Combined aminophylline and ambrisentan is a potentially safe treatment of health complications after rapid ascent to high altitudes

Abstract

Combined theophylline and ambrisentan improve exercise tolerance in rats after rapid ascent to high altitude, by accelerating blood flow and oxygen delivery to peripheral tissues. We hypothesized that this combination is also safe in humans, and that the single drugs do not interact.MethodsHealthy human subjects were randomized to one of two sequences. Sequence A was a single 400 mg dose of aminophylline (soluble form of theophylline) followed by 48 h washout, then 5 mg of ambrisentan followed by 48h washout, then 400mg aminophylline and 5mg ambrisentan combined. Sequence B was the same, except subjects were dosed first with ambrisentan and then aminophylline. Adverse event (AE) and pharmacokinetic (PK) profiles were assessed.ResultsOf 47 subjects recruited, 18 completed all procedures. Total 70 transient AEs of mild (71%), moderate (26%) or severe (3%) intensity occurred, most in the first cohort of subjects [64 (91%)] and following aminophylline given alone (38%) or combined with ambrisentan (47%). As expected, PK curves showed no drug interaction.ConclusionsCombined dosing with the xanthine aminophylline and the endothelin receptor antagonist ambrisentan is safe in healthy humans, and these drugs do not interact. AE profiles were as expected and mostly due to the high dose of aminophylline. An upcoming trial will test this drug combination for safety and efficacy in hypoxic exercising human subjects.