Conflict of Interest: The author was an employee of (then) Glaxo Inc 1990-94, and has been a consultant, from time to time, for its successor companies, Alexza Inc., Allergan Inc., Elan Pharmaceuticals, UCB Pharma, and Zogenix Inc. There was no pharmaceutical company involvement with, nor any outside funding for, this study.
Subcutaneous Sumatriptan Pharmacokinetics: Delimiting the Monoamine Oxidase Inhibitor Effect
Article first published online: 17 NOV 2009
© 2009 the Author. Journal compilation © 2009 American Headache Society
Headache: The Journal of Head and Face Pain
Volume 50, Issue 2, pages 249–255, February 2010
How to Cite
Fox, A. W. (2010), Subcutaneous Sumatriptan Pharmacokinetics: Delimiting the Monoamine Oxidase Inhibitor Effect. Headache: The Journal of Head and Face Pain, 50: 249–255. doi: 10.1111/j.1526-4610.2009.01568.x
- Issue published online: 24 JAN 2010
- Article first published online: 17 NOV 2009
- Accepted for publication October 4, 2009.
- monoamine oxidase;
- drug interaction
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 Tmax = 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 Tmax, 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 Cmax). At t = 10 hours, the concentrations in both sets were <1 ng/mL (ie, below the lower limit of assay quantitation), and AUC0-10h 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.