Pablo Gamallo1, Steven Zhang2, Verity Rawson2
1Novo Nordisk Pharma SA, 2Novo Nordisk Inc.
Introduction: Primary hyperoxaluria is a rare autosomal-recessive disorder resulting in the overproduction of oxalate that leads to recurrent kidney stones and progressive kidney damage [1]. Nedosiran (Rivfloza®) is a small interfering RNA interference therapy approved in the US for individuals aged =9 years with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function (eGFR = 30 mL/min/1.73 m²). Nedosiran inhibits oxalate production by silencing lactate dehydrogenase (LDH) mRNA in hepatocytes. Building upon prior models [2], a population PK/PD model characterizing the plasma concentration-time profile of nedosiran and its effect on the spot urine oxalate-to-creatinine ratio (Uox/Cr) was developed and validated using data from six clinical trials. The population PK/PD model was used to assess the effect of covariates on exposure and efficacy response and to perform simulations in paediatric populations. Objectives: •Update a previous population PK model with additional data from more pediatric patients and longer exposure •Derive a nedosiran population PD model based on accurate spot Uox/Cr (6 measurements at baseline and 4 at each visit) from patients with PH1 •Perform population PK/PD model simulations to support the proposed dosing regimen for children across age subgroups Methods: The population PK analysis consisted in updating a previously developed population PK model [2] with the additional plasma PK observations from studies PHYOX8 (NCT05001269) and PHYOX3 (NCT04042402). The same prior population PK model structure was considered, a two-compartment with dual transit absorption and parallel linear and nonlinear elimination. A reassessment of the significant covariates (body weight, eGFR and PH type) identified in the previous PK model was done. A population PD model analogous to the previously developed for the 24-hour urine oxalate [2] was contemplated for the spot Uox/Cr. The PD consisted of an indirect model with an effect compartment to describe the sustained effect of nedosiran on the reduction of spot Uox/Cr. Body weight and eGFR were assessed as continuous covariates on IC50 and Imax. Based on the results reported by Matos et al [3], age was evaluated as a covariate for the baseline spot Uox/Cr. The population PK and PK/PD analyses were carried out in NONMEM®, using FOCE-I. GOF plots and VPCs were used to evaluate the models. For the PK/PD simulations, a virtual population was generated from the WHO z-scores [4] and the continuous NHANES datasets [5]. For the paediatric population, the maturation function that describes the increase in glomerular filtration rate with age was included in the derivation of their eGFR [6]. The PK/PD simulations were performed in R with the package mrgsolve [7]. Results: A total of 2087 plasma PK data from 148 participants (85 HVs, 49 patients with PH1, and 14 with PH2), across six clinical studies, contributed to the population PK model. The updated population PK parameters were comparable to previous estimates [2]. The effect on the PK exposure, AUCtau,ss and Cmax,ss, of nedosiran by the identified significant covariates in the population PK model: body weight, PH type/HVs and eGFR, was assessed. Body weight in the low and high percentiles showed an increase and a decrease, respectively, in their relative exposures. Moderate renal impairment (eGFR 30 – 59 mL/min/1.73m²) showed an increase in exposure. Mild renal impairment (eGFR 60 – 89 mL/min/1.73m²) and PH type showed no effect on PK exposure of nedosiran. Data from 668 spot Uox/Cr observations of 41 patients with PH1 were utilized for fitting the population PD model. Age was identified as a significant covariate on the baseline spot Uox/Cr. No other significant covariates were identified for the IC50 and Imax in the population PD model. Simulations with the final population PK/PD model showed similar reductions of spot Uox/Cr during treatment and similar time to reach the maximum effect in pediatric patients with PH1 across the different age groups as well as across the different kidney functions (normal, mild and moderate renal impairment) on the dose regimen of 3.5 mg/kg Q1M, when compared to patients with PH1 aged =12 years and weighed =50 kg on the dose regimen 170 mg Q1M. Conclusions: Simulations based on the final population PK/PD model support the 3.5 mg/kg once-monthly dosing regimen in children aged 0 to <12 years with PH1 and relatively intact kidney function (eGFR = 30 mL/min/1.73 m²).
[1] Cochat P et al., N Engl J Med. 2013;369(7):649-58 [2] Zhang S. et al., Br J Clin Pharmacol. 2024;1–14 [3] Matos V., Am J Kidney Dis. 1999;34(2):e1 [4] World Health Organization. The WHO child growth standards. https://www.who.int/tools/child-growth-standards/standards/weight-for-age [5] National Center for Health. Continuous NHANES. https://wwwn.cdc.gov/Nchs/Nhanes/ [6] Anderson BJ, Holford NH. Paediatr Anaesth. 2011;21(3):222-37 [7] Baron K (2024) mrgsolve R package https://github.com/metrumresearchgroup/mrgsolve
Reference: PAGE 33 (2025) Abstr 11436 [www.page-meeting.org/?abstract=11436]
Poster: Drug/Disease Modelling - Paediatrics