The Effect of Dolutegravir on the Pharmacokinetics of Metformin in Healthy Subjects

Song, Ivy; Zong, Jian; Borland, Julie; Jerva, Fred; Wynne, Brian; Zamek‐Gliszczynski, Maciej J.; Humphreys, Joan E.; Bowers, Gary; Choukour, Mike

doi:10.1097/qai.0000000000000983

Cited by 97 publications

(80 citation statements)

References 18 publications

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“…A similar magnitude DDI has also been reported with another antibiotic, cephalexin . Recently, Zong et al reported that the antiretroviral drug dolutegravir caused the largest DDI with metformin reported to date, increasing metformin's C max and AUC by up to 2.11‐ and 2.45‐fold, respectively, after twice‐daily dolutegravir administration . The mechanism of the interaction appears to be the potent inhibition of the organic cation transporter 2 (OCT2, SLC22A2) by dolutegravir …”

Section: Commonly Prescribed Victim Drugssupporting

confidence: 52%

Renal Transporter‐Mediated Drug‐Drug Interactions: Are They Clinically Relevant?

Lepist

Ray

2016

The Journal of Clinical Pharma

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The kidney, through the distinct processes of passive glomerular filtration and active tubular secretion, plays an important role in the elimination of numerous endobiotics (eg, hormones, metabolites), toxins, nutrients, and drugs. Renal transport pathways mediating active tubular secretion and reabsorption in the proximal tubule are complex, involving apical and basolateral transporters acting in concert. Detailed studies of the molecular mechanisms of net active tubular secretion have established the involvement of multiple transporters with overlapping substrate specificity mediating competing secretion and reabsorption pathways. Although drug interactions arising from inhibition of renal transporters are rare relative to other mechanisms, they can involve commonly administered drugs (eg, cimetidine, metformin), may be underappreciated due to muted effects on plasma pharmacokinetics relative to tissue levels, can affect narrow-therapeutic-index medications (eg, antiarrhythmic, oncology medications), and may disproportionately affect sensitive populations where polypharmacy is common (eg, the elderly, diabetics). In particular, there is the potential for larger-magnitude interactions in subjects with reduced glomerular filtration rates due to the increased relative contribution of tubular secretion. The assessment of additional endpoints in drug-drug interaction studies including pharmacodynamics, positron emission tomography imaging, and metabolomics promises to expand our understanding of the clinical relevance of renal drug interactions.

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Section: Commonly Prescribed Victim Drugssupporting

confidence: 52%

Renal Transporter‐Mediated Drug‐Drug Interactions: Are They Clinically Relevant?

Lepist

Ray

2016

The Journal of Clinical Pharma

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“…Efficient phagocytosis and proper adaptive immune priming are necessary to activate cell-mediated immune responses that restrict M. tuberculosis growth, and delayed or altered responses likely contribute to diabetic TB susceptiblity 11 . Diabetic individuals with LTBI have lower frequencies of M. tuberculosis-specific pro-inflammatory (Th1 and Th17), anti-inflammatory (IL-10) and Th2 responses compared to normoglycemic individuals with LTBI 12,13 . The IL-20 family of cytokines is also lower in LTBI-DM whereas IL-22 is higher 14 .…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Defining a Research Agenda to Address the Converging Epidemics of Tuberculosis and Diabetes

Ronacher

Crevel

Critchley

et al. 2017

Chest

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There is growing interest in the re-emerging interaction between type 2 diabetes (DM) and tuberculosis (TB), but the underlying biological mechanisms are poorly understood despite their possible implications in clinical management. Experts in epidemiological, public health, basic science and clinical studies recently convened and identified research priorities for elucidating the underlying mechanisms for the co-ocurrence of TB and DM. We identified gaps in current knowlege of altered immunity in DM patients during TB, where most studies suggest an under-performing innate immunity, but exaggerated adaptive immunity to Mycobacterium tuberculosis. Various molecular mechanisms and pathways that may underly these observations in the DM host. These include signaling induced by excess advanced glycation end products (AGE) and their receptor (RAGE), higher levels of reactive oxidative species and oxidative stress, epigenetic changes due to chronic hyperglycemia, altered nuclear receptors and/or differences in cell metabolism (immuno-metabolism). Studies in humans at different stages of DM (no DM, pre-DM and DM) or TB (latent or active TB) should be complemented with findings in animal models, which provide the unique opportunity to study early events in the host-pathogen interaction. Such studies could also help identify biomarkers that will complement clinical studies in order to tailor the prevention of TB-DM, or avoid the adverse TB treatment outcomes that are more likely in these patients. Such studies will also inform new approaches to host-directed therapies. M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT Summary box• Type 2 diabetes is a syndrome characterised by a range of metabolic (e.g. hyperglycemia, hyperlipidemia), inflammatory, vascular and other changes that may all contribute to increasing TB susceptibility and pathology.• Monocytes and macrophages from diabetic patients and mice have defects leading to altered interactions with M. tuberculosis and delayed adaptive immune responses.• Most human studies have been conducted in patients with active TB, where those with TB-DM comorbidity are characterised by increased secretion of Th1, Th17 and Th2 cytokines. However, the few studies in individuals at risk for TB (LTBI) suggest a different cytokine profile.• Molecular pathways that involve AGE/RAGE, ROS, nuclear receptors and cellular metabolism are potential targets for host-directed therapies to reduce TB susceptibility or pathology in DM patients.• Animal models for TB-DM can improve our understanding of underlying mechanisms and effective treatment approaches for the comorbidity of TB and DM. IntroductionType 2 diabetes mellitus (DM) increases the risk of many infectious diseases, including tuberculosis 1 (TB), and it is now recognized that the increasing DM prevalence in high TB incidence countries such as Sub-Saharan Africa (SSA) is a challenge to TB control. 2 The known association between a chronic syndome like DM and an infectious disease like TB requires the near term development...

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“…11,12 Other minor biotransformation pathways include oxidation by cytochrome P450 3A4 and metabolism by UGT1A3 and UGT1A9. 15 Dolutegravir is also a substrate for P-glycoprotein and breast cancer resistance protein in vitro. Dolutegravir also potently inhibits the organic cation transporter 2 12 and multidrug and toxin extrusion 1 transporter.…”

mentioning

confidence: 99%

Bioequivalence and Food Effect Assessment of 2 Fixed‐Dose Combination Formulations of Dolutegravir and Lamivudine

Dumitrescu

Peddiraju

et al. 2019

Clinical Pharm in Drug Dev

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This single-dose study evaluated the bioequivalence, food effect, and safety of 2 experimental, 2-drug, fixed-dose formulations of 50 mg dolutegravir and 300 mg lamivudine (formulation AH and formulation AK) as compared with coadministration of single-entity tablets of 50 mg dolutegravir and 300 mg lamivudine (reference). In fasted subjects, formulation AH lamivudine exposure was similar to the reference; however, dolutegravir exposure was consistently higher in formulation AH, with area under the concentration-time curve (AUC) and maximum concentration (C max ) approximately 27% to 28% greater than reference. Formulation AK met bioequivalence standards to the reference for dolutegravir (AUC 0-Ý and C max ) and lamivudine (AUC 0-Ý and AUC 0-t ) exposure; however, dolutegravir AUC 0-t and lamivudine C max were approximately 16% and 32% higher than the reference, respectively. A high-fat meal increased dolutegravir AUC and C max by up to 33% and 21%, respectively, and decreased lamivudine C max by approximately 30%. Both test and reference formulations were well tolerated. The results support further development of formulation AK as a novel, 2-drug, fixed-dose combination tablet treatment for patients with HIV.

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The Effect of Dolutegravir on the Pharmacokinetics of Metformin in Healthy Subjects

Abstract: Supplemental Digital Content is Available in the Text.

Cited by 97 publications

References 18 publications

Renal Transporter‐Mediated Drug‐Drug Interactions: Are They Clinically Relevant?

Renal Transporter‐Mediated Drug‐Drug Interactions: Are They Clinically Relevant?

Defining a Research Agenda to Address the Converging Epidemics of Tuberculosis and Diabetes

Bioequivalence and Food Effect Assessment of 2 Fixed‐Dose Combination Formulations of Dolutegravir and Lamivudine

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