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)).