A dose selection rationale based on hemodynamics for sildenafil in pediatric patients with pulmonary arterial hypertension (PAH)
P. Chanu(1), X. Gao(2), M. Smith(3), R. Bruno(1), L. Harnisch(3)
(1)Pharsight, a CertaraTM company, St. Louis, MO, USA; (2)Pfizer, Clinical Pharmacology, New London, CT, USA; (3)Pfizer, Pharmacometrics, Sandwich, UK
Objectives: The efficacy of medications in PAH is mainly based on improvements in exercise capacity: six-minute walk distance (6MWD) or peak oxygen consumption (pVO2) in adults. In children ≥7 y, 6MWD is not well reproducible and pVO2 is thus the preferred test. In younger patients an exercise capacity test is not doable and hemodynamic endpoints may be used to assess efficacy [1, 2]. A recent FDA analysis  showed a relationship between changes from baseline in 6MWD and pulmonary vascular resistance index (PVRI) in the adult PAH population. Sildenafil (REVATIO®), 20 mg TID, received approval for the treatment of adult PAH in the US based on 6MWD data. The objective of this analysis was to support the dose selection of sildenafil in the pediatric PAH population using a model-based approach to pulmonary vascular resistance (PVR) outcomes bridging efficacy from adults to children.
Methods: A population PK/PD analysis of PVR data from two pivotal sildenafil trials in adult  (n=218) and pediatric patients  (n=219, 1-17 y) was performed in NONMEM 7. A model was developed to characterize the relationships between PVR, baseline pathophysiological covariates and sildenafil exposure (obtained using a previously developed population PK model [6, 7]). Simulations based on clinically defined success criteria to achieve similar hemodynamic responses in children compared to those seen in adults under the labeled dose were conducted to support the dose selection in pediatric PAH patients.
Results: PVR was modeled as a function of baseline covariates (functional class, etiology, age, body surface area, ability for exercise capacity assessment) and sildenafil exposure. Model based simulations suggested that for children a dose of 10 mg TID up to 20 kg and 20 mg TID beyond achieves a comparable PVR response to adults at the labeled dose of 20 mg TID, i.e., a 20% improvement in change from baseline in 40% of patients. Clinical results and similar analyses [8, 9] on pVO2 data in children 7-17 y confirmed the selected regimen.
Conclusions: A recent FDA assessment of the relationship between 6MWD and PVRI proposes the use of HD endpoints to support drug development in PAH especially in the pediatric population. Leveraging the FDA assessment, contrasting it with Pfizer's sildenafil data, and utilizing model based simulations of HD endpoint outcomes allowed bridging efficacy from adults to children supporting dose recommendations for sildenafil in pediatric PAH patients.
 L Harnisch, P Chanu, K Dykstra, L Claret, R Bruno, X Gao, Hemodynamics as a substitute for exercise capacity endpoints in patients with pulmonary arterial hypertension (PAH): A model based assessment for sildenafil, ERS, Barcelona, 2010, Presentation 200.
 J Wagg, L Claret, R Bruno, K Dykstra, X Gao, L Harnisch, Exploratory modeling of exercise capacity and hemodynamic endpoints in patients with pulmonary arterial hypertension, ESC, Stockholm, 2010, Presentation 86389.
 FDA Cardiovascular and Renal Drugs Advisory Committee Meeting, July 29, 2010. http://www.fda.gov/AdvisoryCommittees/Calendar/ucm217266.htm
 Galie et al, Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension N Engl J Med, 353:2148-57, 2005.
 Simonneau et al, Addition of Sildenafil to Long-Term Intravenous Epoprostenol Therapy in Patients with Pulmonary Arterial Hypertension, Ann Intern Med, 2008;149:521-530.
 L Harnisch, N Hayashi Population pharmacokinetic (PK) of sildenafil in paediatric and adult pulmonary arterial hypertension (PAH) patients, ERS, Vienna, 2009, P3916.
 S Watt, N Hayashi, L Harnisch, X Gao, Population pharmacokinetics of sildenafil in paediatric and adult patients with pulmonary arterial hypertension, ESC, Stockholm, 2010, Poster 83747.
 N Hayashi, L Harnisch, Population PK of Sildenafil and PK/PD assessment of Exercise tolerability in children with Pulmonary Arterial Hypertension (PAH), PAGE, St Petersburg, 2009, Abstr 1523. www.page-meeting.org/?abstract=1523
 L Harnisch, N Hayashi Exercise tolerability in children with pulmonary arterial hypertension (PAH), a population PK/PD assessment of the effects of sildenafil, ERS, Vienna, 2009, P3890.