Pharmacokinetic Interactions between BMS-626529, the Active Moiety of the HIV-1 Attachment Inhibitor Prodrug BMS-663068, and Ritonavir or Ritonavir-Boosted Atazanavir in Healthy Subjects

Zhu, Li; Hruska, Matthew; Hwang, Carey; Shah, Vaishali; Furlong, Melissa; Hanna, George J.; Bertz, Richard; Landry, Ishani

doi:10.1128/aac.04914-14

Cited by 22 publications

(22 citation statements)

References 13 publications

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“…2e ). An attachment inhibitor that targets HIV-1 gp120 and blocks its binding to CD4 + T cells, BMS-626529 42 , was added to prevent new rounds of infection. Treatments with IDB, ABT-263, and SAR4505 alone or together killed HIV-1-infected cells, whereas uninfected cells were resistant (Fig.…”

Section: Resultsmentioning

confidence: 99%

Clearance of HIV infection by selective elimination of host cells capable of producing HIV

Li¹,

Liu²,

Bauch³

et al. 2020

Nat Commun

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The RNA genome of the human immunodeficiency virus (HIV) is reverse-transcribed into DNA and integrated into the host genome, resulting in latent infections that are difficult to clear. Here we show an approach to eradicate HIV infections by selective elimination of host cells harboring replication-competent HIV (SECH), which includes viral reactivation, induction of cell death, inhibition of autophagy and the blocking of new infections. Viral reactivation triggers cell death specifically in HIV-1-infected T cells, which is promoted by agents that induce apoptosis and inhibit autophagy. SECH treatments can clear HIV-1 in >50% mice reconstituted with a human immune system, as demonstrated by the lack of viral rebound after withdrawal of treatments, and by adoptive transfer of treated lymphocytes into uninfected humanized mice. Moreover, SECH clears HIV-1 in blood samples from HIV-1-infected patients. Our results suggest a strategy to eradicate HIV infections by selectively eliminating host cells capable of producing HIV.

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Section: Resultsmentioning

confidence: 99%

Clearance of HIV infection by selective elimination of host cells capable of producing HIV

Li¹,

Liu²,

Bauch³

et al. 2020

Nat Commun

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“…has been shown to have less impact on TMR plasma C max than cobicistat 150 mg q.d. (45-53% increase with ritonavir vs. 71% with cobicistat) 18,21 and, hence, these conclusions apply to the use of fostemsavir with both cobicistat and ritonavir-boosted protease inhibitors and other medications that may inhibit CYP3A4, BRCP, and P-gp. These findings can be interpolated to other clinical scenarios of DDIs in heavily treatment-experienced populations given that coadministration with cobicistat represents a worst-case increase in C max (1.71-fold increase compared to without concomitant cobicistat).…”

Section: Discussionmentioning

confidence: 94%

“…Plasma TMR in both parts of the study was analyzed using a validated liquid chromatography/mass spectrometry assay with a lower limit of quantitation of 5 ng/mL. 18 Predose sampling times were set to zero for PK parameter assessments. Samples from subjects receiving placebo were not assayed.…”

Section: Methodsmentioning

confidence: 99%

Effects of Temsavir, Active Moiety of Antiretroviral Agent Fostemsavir, on QT Interval: Results From a Phase I Study and an Exposure–Response Analysis

Lagishetty

Moore²,

Ackerman³

et al. 2020

Clinical Translational Sci

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Fostemsavir, a prodrug of human immunodeficiency virus attachment inhibitor temsavir (TMR), is in phase III development in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type I (HIV-1) infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection for whom it is otherwise not possible to construct a suppressive antiviral regimen due to resistance, intolerance, or safety considerations. The proarrhythmic potential of fostemsavir was studied in a thorough QT study and exposure-response modeling was performed at therapeutic and supratherapeutic concentrations of TMR. Fostemsavir 1,200 mg b.i.d. did not result in a clinically meaningful change from placebo in baseline-adjusted Fridericia-corrected QTc (ddQTcF); however, at a supratherapeutic dose of 2,400 mg b.i.d., the upper bound of the two-sided 90% confidence interval (CI) of ddQTcF was 13.2 msec, exceeding the clinically important 10 msec threshold. A linear model of ddQTcF as a function of TMR plasma concentrations described these observations. Based on simulations with this model, TMR concentrations up to 7,500 ng/mL are expected to have an upper 90% CI bound for QTcF ≤ 10 msec. This concentration is 4.2-fold higher than the geometric mean TMR peak plasma concentration (C max) of 1,770 ng/mL in heavily treatment-experienced HIV-1 infected patients administered fostemsavir 600 mg b.i.d. in the phase III BRIGHTE study (NCT02362503). Fostemsavir is a first-in-class oral human immunodeficiency virus type 1 (HIV-1) attachment inhibitor prodrug that is hydrolyzed in vivo to its active moiety, temsavir (TMR). 1 Fostemsavir is in phase III development in combination with other antiretroviral agents for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection for whom it is otherwise not possible to construct a suppressive antiviral regimen due to resistance, intolerance, or safety considerations. TMR binds directly to the HIV-1 envelope glycoprotein gp120, close to the CD4 binding sites, locking it in a conformational state that prohibits the initial interaction between the virus and CD4 cell-surface receptors to prevent viral attachment and subsequent entry into host CD4+ target cells. 2 TMR has good membrane permeability but low solubility and a short half-life, requiring its administration as an

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“…Geometric mean (coefficient of variation [%]) TMR Cmax, AUCτ and C12 were 1498 (41) ng/mL, 9758 (40) ng h/mL and 409 (60) ng/mL, respectively, when FTR 600 mg ER BID was coadministered with MET; and 2052 (39) ng/mL, 13 176 (35) ng h/mL and 468 (80) ng/mL, respectively, when FTR 600 mg ER BID was coadministered with BUP/NLX. TMR exposures and variability were consistent with historical observations in healthy participants receiving multiple oral doses of FTR 600 mg ER BID with a standard meal …”

Section: Resultsmentioning

confidence: 99%

Methadone and buprenorphine pharmacokinetics and pharmacodynamics when coadministered with fostemsavir to opioid‐dependent, human immunodeficiency virus seronegative participants

Moore¹,

Magee

Sevinsky

et al. 2019

Brit J Clinical Pharma

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Aims Regional human immunodeficiency virus (HIV) prevalence rates are high in people with history of injection drug use, including those managed with maintenance opioids. Fostemsavir (FTR) is an oral prodrug of temsavir, a first‐in‐class attachment inhibitor that binds HIV‐1 gp120, preventing initial HIV attachment and entry into host immune cells. Here we determine the impact of FTR on the pharmacokinetics of opioids methadone (MET: R‐, S‐ and total) or buprenorphine and norbuprenorphine (BUP and norBUP) when coadministered. Methods Study 206216 (NCT02666001) was a Phase I, open‐label study, assessing the effect of FTR 600 mg (extended‐release formulation) twice daily on pharmacokinetics of MET or BUP and norBUP, in non‐HIV‐infected participants on stable maintenance therapy with MET (40–120 mg; n = 16) or BUP plus naloxone (8–24 mg plus 2–6 mg; n = 16); pharmacodynamic response was assessed using standard opioid rating scales. Results Following coadministration with FTR, dose‐normalized MET (R‐, S‐ and total) exposures (maximum concentration in plasma, area under the plasma concentration–time curve over the dosing interval and concentration in plasma at 24 hours) increased 9–15% and BUP and norBUP exposures increased 24–39%. The 90% confidence interval ranges for MET (1.01–1.21) and BUP and norBUP (1.03–1.69) were within respective no‐effect ranges (0.7–1.43 and 0.5–2.0). Opioid pharmacodynamic scores were similar with and without MET/BUP with no symptoms of withdrawal/overdose; no new safety signal for FTR when combined with a stable opioid regimen. Conclusions FTR did not impact MET and had no clinically significant impact on BUP pharmacokinetics. Standardized assessments of opioid pharmacodynamics were unchanged throughout FTR administration with MET or BUP. FTR can be administered with MET or BUP without dose adjustment.

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Pharmacokinetic Interactions between BMS-626529, the Active Moiety of the HIV-1 Attachment Inhibitor Prodrug BMS-663068, and Ritonavir or Ritonavir-Boosted Atazanavir in Healthy Subjects

Cited by 22 publications

References 13 publications

Clearance of HIV infection by selective elimination of host cells capable of producing HIV

Clearance of HIV infection by selective elimination of host cells capable of producing HIV

Effects of Temsavir, Active Moiety of Antiretroviral Agent Fostemsavir, on QT Interval: Results From a Phase I Study and an Exposure–Response Analysis

Methadone and buprenorphine pharmacokinetics and pharmacodynamics when coadministered with fostemsavir to opioid‐dependent, human immunodeficiency virus seronegative participants

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