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Bp, Smith; Vandenhende, FR; DeSante, KA; Farid, NA; Welch, PA; Callaghan, JT; Forgue, S. Thomas

doi:10.1023/a:1026451721686

Cited by 319 publications

(87 citation statements)

References 8 publications

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“…Coefficients of determination (R 2 values), and 95% confidence limits were determined from the power regression analysis. Results were considered linear when R 2 was ∼1, and lower confidence limits were ≥0.8 and upper confidence limits were ≤1.25 (Smith et al, 2000). For the cellular assays, triplicate wells were run for each experiment.…”

Section: Methodsmentioning

confidence: 99%

The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs

Malfatti

Enright

et al. 2017

Chemico-Biological Interactions

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Organophosphorus-based (OP) nerve agents represent some of the most toxic substances known to mankind. The current standard of care for exposure has changed very little in the past decades, and relies on a combination of atropine to block receptor activity and oxime-type acetylcholinesterase (AChE) reactivators to reverse the OP binding to AChE. Although these oximes can block the effects of nerve agents, their overall efficacy is reduced by their limited capacity to cross the blood-brain barrier (BBB). RS194B, a new oxime developed by Radic et al. (J. Biol. Chem., 2012) has shown promise for enhanced ability to cross the BBB. To fully assess the potential of this compound as an effective treatment for nerve agent poisoning, a comprehensive evaluation of its pharmacokinetic (PK) and biodistribution profiles was performed using both intravenous and intramuscular exposure routes. The ultra-sensitive technique of accelerator mass spectrometry was used to quantify the compound's PK profile, tissue distribution, and brain/plasma ratio at four dose concentrations in guinea pigs. PK analysis revealed a rapid distribution of the oxime with a plasma t1/2 of ∼1 hr. Kidney and liver had the highest concentrations per gram of tissue followed by lung, spleen, heart and brain for all dose concentrations tested. The Cmax in the brain ranged between 0.03-0.18% of the administered dose, and the brain-to-plasma ratio ranged from 0.04 at the 10 mg/kg dose to 0.18 at the 200 mg/kg dose demonstrating dose dependent differences in brain and plasma concentrations. In vitro studies show that both passive diffusion and active transport contribute little to RS194B traversal of the BBB. These results indicate that biodistribution is widespread, but very low quantities accumulate in the guinea pig brain, indicating this compound may not be suitable as a centrally active reactivator.

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Section: Methodsmentioning

confidence: 99%

The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs

Malfatti

Enright

et al. 2017

Chemico-Biological Interactions

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“…The estimate of the exponent ␤ and its 90% CI values were determined, using this linear model of log-transformed pharmacokinetic parameters and log dose. Dose proportionality was concluded if the 90% CI interval for ␤ (slope estimate) was completely contained within the prespecified critical region (0.943 to 1.057) (11).…”

Section: Methodsmentioning

confidence: 99%

A First-in-Human Study To Assess the Safety and Pharmacokinetics of Monoclonal Antibodies against Human Cytomegalovirus in Healthy Volunteers

Dole

Segal

Feire

et al. 2016

Antimicrob Agents Chemother

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Human cytomegalovirus (HCMV) can cause significant disease in immunocompromised patients and treatment options are limited by toxicities. CSJ148 is a combination of two anti-HCMV human monoclonal antibodies (LJP538 and LJP539) that bind to and inhibit the function of viral HCMV glycoprotein B (gB) and the pentameric complex, consisting of glycoproteins gH, gL, UL128, UL130, and UL131. Here, we evaluated the safety, tolerability, and pharmacokinetics of a single intravenous dose of LJP538 or LJP539 or their combination in healthy volunteers. Adverse events and laboratory abnormalities occurred sporadically with similar incidence between antibody and placebo groups and without any apparent relationship to dose. No subject who received antibody developed a hypersensitivity, infusion-related reaction or anti-drug antibodies. After intravenous administration, both LJP538 and LJP539 demonstrated typical human IgG1 pharmacokinetic properties, with slow clearances, limited volumes of distribution, and long terminal half-lives. The pharmacokinetic parameters were linear and dose proportional for both antibodies across the 50-fold range of doses evaluated in the study. There was no apparent impact on pharmacokinetics when the antibodies were administered alone or in combination. CSJ148 and the individual monoclonal antibodies were safe and well tolerated, with pharmacokinetics as expected for human immunoglobulin. Human cytomegalovirus (HCMV) can cause significant disease in immunocompromised individuals, including transplant patients and neonates infected in utero (1). Therapies available to treat HCMV disease in transplant recipients, including ganciclovir, cidofovir, and foscarnet, are effective but associated with serious toxicities; there are no approved treatments for congenital HCMV (2). Passive immunization with HCMV hyperimmunoglobulin, which is polyclonal IgG from human plasma pools, is also used to prevent HCMV disease in some transplant recipients. It is safe and well tolerated but is less effective than other antiviral therapies. Preliminary data from a combination of anti-HCMV monoclonal antibodies, showed a modest, therapeutic benefit in renal transplant recipients (3-6).CSJ148 is a combination of two fully human anti-HCMV IgG1 monoclonal antibodies, LJP538 and LJP539 (7), and offers the potential to be a safe and well-tolerated alternative to available therapies for the prevention and treatment of HCMV disease. Each antibody binds to and inhibits the function of viral glycoproteins essential for HCMV infectivity. In vitro studies demonstrated that LJP538 and LJP539 were up to 100 to 1000-fold more potent, respectively, than HCMV-hyperimmunoglobulin at inhibiting infection of various cell lines. Furthermore, LJP538 and LJP539 were active against a panel of clinical isolates in vitro and demonstrated minor to moderate synergy in combination (A. Patel et al., unpublished data). Importantly, viruses with reduced susceptibility to either LJP538 or LJP539 remained susceptible to the other antibody, and no cross-...

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“…A point estimate and 90% confidence interval (CI) were produced for the population mean slope. Approximate dose proportionality was to be concluded when the 90% CI for the slope was completely within the interval of 0.82 to 1.18 [1 ϩ log(0.5)/log(r), 1 ϩ log(2)/log(r)], where r is either C max or AUC of the highest dose/lowest dose (13).…”

Section: Methodsmentioning

confidence: 99%

First-in-Humans Study of the Safety, Tolerability, and Pharmacokinetics of ACT-451840, a New Chemical Entity with Antimalarial Activity

Bruderer

Hurst

Kanter

et al. 2015

Antimicrob Agents Chemother

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Emerging resistance to antimalarial agents raises the need for new drugs. ACT-451840 is a new compound with potent activity against sensitive and resistant Plasmodium falciparum strains. This was a first-in-humans single-ascending-dose study to investigate the safety, tolerability, and pharmacokinetics of ACT-451840 across doses of 10, 50, 200, and 500 mg in healthy male subjects. In the 200-and 500-mg dose groups, the effect of food was investigated, and antimalarial activity was assessed using an ex vivo bioassay with P. falciparum. No (serious) adverse events leading to discontinuation were reported. At the highest dose level, the peak drug concentration (C max ) and the area under the plasma concentration-time curve from zero to infinity of ACT-451840 under fasted conditions reached 11.9 ng/ml and 100.6 ng · h/ml, respectively, and these were approximately 13-fold higher under fed conditions. Food did not affect the half-life (approximately 34 h) of the drug, while the C max was attained 2.0 and 3.5 h postdose under fasted and fed conditions, respectively. The plasma concentrations estimated by the bioassay were approximately 4-fold higher than those measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Several potentially active metabolites were also identified. ACT-451840 was well tolerated across all doses. Exposure to ACT-451840 significantly increased with food. The bioassay indicated the presence of circulating active metabolites. (This study has been registered at ClinicalTrials.gov under registration no. NCT02186002.)

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Abstract: The proposed method enhances the information from a clinical dose-proportionality study and helps to standardize decision rules.

Cited by 319 publications

References 8 publications

The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs

The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs

A First-in-Human Study To Assess the Safety and Pharmacokinetics of Monoclonal Antibodies against Human Cytomegalovirus in Healthy Volunteers

First-in-Humans Study of the Safety, Tolerability, and Pharmacokinetics of ACT-451840, a New Chemical Entity with Antimalarial Activity

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