Sildenafil exposure in neonates with pulmonary hypertension after administration via a nasogastric tube.
OBJECTIVE
To describe the pharmacokinetics and exposure of oral sildenafil (SIL) in neonates (2-5 kg) with pulmonary hypertension (PH).


METHODS
We included 11 neonates (body weight 2-5 kg, postnatal age 2-121 days) who received SIL and extracorporeal membrane oxygenation (ECMO) treatment for PH. SIL capsules were given via a nasogastric tube. Blood samples were collected via a pre-existing arterial line to quantify SIL and metabolite plasma levels (219 samples). Non-linear mixed effects modelling was used to describe SIL and desmethylsildenafil (DMS) pharmacokinetics.


RESULTS
A one-compartment model was suitable for SIL and DMS. Interpatient and intrapatient variability for clearance at 100% bioavailability were 87% and 27% (SIL) and 62% and 26% (DMS). Patient weight, postnatal age and post-ECMO time did not explain variability. Concomitant fluconazole use was associated with a 47% reduction in SIL clearance. The exposure expressed as average plasma concentration area under the curve over 24 h (AUC(24 (SIL+DMS))) ranged from 625 to 13 579 ng/h/ml. An oral dose of 4.2 mg/kg/24 h would lead to a median AUC(24 (SIL+DMS)) of 2650 ng/h/ml equivalent to 20 mg three times a day in adults. Interpatient variability was large, with a simulated AUC(24 (SIL+DMS)) range (10th and 90th percentiles) of 1000-8000 ng/h/ml.


CONCLUSIONS
SIL pharmacokinetics are highly variable in post-ECMO neonates and infants. In a median patient, the current dose regimen of 0.5-2.0 mg/kg four times a day leads to an exposure comparable to the recommended adult dose of 20 mg four times a day. Careful dose titration, based on efficacy and the occurrence of hypotension, remains necessary. Follow-up research should include appropriate pharmacodynamic endpoints, with a population pharmacokinetic/pharmacodynamic analysis to assign a suitable exposure window or target concentration.
Ahsman
Maurice J
MJ
Department of Hospital Pharmacy (Clinical Pharmacology Unit), Erasmus University Medical Center, Rotterdam, The Netherlands.
Witjes
Bregje C
BC
Wildschut
Enno D
ED
Sluiter
Ilona
I
Vulto
Arnold G
AG
Tibboel
Dick
D
Mathot
Ron A
RA
D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D001724:Birth Weight; D002214:Capsules; D015199:Extracorporeal Membrane Oxygenation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000628:therapy; D007223:Infant; D007231:Infant, Newborn; D007441:Intubation, Gastrointestinal; D056687:Off-Label Use; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011687:Purines / Q000008:administration & dosage / Q000493:pharmacokinetics; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000959:Antihypertensive Agents; D002214:Capsules; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate