Paediatric population pharmacokinetic and pharmacodynamic modelling of
ambrisentan in pulmonary arterial hypertension and comparison with adult
data
Abstract
Aims: To develop a population pharmacokinetic (PK) model of ambrisentan
in paediatric patients aged 8 to <18 years with pulmonary
arterial hypertension (PAH), compare paediatric ambrisentan systemic
exposure to historical adult data, and assess PK–PD relationships.
Methods: A previously developed adult population PK model provided an
initial step for modelling the 211 PK observations from 39 paediatric
patients with PAH in the randomised Phase IIb study AMB112529
(NCT01332331). Subsequently, a population PK model was developed using
only paediatric PK data. Steady-state systemic exposure metrics were
estimated for the paediatric population and compared with historical
adult data (adult patients with PAH and healthy volunteers). Exploratory
exposure–response analysis assessed ambrisentan systemic exposure
versus change from baseline in 6-minute walking distance in paediatric
patients; findings were compared with adult data. An exploratory
analysis of ambrisentan exposure versus incidence of ambrisentan-related
adverse events in paediatric patients was also performed. Results: The
final paediatric population PK model was a two-compartment model which
includes the effect of body weight (allometric scaling), first-order
absorption and elimination, and absorption lag time. Similar
steady-state ambrisentan exposure was confirmed in paediatric patients
and historical adult data when differences in body weight were accounted
for. There was no apparent correlation in the paediatric or adult
population between ambrisentan exposure and change in 6-minute walking
distance, or between ambrisentan exposure and incidence of
ambrisentan-related adverse events in paediatric patients. Conclusions:
Similar ambrisentan exposure and PK–PD profiles were observed in
paediatric and adult populations with PAH.