P. Chanu(1), X. Gao(2), R. Bruno(1), L. Harnisch(3)
(1)Pharsight Consulting Services, A division of Certara, St. Louis, MO, USA; (2)Pfizer, Clinical Pharmacology, New London, CT, USA; (3)Pfizer, Pharmacometrics, Sandwich, UK
Objectives: The assessment of efficacy of pulmonary arterial hypertension treatments is mainly based on improvements in exercise capacity: six-minute walk distance (6MWD). Sildenafil (REVATIO®), 20 mg TID, received approval for the treatment of adult PAH in the US based on 6MWD data. A recent FDA analysis [1] showed a relationship between changes from baseline in 6MWD and pulmonary vascular resistance index (PVRI), an hemodynamic (HD) endpoint in the adult PAH population. The objective of this analysis was to assess whether some patients could have reached their PVRI reduction target from a higher sildenafil dose than the one currently registered according to their baseline and patho-physiological characteristics.
Methods: A previous population PK/PD analysis of PVR data from two pivotal sildenafil trials in adult [2] (n=218) and pediatric patients (n=219, 1-17 y) was performed in NONMEM 7 to characterize the relationships between PVR (=PVRI/BSA), baseline patho-physiological covariates and sildenafil exposure [3]. Simulations, based on pre-defined success criteria to achieve expected HD responses as a function of age, functional class and baseline PVR were conducted to assess the potential PVRI reduction associated with higher doses (40 and 80 mg TID) of sildenafil in some PAH patients compared to the labeled dose.
Results: The model based simulations of HD outcomes showed that while 20 mg TID provides a clear improvement over placebo, the 80 mg TID regimen provides a substantial additional improvement over the labeled dose, whereas a 40 mg TID regimen provides only a marginal additional improvement. Simulations focusing on a target PVR improvement from baseline (200 dyne.s.cm-5 reduction) showed that elderly patients (60 to 80 y) may expect a lower response rate with the labeled dose but a similar response rate with 80 mg TID compared to that obtained in younger patients at the labeled dose. Simulations focusing on the achievement of a target PVR value of less than 350 dyne.s.cm-5 showed that more severe patients at functional class 3 or 4 and/or high baseline PVR may also reach the PVR target with a 80 mg TID regimen.
Conclusions: Model based simulations of PVR outcome showed that a dose of 80 mg TID might provide additional PVR improvement in specific PAH populations (elderly, severe patients). The implication of these simulation results into 6MWD improvement remains to be further investigated.
References:
[1] FDA Cardiovascular and Renal Drugs Advisory Committee Meeting, July 29, 2010. http://www.fda.gov/AdvisoryCommittees/Calendar/ucm217266.htm
[2] Galie et al, Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension N Engl J Med, 353:2148-57, 2005.
[3] P Chanu, X Gao, M Smith, R Bruno, L Harnisch, A dose selection rationale based on hemodynamics for sildenafil in pediatric patients with pulmonary arterial hypertension (PAH), PAGE, Athens, 2011, PAGE 20 (2011) Abstr 2104 [www.page-meeting.org/?abstract=2104].
Reference: PAGE 21 () Abstr 2395 [www.page-meeting.org/?abstract=2395]
Poster: Other Modelling Applications