Mita M Thapar (1), Colm Farrell (1), Gordon Graham (2), Olivier Petricoul (2)
(1) ICON Plc, (2) Novartis
Objectives:
The objectives of the present analysis were:
- to develop a linear mixed effects PK model to describe the FTY720-P concentrations at steady-state in the MS pediatric patient population using data from Study CFTY720D2311 (D2311).
- to assess by performing a visual predictive check (VPC) whether the previously developed adult FTY720-P exposure-lymphocyte model described the pediatric lymphocyte data from study D2311 and to re-estimate the parameters of the exposure-lymphocyte model using a combined dataset of adult and pediatric patient data.
Methods:
Population PK model
- A linear mixed effect model was developed to describe the FTY720-P concentrations at steady-state in the pediatric MS patients using data from Study D2311 alone;
- Age, weight and dose group were investigated (both as time-varying and time-invariant) covariates in the present analysis;
- The final population PK model was evaluated by performing a prediction corrected (pc) VPC.
Exposure-lymphocyte count model
- An exploratory pc-VPC was performed to assess whether a previously developed adult exposure-lymphocyte model described the pediatric lymphocyte data from Study D2311;
- The parameters of the exposure-lymphocyte model were re-estimated using a combined dataset from adult and pediatric patients to determine which parameters were different between the adult and pediatric populations. A binary pediatric/adult covariate was added on the model parameters, baseline, IC50 and Imax to assess the potential difference between adult and pediatric patients;
- The final exposure-lymphocyte count model was evaluated by performing a pc-VPC.
NONMEM® program version VII level 3.0 was used for all analyses using PDx-Pop (Version 5.2) as an interface.
Results:
Population PK model
- Following administration of 0.5 mg per day of FTY720 in a pediatric population, the typical steady-state FTY720-P concentration for a body weight of 70 kg (0.978 ng/mL) was within the 90% CI around the median of the adult target FTY720-P steady-state concentration and higher than the 65% relative bound (0.878 ng/mL) of the adult target FTY720-P steady-state concentration level.
- The steady-state FTY720-P concentrations were dose proportional following 0.25 and 0.50 mg capsule formulation of FTY720 in the pediatric population.
- The steady-state FTY720-P concentrations decreased slightly with increasing body weight. The decrease in concentration was non-linear. An increase of 10 kg weight from 20 to 30 kg and from 70 to 80 kg resulted in a 15.2% and a 5.3% decrease in FTY720-P concentrations, respectively.
Exposure-lymphocyte count model
- The FTY720-P exposure-lymphocyte relationship in adults is an Imax model relating the estimated FTY720-P concentrations at steady state to the absolute lymphocyte count.
- The baseline lymphocyte count was estimated to be 17.2% higher in pediatric patients compared to the adult population. Both Imax and IC50 were comparable between pediatric and adult populations with Imax 6% lower (95% CI: 8% higher to 20% lower) and IC50 12% lower (95% CI: 4% higher to 66% lower) in pediatric versus adult patients.
- The baseline lymphocyte count was slightly higher for higher baseline weights. A 10-kg increase in weight (from 70 to 80 kg) resulted in only a 2% increase in lymphocyte count.
Conclusions:
Overall, the FTY720-P exposure was considered similar between adult and pediatric patients. The exposure-lymphocyte count analysis suggested that there is no evidence of a difference in the exposure-response relationship between adult and pediatric patients once the difference in baseline is taken into account.
Reference: PAGE 27 (2018) Abstr 8428 [www.page-meeting.org/?abstract=8428]
Poster: Drug/Disease Modelling - Paediatrics