Chanu P(1), Weichert A(2), Schaefer F(3), Frey N(4)
(1) Clinical Pharmacology, Genentech/Roche, France and Certara Strategic Consulting, France; (2) Clinical Science, Roche Pharma Development, Switzerland; (3) Division of Pediatric Nephrology, Heidelberg University Hospital, Germany; (4) Clinical Pharmacology, Roche pRED, Roche Innovation Center Basel, Switzerland
Objectives:
C.E.R.A. indicated in Chronic Kidney Disease (CKD) patients (pts) to correct and maintain hemoglobin (Hb) levels has been approved in Europe and US in 2007 in adults. Roche also submitted Pediatric Investigation and Pediatric Study Plans for C.E.R.A. As part of the pediatric development plans, a 20-week open-label Phase II study (NH19707) of intravenous (IV) C.E.R.A. in pts aged 5–17 years was conducted. In pediatric patients, the goal is to maintain Hb levels with C.E.R.A. after correction by another Erythropoietin Stimulating Agent. The data collected in this trial was analysed with adult IV and subcutaneous (SC) data. The objectives were to determine the PK/PD characteristics of C.E.R.A. in a broad population and, using simulations, to optimize the design of a second pediatric study using SC administration of C.E.R.A.
Methods:
PK and Hb data from 63 pediatric pts were pooled with 400 pts adult IV and SC data. Adult PK/PD structural models previously developed were used for the analyses1. A non-linear mixed effect modeling approach was applied. Assumptions on C.E.R.A. SC bioavailability in pediatric patients were based on darbepoetin data2,3. Simulations tested various values of bioavailability. Model inferences were challenged versus Real World Data (RWD) from registries maintained by the International Pediatric Dialysis Network (IPDN, www.pedpd.org). RWD were obtained in 107 pediatric patients receiving C.E.R.A. SC and 22 pediatric patients receiving C.E.R.A. IV.
Results:
The adult PK model (1-compartment model with first order absorption and elimination) adequately described the pediatric data. As in adults, C.E.R.A. clearance increased with body weight and the volume of distribution increased with body weight and age. Once those body-size related covariates were accounted for, there was no difference in PK between adult and pediatric pts. The PK/PD model developed on adult data could be successfully applied to pediatric data. The drug dependent parameters were comparable in pediatric and adult pts indicating a similar exposure-response relationship in both populations. The SC study design was simulated assuming a reduced number of subjects (N=25) compared to the one foreseen in existing pediatric plans (N=150). The different scenarios tested either no increase or 30% to 50% increase in bioavailability in pediatric patients compared to adults. Results are presented in Table 1 and showed that prediction intervals of the mean change of Hb from baseline included the value 0.
Table 1: Simulations of Hb and Dose Distribution at the End of Evaluation Period (Week 20)
|
Scenarios |
SC simulations |
Observations (SC) from IPDN |
IV simulations |
Observations (IV) from NH19707 |
|
|
Mean change in Hb from baseline (g/dL) and 95% prediction interval |
|||
|
F |
-0.26 [-1.39;0.80] |
IPDN: NA |
0.07 [-0.22;0.43] |
NH19707: -0.09 |
|
1.3F |
-0.14 [-1.47;0.82] |
|||
|
1.5F |
0.04 [-1.07;1.05] |
|||
|
|
Mean Hb (g/dL) and 95% prediction interval |
|||
|
F |
10.80 [10.36;11.26] |
IPDN: 10.9 |
10.95 [10.57;11.31] |
NH19707: 10.94 |
|
1.3F |
10.88 [10.49;11.26] |
|||
|
1.5F |
10.92 [10.46;11.34] |
|||
|
|
Median dosea (μg every 4 weeks) and 95% prediction interval |
|||
|
F |
125 [81;220] |
IPDN: 100 |
84 [60,123] |
NH19707: 120 |
|
1.3F |
110 [73;184] |
|||
|
1.5F |
101 [60;170] |
F: assuming adult bioavailability, 1.3F and 1.5F: assuming 30% and 50% increase in bioavailaility respectively compared to adults
a: C.E.R.A. doses are adjusted according to Hb levels
Previous data on darbepoetin suggested that the most likely scenario is a 50% increase in bioavailability compared to adults. RWD confirmed model predictions as shown in Table 1. Additional safety information was obtained from the literature4,5. Revised pediatric plans were approved by FDA and EMA.
Conclusions:
The PK/PD characteristics of C.E.R.A. are similar between adult and pediatric populations. Simulations of clinical outcomes support pediatric plans optimization with reduced costs, time and burden to patients while maximizing information on the target pediatric population; and support C.E.R.A. IV and SC dosing in pediatric pts with CKD.
References:
[1] Chanu P, Gieschke R, Charoin JE, Pannier A, Reigner B. Population pharmacokinetic/pharmacodynamic model for C.E.R.A. in both ESA-naïve and ESA-treated CKD patients with renal anemia. Journal of Clinical Pharmacology. J Clin Pharmacol. 2010; 50(5):507-520.
[2] Darbepoietin USPI
[3] Darbepoietin PIP
[4] Cano F, Alarcon C, Azocar M, Lizama C, Maria Lillo A, Delucchi A, Gonzalez M, Arellano P, Delgado I, Droguett MT. Continuous EPO receptor activator therapy of anemia in children under peritoneal dialysis. Pediatr Nephrol. 2011;26:1303-1310.
[5] Wedekin M, Ehrich JH, Pape L. Effective treatment of anemia in paediatric kidney transplant recipients with methoxy polyethylene glycol-epoetin beta. Pediatr Transplant. 2011;15:329-333.
Reference: PAGE 27 (2018) Abstr 8759 [www.page-meeting.org/?abstract=8759]
Poster: Drug/Disease Modelling - Paediatrics