Xiang Gao (1) and Lutz Harnisch (2)
(1) Clinical Pharmacology, Pfizer Inc, Groton, USA (2) Global Clinical Pharmacometrics, Pfizer Inc, Sandwich, UK
Objective: To predict the sildenafil PK in children with PAH 1 to 12 months old and to derive corresponding dosing recommendations.
Methods: Sets of predicted PK exposure data were generated in children 1 to 12 months old by two PK models developed previously: 1) a Persistent Pulmonary Hypertension of the Newborn (PPHN) PK model (1) (11 hours to 10 days old) to project forward to 1 year and 2) a PAH PK model (2) (1 to 17 years old) to project backwards to 1 month.
To qualify either model for selection, two simulation schemes were conducted: 1) a weight based regimen (0.4 to 4 mg/kg), commonly used in clinical practice; and 2) a fixed dose regimen (2 to 20 mg). The ontology of CYP3A, responsible for sildenafil clearance, provided additional scientific basis for the model selection. The results were compared to the PPHN PK exposure at one month, and the PAH PK exposure at one year, with the better PK model chosen based on the closeness of its generated PK exposure to these two reference points. A sensitivity analysis with alternative models and a limited external validation were performed to justify the model selection. The selected model was finally used to derive the dose recommendation for pediatric PAH patients, one month to one year old.
Results: Under the two simulation schemes, the CL/F and Css values extrapolated back to 1 month, using the PAH PK model, were very close to the 1 month values predicted by the PPHN PK model; whereas the CL/F and Css values extrapolated to 1 year from 1 month by the PPHN PK model deviated substantially from the 1 year values predicted by the PAH PK model. Hence, the PAH population PK model was chosen to predict the PK for children from 1 month to 1 year. Subsequently, two dose regimens, 1.2 mg/kg or 7 mg TID, were proposed for the treatment of PAH pediatric patients from one month to one year old as they would predict to produce a similar exposure compared to the labeled dose in PAH pediatric patients. The sensitivity analysis revealed that if the alometric scaling would have been used, there were no substantial differences between the selected model and alternative scaling methods. A limited external validation using data extracted from literature (3) showed that the selected model described the observed data quite well.
Conclusions: The PAH PK model adequately predicts the sildenafil PK in PAH patients aged one month to one year. Using this model, an oral dosing regimen of 1.2 mg/kg TID or a fixed dose of 7 mg TID can be recommended for this age group for the treatment of PAH.
References:
[1] Mukherjee A, Dombi T, Wittke B, Lalonde R. Population pharmacokinetics of sildenafil in term neonates: evidence of rapid maturation of metabolic clearance in the early postnatal period. Clin Pharmacol Ther. Jan 2009;85(1):56-63.
[2] Watt S, Nahashi N, Harnisch L, Gao X. Population pharmacokinetics (PK) of sildenafil in paediatric and adult patients with pulmonary arterial hypertension. ESC. Stockholm, Sweden; 2010.
[3] Ahsman MJ, Witjes BC, Wildschut ED, et al. Sildenafil exposure in neonates with pulmonary hypertension after administration via a nasogastric tube. Arch Dis Child Fetal Neonatal Ed. Mar;95(2):F109-114. 2010.
Reference: PAGE 21 (2012) Abstr 2379 [www.page-meeting.org/?abstract=2379]
Poster: Paediatrics