Pharmacokinetics of Unboosted Atazanavir in Treatment-experienced HIV-infected Children, Adolescents and Young Adults

Cressey, Tim R.; Hazra, Rohan; Wiznia, Andrew; Foca, Marc; Jean‐Philippe, Patrick; Graham, Bobbie; King, Jennifer R.; Britto, Paula; Carey, Vincent J.; Acosta, Edward P.; Yogev, Ram

doi:10.1097/inf.0000000000001320

Cited by 3 publications

(2 citation statements)

References 10 publications

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“…69 Bunupuradah et al 67 showed that 200-mg ATV boosted with 100 mg of ritonavir within a regimen containing TDF was able to achieve ATV levels comparable with adult levels in Asian children aged 6–18 years. Another study, by Cressey et al, 70 investigated the possibility of using unboosted ATV in ART-experienced Thai children unable to take ritonavir. Doses of 400-mg and 600-mg unboosted ATV did not achieve target C trough levels and were highly variable between patients.…”

Section: Methodsmentioning

confidence: 99%

Optimizing Pediatric Dosing Recommendations and Treatment Management of Antiretroviral Drugs Using Therapeutic Drug Monitoring Data in Children Living With HIV

Waalewijn

Turkova

Rakhmanina

et al. 2019

Therapeutic Drug Monitoring

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Section: Methodsmentioning

confidence: 99%

Optimizing Pediatric Dosing Recommendations and Treatment Management of Antiretroviral Drugs Using Therapeutic Drug Monitoring Data in Children Living With HIV

Waalewijn

Turkova

Rakhmanina

et al. 2019

Therapeutic Drug Monitoring

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“…The maximum concentration (Cmax) is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given. The Cmax of ATV in plasma after a standard dose ranges from 1.5 to 8 µM in patients [20][21][22]. 4 x 10 4 /ml cells (total volume of 30 ml) were cultured with different concentrations of ATV, multiplicities of Cmax-0, 2.5, 5.0, 7.5, 15, 22.5, and 30.0 µM.…”

Section: Cell Culture and Drugsmentioning

confidence: 99%

Activation of NLRP3 inflammasome/pyroptosis by protease inhibitor atazanavir at high concentrations is mediated through mitochondrial dysfunction

Zhou,

Cosme,

et al. 2024

Preprint

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Protease inhibitor (PI)-based antiretroviral therapy increases CD4 and CD8 cell counts through anti-apoptosis mechanism. However, there are emerging reports that PIs could have pro-apoptotic effects; thus, PIs may have biphasic effect on apoptosis. We hypothesized that PI-induced apoptosis may be mediated through PI-induced mitochondrial dysfunction resulting in increased production of reactive oxygen species (ROS).To test this hypothesis, we used human T lymphoblastoid cell line (CEM) cultured with increasing concentrations of atazanavir (ATV). We assessed mitochondrial function—i.e., cell growth, apoptosis, mitochondrial membrane potential (ΔΨ), ROS, and electron transport chain (ETC) proteins. Apoptosis pathway genes were interrogated using the Human Apoptosis RT² Profiler PCR Array kit (QIAGEN), followed by quantitative PCR for validation.CEM cells treated with 15, 22.5, and 30 µM of ATV resulted in significant reduction in cell growth and increased apoptosis. Further, high concentrations of ATV resulted in decreased mitochondrial ΔΨ, increased ROS production, and decreased protein expression of ETC I, II, III, and V. The following apoptosis pathway genes—caspase-1, BCL2A1, TP73 and TNFRSF1B—were differentially expressed. Caspase-1 is known to play a role in inducing NLRP3 inflammasome/pyroptosis pathway. We validated this with qPCR of the genes in the NLRP3 inflammasome pathway. Of note, NLRP3 inhibitor MCC950 and caspase-1 inhibitor YVAD reversed mitochondrial dysfunction and cell death. Our findings suggest that ATV-induced cell death is through the NLRP3 inflammasome/pyroptosis pathway. ATV-induced mitochondrial dysfunction plays an important role in the regulation of ATV-activated NLRP3 inflammasome pathway.

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Drug-induced cholestasis assay in primary hepatocytes

Brantegem

Chatterjee

Bruyn³

et al. 2020

MethodsX

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Drug-induced cholestasis (DIC) is a major cause of clinical failure of drug candidates. Numerous patients worldwide are affected when exposed to marketed drugs exhibiting a DIC signature. Prospective identification of DIC during early compound development remains challenging. Here we describe the optimized in vitro procedure for early assessment and prediction of an increased DIC risk. Our method is based on three principles: Exposure of primary human hepatocyte cultures to test compounds in the absence and presence of a physiologically relevant mixture of endogenous bile salts. Rapid and quantitative assessment of the influence of concomitant bile salt exposure on hepatocyte functionality and integrity after 24 h or 48 h of incubation. Translation of the in vitro result, expressed as a DIC index (DICI) value, into an in vivo safety margin. Using our historical control data, a new (data driven) DICI cut-off value of 0.78 was established for discerning cholestatic and non-cholestatic compounds. Our DIC assay protocol was further improved by now relying on the principle of the no observable adverse effect level (NOAEL) for determining the highest test compound concentration corresponding to a DICI ≥ 0.78. Predicted safety margin values were subsequently calculated for compounds displaying hepatotoxic and/or cholestatic effects in patients, thus enabling evaluation of the performance of our DIC assay. Of note, this assay can be extended to explore the role of drug metabolites in precipitating DIC.

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Pharmacokinetics of Unboosted Atazanavir in Treatment-experienced HIV-infected Children, Adolescents and Young Adults

Cited by 3 publications

References 10 publications

Optimizing Pediatric Dosing Recommendations and Treatment Management of Antiretroviral Drugs Using Therapeutic Drug Monitoring Data in Children Living With HIV

Optimizing Pediatric Dosing Recommendations and Treatment Management of Antiretroviral Drugs Using Therapeutic Drug Monitoring Data in Children Living With HIV

Activation of NLRP3 inflammasome/pyroptosis by protease inhibitor atazanavir at high concentrations is mediated through mitochondrial dysfunction

Drug-induced cholestasis assay in primary hepatocytes

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