Substantial Increase of Sildenafil Bioavailability after Sublingual Administration in Two Children with Congenital Heart Defects

Background: Pulmonary hypertension is a progressive disease of diverse origin with devastating consequences in children. The phosphodiesterase-5 inhibitor sildenafil successfully lowers pulmonary vascular resistance. However, responses in infants and children are often erratic due to poor oral absorption resulting in ineffective plasma concentrations. In adults, bioavailability (F) of sublingual sildenafil appears considerable suggesting that this might be a promising alternative route of administration in children with poor absorption.

Methods: The authors evaluated the plasma concentrations of orally and sublingually administered sildenafil suspension (4 – 10 mg/d qid) in two children suffering from structural cardiac and pulmonary defects. Because one child also received sildenafil intravenously, absolute F could be estimated. Sildenafil and N-desmethyl-sildenafil were measured using a validated LC/MS/MS methodology.

Results: In the first case (6 mo-old boy) sublingual administration resulted in ˜3 times higher plasma concentrations (12 – 20 vs. 2.7 – 6.9 ng/mL). Exposure of the second child (2.5-y-old boy) expressed as the area under the curve in the dosing interval (AUC0 – 6h) was 918 (intravenous), 106 (sublingual), and 25 hour ng/mL after oral administration indicating that estimated oral F increased by 314%. Concurrently in both children molar metabolic ratios after sublingual sildenafil increased 3- to 8-fold suggesting a successful bypass of first pass metabolism.

Conclusion: Sublingual sildenafil achieved considerably higher exposure than oral suggesting that this route of administration might be an attractive way to overcome the frequently observed poor gastrointestinal absorption and low systemic availability.