Study Purpose: To study the variability of response in patients with fibromyalgia to
treatment with duloxetine
Duloxetine is a common FDA-approved pharmacotherapy for fibromyalgia. However, there is
significant treatment response variability. Prior work has explored the role of liver
drug-metabolizing enzymes CYP2D6 and CYP1A2 in the biotransformation of duloxetine. The
genes coding for these enzymes have many variants; some variants are rapid metabolizers,
whereas others are slow metabolizers of duloxetine. The different variants may contribute
to the wide range of treatment responses to duloxetine among fibromyalgia patients.
Supporting duloxetine metabolism as a contributor to drug response variability,
researchers have measured plasma duloxetine concentrations following recommended dosing
regimens and found concentrations to have substantial variability.
A strong correlation between an ultra-rapid duloxetine metabolizer with a poor response
to duloxetine will provide useful information when formulating a treatment plan. Patients
with a poor response to duloxetine phenotype may be better served by another serotonin
norepinephrine reuptake inhibitor such as milnacipran. Early identification of those who
would benefit from duloxetine will help a personalized approach to treating fibromyalgia
and optimize the cost-effectiveness of pharmacological interventions.
Drug interactions with duloxetine that influence drug effect: An important consideration
in characterizing duloxetine metabolism is to account for drug interactions that may
inhibit or induce CYP1A2 or CYP2D6.
The main objective of this proposal is to conduct a feasibility study/pilot study to
serve as the basis for a larger study where we refine our study methodology. In a cohort
of patients treated with duloxetine for fibromyalgia, this study will measure:
(i) Symptoms of fibromyalgia using a validated questionnaire.
(ii) Duloxetine plasma concentrations.
(iii) Genotype CYP2D6 and CYP1A2 and correlate their plasma concentrations and genotype
(rapid, normal, or slow metabolizer) with fibromyalgia symptoms.
Hypotheses:
(i) Patients with rapid or slow metabolizing variants will have low and high duloxetine
plasma concentrations respectively.
(ii) Patients with rapid metabolizing variants will have ineffective treatment with
duloxetine and patients with slow metabolizing variants will have signs and symptoms of
effective treatment or duloxetine toxicity.
(iii) Patients who consume inducers or inhibitors of CYP2D6 or CYP1A2 will have low and
high duloxetine plasma concentrations, respectively. Patients who consume inducers of
CYP2D6 or CYP1A2 will have ineffective treatment with duloxetine, and patients that
consume inhibitors of CYP2D6 or CYP1A2 will have signs and symptoms of effective
treatment or duloxetine toxicity.