Drug monitoring in systemic lupus erythematosus

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Abstract

Therapeutic drug monitoring (TDM) is not yet accepted by systemic lupus erythematosus (SLE) treatment guidelines. Studies in SLE, however, have proven benefit in three areas: identification of non-adherence or poor adherence; targets for clinical benefit; and ranges of toxicity. This review covers the data on three medications commonly used for SLE, drawing on studies from both the SLE and non-SLE literature.

Introduction

Therapeutic drug monitoring (TDM) is important when there are complicated pharmacokinetics and/or patient-related factors (i.e., genetic control of metabolism, adherence, obesity, renal impairment, liver disease, and gender or ethnicity) that affect the therapeutic or toxic effect. In non-rheumatology fields, such as neurology and gastroenterology, TDM is more widely accepted. To summarize:

“The aim of therapeutic drug monitoring (TDM) is to optimize pharmacotherapy by maximizing therapeutic efficacy, while minimizing adverse events, in those instances where the blood concentration of the drug is a better predictor of the desired effect(s) than the dose” [1].

Section snippets

Hydroxychloroquine

Hydroxychloroquine remains the mainstay of initial and long-term treatment of systemic lupus erythematosus (SLE). In randomized clinical trials, about 70% of SLE patients have prescribed hydroxychloroquine. It has benefits on multiple organ manifestations. It reduces flares [2] and triples the complete renal response to mycophenolate [3]. One of its major benefits is prevention, in that it reduces organ damage [4] and reduces thrombosis [5,6]. It is the only drug proved in multiple studies to

Azathioprine

Azathioprine is an older oral immunosuppressant, still widely used in SLE as well as for autoimmune hepatitis, inflammatory bowel disease, and other diseases. It remains one of the very few oral immunosuppressants that can be used in pregnancy as the fetus lacks the enzyme that metabolizes it to an active form. Its metabolism can be understood by two pathways. First, the activation pathway converts azathioprine non-enzymatically by sulfhydryl compounds to mercaptopurine. Mercaptopurine is then

Mycophenolate mofetil

Data on therapeutic blood monitoring of mycophenolate mofetil come from both the transplant and rheumatology literature. In SLE, it is one of the primary therapies for both induction therapy [64] and maintenance therapy of lupus nephritis [65]. Mycophenolic acid is glucuronidated by uridine diphosphate-glucosyltransferases to the pharmacologically inactive 7-O-glucuronide metabolite mycophenolic acid glucuronide (MPAG). MPAG is excreted into bile via the multidrug resistance-associated protein

Summary

Therapeutic blood monitoring for three medications commonly used in SLE has demonstrated clinical benefit. Hydroxychloroquine whole blood levels identify adherence, can be used to achieve clinical efficacy including prevention of thrombosis, and also identify those at higher risk of retinopathy. Azathioprine guidelines now include the identification of two genetic risk factors, TPMT and NUDT15, for toxicity. Azathioprine metabolites may also be useful in achieving efficacy. For mycophenolate

Conflict of interest statement

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Michelle Petri reports financial support was provided by National Institute of Arthritis and Musculoskeletal and Skin Diseases. Michelle Petri reports a relationship with AstraZeneca that includes consulting or advisory and funding grants. Michelle Petri reports a relationship with Alexion Pharmaceuticals Inc that includes consulting or advisory. Michelle Petri

Acknowledgements

Work on hydroxychloroquine whole blood levels was supported by a grant from the National Institutes of Health grant number R01-AR069572.

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