 95% CI 3.3, 21.9) but the difference disappeared when CL/F was adjusted for body weight. C trough was significantly ( P < 0.01) lower in pregnant compared with nonpregnant women (median 0.8 µ g ml − 1 , range 0-2.6 µ g ml − 1 vs. 1.5 µ g ml − 1 , range 0.5-4.9 µ g ml − 1 ; mean difference − 1.0 µ g ml − 1 ; 95% CI − 1.7, − 0.31). The median elimination half-life of NFV observed during pregnancy was 3.7 h (range 1.4-6.6 h), compared with 5.2 (range 3.1-10.1 h) in the control group (mean difference − 1.7; 95% CI − 2.8, − 0.51). ConclusionsOur results indicate that women in the later stages of pregnancy may be exposed to subtherapeutic concentrations of NFV. Thus, adjustments in drug dosage or frequency of administration may be required. P. Villani et al. 31062 :3 Br J Clin Pharmacol

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“…Formation of the equally active hydroxy-t-butylamidenelfinavir metabolite (M8) is mediated exclusively by CYP2C19, with further metabolism by CYP3A4 after its formation. 7,8 Previous studies have shown that CYP3A4 and CYP2C19 activity may be altered during pregnancy, and this alteration may potentially affect the pharmacokinetics of nelfinavir and M8 in pregnant women. 9,10 In addition to altered activity of certain hepatic enzymes, other physiologic changes that occur during pregnancy have the potential to influence drug disposition (eg, altered gastrointestinal motility, increased total body water and fat, increased cardiac output, and reduced serum albumin; for review see reference 11).…”

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The pharmacokinetics of nelfinavir and M8 during pregnancy and post partum

Heeswijk

Khaliq

Gallicano

et al. 2004

Clinical Pharmacology & Therapeutics

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Nelfinavir exposure was reduced during pregnancy, and the reduction was statistically significant for C 12 . M8 concentrations were about 70% lower during pregnancy compared with post partum, suggesting either induction of hepatic cytochrome P450 (CYP) 3A4 or inhibition of CYP2C19, or both, during pregnancy. Because 8 of 11 women had subtherapeutic nelfinavir trough concentrations during pregnancy, the safety and efficacy of therapeutic drug monitoring should be investigated.

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Circulating Metabolites of the Human Immunodeficiency Virus Protease Inhibitor Nelfinavir in Humans: Structural Identification, Levels in Plasma, and Antiviral Activities

Cited by 23 publications

References 0 publications

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

Pharmacokinetics of nelfinavir in HIV‐1‐infected pregnant and nonpregnant women

The pharmacokinetics of nelfinavir and M8 during pregnancy and post partum

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