Characterisation of Population Pharmacokinetics and Endogenous Follicle Stimulating Hormone (FSH) Levels after Multiple Dosing of a Recombinant Human FSH, FE 999049, in Healthy Women

Objective: The aim of this study was to characterise the
population pharmacokinetics of FE 999049, a novel
recombinant human follicle-stimulating hormone (FSH),
after multiple dosing in healthy women, taking into
account endogenous FSH levels and the reproductive hormone
dynamics.
Methods: Longitudinal measurements of FSH, luteinising
hormone, progesterone, estradiol, and inhibin B levels were
collected after repeated subcutaneous dosing with 225 IU
of FE 999049 in 24 gonadotropin downregulated healthy
women. The FSH data were described using nonlinear
mixed-effects modelling.
Results: The measured FSH levels were modelled as a
sum of endogenous FSH and FE 999049. The FE 999049
population pharmacokinetics were best described using a
one-compartment model with first-order absorption and
elimination, and a transit model for delayed absorption.
The apparent clearance and volume of distribution
increased with body weight in accordance with an allometrically
scaled power exponent of 0.75 and 1, respectively.
Endogenous FSH levels were lower in individuals
with higher progesterone levels at baseline and were further
suppressed over time with increasing inhibin B levels.
Conclusions: This characterisation of FE 999049 population
pharmacokinetics after repeated dosing is in line with
previous findings after single-dose administration. The
results provide a basis for study design and data evaluation
in the future development of recombinant FSH products,
and show it can be of importance to account for endogenous
FSH levels and its variation over time for accurate
estimation of exogenously administered FSH pharmacokinetic
parameters. Thus, correcting FSH concentrations by
the observed endogenous