Population PK analysis using the PRIOR subroutine in NONMEM
In literature the PK of tezacaftor-ivacaftor has been described by
two-compartment models (figure 1 and 2) (4, 9). In the present study,
the available sparse data did not allow a precise estimation of all
model PK parameters. Instead of fixing parameters to known values from
the literature, the PRIOR subroutine was used in the nonlinear
mixed-effects modelling (NONMEM) software (v7.5.1 ICON
Development Solutions, Dublin, Ireland ). (6) For development of the
popPK models for tezacaftor-ivacaftor and their active metabolites,
popPK information was derived from the registration document of
tezacaftor-ivacaftor (Symdeko®). (4) In this document popPK parameters
for tezacaftor, tezacaftor-M1 and ivacaftor models were described; no
information was available for ivacaftor-M1/M6.
The PK of tezacaftor(-M1) was described by a two-compartment model for
both the parent compound and the metabolite, with zero-order absorption
into the depot compartment, followed by first order absorption to the
central compartment and first-order elimination of both the parent and
metabolite (figure 1). (4) The PK of ivacaftor was described by a
two-compartment model for the parent compound with zero-order absorption
into the depot compartment, followed by first order absorption to the
central compartment. Elimination and conversion of the parent to the
metabolites was described with first-order rate constants. (4) As there
were no models available for ivacaftor’s metabolites, they were
described by a one-compartment model with first order absorption and
elimination, and linked to the central compartment of ivacaftor (figure
2). (9, 10)
These models were used as a starting point for the popPK analysis of the
current study. Concentrations of the metabolites were adjusted
to their parent equivalents using the molecular weight. Since there is
no intravenous formulation available, PK parameters of the parent
compounds were estimated as apparent clearance (CL/F), apparent
intercompartmental clearance (Q/F) and apparent volume of distribution
(V/F). For the metabolites the fraction parent drug metabolized into the
metabolite was fixed to 1, and therefore PK parameters of the
metabolites were estimated as apparent clearance of the fraction
metabolized (CL/(F*fm)) and apparent volume of
distribution of the fraction metabolized (V/(F*fm)).