J Clin Pharmacol
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PHARMACOKINETICS AND PHARMACODYNAMICS

Does the Unfavorable Pharmacokinetic and Pharmacodynamic Profile of the iNOS Inhibitor GW273629 Lead to Inefficacy in Acute Migraine?

B. J. Van der Schueren, MD, M. W. Lunnon, BSc, PhD, B. E. Laurijssens, PhD, F. Guillard, MSc, J. Palmer, PhD, A. Van Hecken, PhD, M. Depré, MSc, PhD, F. H. Vanmolkot, MD, PhD and J. N. de Hoon, MSc, MD, PhD

From the Center for Clinical Pharmacology, University Hospital Gasthuisberg (K.U. Leuven), Leuven, Belgium (B. J. Van der Schueren, A. Van Hecken, M. Depré, F. H. Vanmolkot, J. N. de Hoon); Clinical Pharmacology & Discovery Medicine (M. W. Lunnon, J. Palmer) and Clinical Pharmacology, Statistics & Programming (F. Guillard), GSK, Harlow, UK; and Clinical Pharmacokinetics, Modeling & Simulation, GSK, Greenford, UK (B. Laurijssens).

The objective of this study was to investigate the pharmacodynamics and pharmacokinetics of a single dose of GW273629, a selective iNOS inhibitor, given during and outside a migraine attack. GW273629 1500 mg was administered to 15 migraine patients both ictally and interictally. Nasal and exhaled nitric oxide (NO), plasma 3-nitrotyrosine, and nitrates were measured to assess systemic NO production. In addition, pharmacokinetics and treatment response were assessed. Data are mean (95% confidence interval [CI]). Plasma 3-nitrotyrosine was higher ictally: 11.96 (8.22, 15.71) ictally versus 2.74 (2.24, 3.24) ng/10 mg interictally (P < .0001). Exhaled and nasal NO showed a similar trend: 12.5 (6.5, 18.6) and 62.2 (41.5, 82.8) ppb ictally versus 9.9 (6.3, 13.4) ppb and 52.5 (38.5, 66.0) ppb interictally, respectively. Early absorption of GW273629 (AUC0-2 [90% CI]) was reduced by 41 (22, 55)% during an attack. There was no improvement of headache or associated symptoms. Migraine headache is associated with reduced early absorption of GW273629 and excess NO production. In this open-label study, GW273629 was ineffective in the treatment of acute migraine.

Key Words: iNOS • pharmacokinetics • pharmacodynamic assay • migraine therapy

Address for reprints: Bart Van der Schueren, Center for Clinical Pharmacology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium; e-mail: bart.vanderschueren{at}uz.kuleuven.be.


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