Population PK of Sildenafil and PK/PD assessment of Exercise tolerability in children with Pulmonary Arterial Hypertension (PAH)
N. Hayashi (1), L. Harnisch (2)
(1) Clinical Pharmacology, CDMA, Specialty Care Business Unit, Pfizer Limited, Sandwich, UK; (2) Global Pharmacometrics, Pfizer Limited, Sandwich, UK
Objectives: PAH is characterised by an increase in pulmonary vascular resistance, leading to right ventricular failure and, ultimately, death. Sildenafil a PDE5 inhibitor is approved for the treatment of adult PAH. Study A1481131 investigated the sildenafil use in children. Objectives were to assess the sildenafil PK and the peak oxygen consumption (pVO2) a cardio pulmonary exercise tolerance PD endpoint, which substitutes in children for the clinically frequently used 6 Minute-Walking-Test, only practical in adults. Final goal is to provide an optimal dosage for children.
Methods: PK data from this study was combined with previous adult data to explore the maturation process of the clearance covering neonate, children, and adult PAH patients. Using non-linear mixed effect modelling, a 1 compartment model with 1st order absorption and lag time was applied. The PK/PD analysis used pVO2 at baseline and end of treatment (16 wks) in conjunction with model predicted and individual PK exposure estimates
Results: PK samples from 173 children (1-17 years) and 207 adult patients were available. The relationship between body weight (BW) and oral clearance (CL/F) was well described by a sigmoid model with an intercept, reflecting the state and maturation process beyond the age of 1 year. Estimated model parameters were CLmax/F (57.8 L/h), CL0/F (13.9 L/h), slope (3.7), and weight at half CLmax/F (21.3 kg). CL increased 3 fold during 7 days after birth and showed a high correlation with BW  but BW or age didn't influence CL/F in adults.
Only 115 children (above 8 years) were developmentally able to perform the exercise test. A sigmoid Emax model described the relationship between average steady-state concentration (Cav,ss) and pVO2 increase. The maximal drug effect was estimated at 9.1%, a level considered to be clinically relevant. Cav,ss producing 90% of the maximal sildenafil response was estimated at 31 ng/mL. 48% of patients (plc: 20%) would meet a clinical responder criteria at the highest dose, defined as 10% improvement in pVO2. A dosage of 10 mg for children up to 20 kg, and 20 mg beyond is likely to achieve 85% of the maximum responder rate.
Conclusions: The integrated PK/PD assessment characterised the CL/F maturation (<4 fold change) from neonates to adult PAH patients as well an exposure range translating into a clinically meaningful response, which allowed to project a dose regimen expected to be efficacious in children with PAH.
 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. 2009;85(1):56-63.