Subcutaneous Sumatriptan Pharmacokinetics: Delimiting the Monoamine Oxidase Inhibitor Effect

( Headache 2010;50:249‐255) 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.