First name
Ganesh
Last name
Moorthy

Title

Vancomycin-Induced Kidney Injury: Animal Models of Toxicodynamics, Mechanisms of Injury, Human Translation, and Potential Strategies for Prevention.

Year of Publication

2020

Date Published

2020 Apr 02

ISSN Number

1875-9114

Abstract

<p>Vancomycin is a recommended therapy in multiple national guidelines. Despite the common use, there is a poor understanding of the mechanistic drivers and potential modifiers of vancomycin-mediated kidney injury. In this review, historic and contemporary rates of vancomycin-induced kidney injury (VIKI) are described, and toxicodynamic models and mechanisms of toxicity from preclinical studies are reviewed. Aside from known clinical covariates that worsen VIKI, preclinical models have demonstrated that various factors impact VIKI, including dose, route of administration, and thresholds for pharmacokinetic parameters. The degree of acute kidney injury (AKI) is greatest with the intravenous route and higher doses that produce larger maximal concentrations and areas under the concentration curve. Troughs (i.e., minimum concentrations) have less of an impact. Mechanistically, preclinical studies have identified that VIKI is a result of drug accumulation in proximal tubule cells, which triggers cellular oxidative stress and apoptosis. Yet, there are several gaps in the knowledge which may represent viable targets to make vancomycin therapy less toxic. Potential strategies include prolonging infusions and lowering maximal concentrations, administration of antioxidants, administering agents that decrease cellular accumulation, and reformulating vancomycin to alter the renal clearance mechanism. Based on preclinical models and mechanisms of toxicity, we propose potential strategies to lessen VIKI.</p>

DOI

10.1002/phar.2388

Alternate Title

Pharmacotherapy

PMID

32239518

Title

CYP2B6 genotypes and early efavirenz-based hiv treatment outcomes in botswana.

Year of Publication

2017

Date Published

2017 Jul 07

ISSN Number

1473-5571

Abstract

<p><strong>OBJECTIVES: </strong>To determine the association between cytochrome p450 2B6 genotypes and efavirenz-based HIV treatment outcomes.</p>

<p><strong>DESIGN: </strong>Observational cohort study of HIV infected adults initiating efavirenz-based regimens in Botswana.</p>

<p><strong>METHODS: </strong>The primary endpoint was a composite of death or loss to care or HIV RNA&gt;25 copies/ml at 6 months. CYP2B6 516G&gt;T and 983T&gt;C genotyping was done with Taqman Open Array platform. Adverse experiences were measured using the Subject Experience Questionnaire. Metabolism alleles were included in logistic regression models of the composite endpoint.</p>

<p><strong>RESULTS: </strong>801 individuals included 406 (51%) males, median age 37 years, median baseline CD4 count 195 cells/mm and plasma HIV RNA 4·9 log10 copies/ml. 277 (35%) reached the endpoint including 34 (4%) deaths, 151 (19%) lost to care, and 92 (11%) with plasma HIV RNA&gt;25 copies/ml. Metabolism variant alleles were common with 396 (49%) intermediate and 192 (24%) slow metabolizers. There were no statistically significant associations between metabolism and treatment endpoints. However, slower metabolism was associated with fewer adverse experiences.</p>

<p><strong>CONCLUSIONS: </strong>Slow metabolism alleles were associated with lower efavirenz clearance but not any of the treatment endpoints. Slow efavirenz metabolism did not exacerbate CNS toxicity. These results should allay concern that slow efavirenz metabolism adversely impacts individuals in sub-Saharan African settings in which these alleles are common.</p>

DOI

10.1097/QAD.0000000000001593

Alternate Title

AIDS

PMID

28692529

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