Subcutaneous sumatriptan pharmacokinetics: delimiting the monoamine oxidase inhibitor effect.
BACKGROUND
The absolute bioavailability of subcutaneous (s.c.) sumatriptan is 96-100%. The decay curve for plasma concentration after 6 mg s.c. sumatriptan (ie, after T(max) = about 0.2 hours) includes a large distribution component. Metabolism by monoamine oxidase-A (MAO-A) leads to about 40% of the s.c. dose appearing in the urine as the inactive indole acetic acid. Product labeling states that co-administration of an inhibitor of MAO-A (a MAOI-A) causes a 2-fold increase in sumatriptan plasma concentrations, and a 40% increase in elimination half-life.


OBJECTIVE
The objective of this study is to determine whether MAOI-A therapy should deter the use of 6 mg s.c. sumatriptan on pharmacokinetic grounds.


METHODS
Summary pharmacokinetic data were taken from the literature and from GlaxoSmithKline (GSK) study C92-050. Half-times were converted into rate constants, which were then used in a parsimonious compartmental model (needing only 3 simultaneous differential equations). Acceptance criteria for the model included observed plasma sumatriptan concentrations at T(max), 1, 2, and 10 hours post-dose. A set of 1000 concentration measurements at a resolution of 36 seconds was generated. The model was then perturbed with elimination constants observed during concomitant moclobemide administration, creating a second set of concentration measurements. The 2 sets were then plotted, examined for their differences, and integrated for a second time to obtain and compare areas under the curve (AUCs).


RESULTS
The greatest absolute difference between the 2 sets of measurements was 2.85 ng/mL at t = 2.95 hours. A 2-fold difference between the 2 sets occurred only after t = 5.96 hours, when the concentration in the presence of the MAOI-A was 3.72 ng/mL (or <4% of C(max)). At t = 10 hours, the concentrations in both sets were <1 ng/mL (ie, below the lower limit of assay quantitation), and AUC(0-10h) was 97.4 and 117 ng.hour/mL in the absence and presence of the MAOI-A.


CONCLUSIONS
There are no pharmacokinetic grounds to deter co-administration of an MAOI-A and subcutaneous sumatriptan. The dominance of the distribution phase and completeness of absorption of a 6 mg dose of s.c. sumatriptan explains the trivial effect size of the MAOI-A on plasma sumatriptan concentrations. Importantly, these findings should not be extrapolated to other routes of administration for sumatriptan.
Fox
Anthony W
AW
Skaggs SPPS, University of California, San Diego, CA, USA.
D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions / Q000502:physiology*; D005260:Female; D006801:Humans; D007210:Indoleacetic Acids / Q000378:metabolism; D008881:Migraine Disorders / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000009:adverse effects*; D010599:Pharmacokinetics; D012701:Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D018170:Sumatriptan / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*
D007210:Indoleacetic Acids; D008996:Monoamine Oxidase Inhibitors; D017366:Serotonin Receptor Agonists; D012701:Serotonin; C030737:indoleacetic acid; D018170:Sumatriptan; D008995:Monoamine Oxidase