(T-080) Population Pharmacokinetic/Pharmacodynamic Modeling and Analysis of Tetrahydrobiopterin and Blood Phenylalanine Response in Adult and Pediatric Patients with Phenylketonuria During Sepiapterin Treatment

Lan Gao – PTC Therapeutics, Inc; Yongjun Hu – PTC Therapeutics, Inc; Leng Hong Pheng – Certara, Certara Drug Development Solutions; Nathalie Gosselin – Certara, Certara Drug Development Solutions; Zhenming Zhao – PTC Therapeutics, Inc; Kimberly Ingalls – PTC Therapeutics, Inc; Ronald Kong – PTC Therapeutics, Inc; Neil Smith – PTC Therapeutics, Inc

Background: Sepiapterin is a novel small molecular entity, synthetically manufactured equivalent of endogenous sepiapterin. Sepiapterin has dual roles: (1) as a pharmacologically active chaperone for maintaining phenylalanine hydroxylase (PAH) native state conformation and activity; and (2) as a precursor to the active metabolite 5,6,7,8-tetrahydrobiopterin (BH4). BH4 is an essential cofactor for PAH that catalyzes hydroxylation of phenylalanine (Phe) to tyrosine, and acts as a chaperone to stabilize PAH. This analysis aimed to conduct pharmacokinetic (PK)/pharmacodynamic (PD) modeling and simulations to optimize dosing regimens for patients with PKU from neonates to adults and specific races (Asian vs non-Asian).

Methods: Non-linear mixed effect models were developed to analyze pooled PK data of BH4 in healthy volunteers (N=165) and PK/PD data of BH4 and Phe in patients with PKU (N=161) following single or multiple oral administrations of sepiapterin. A population PK model for BH4 was established with allometric scaling factors for apparent clearance (CL/F) and apparent volume of distribution (Vc/F). This population PK model was linked to a turnover response model to describe the effect of sepiapterin treatment (as BH4) on blood Phe levels in patients with PKU. Monte-Carlo simulations were performed to identify and justify the optimal sepiapterin dosage for treating pediatric and adult patients with PKU.

Results: Following oral administration, sepiapterin was quickly absorbed and extensively converted to BH4 and declined to non-detectable levels within < 12 h; hence, sepiapterin was not included in this model. Concentration-time profiles of log-transformed BH4 were adequately described by a one-compartment model with time-delayed zero-order absorption and linear elimination. The final PK model identified covariates: fasted status, ethnicity (Asian) and dose level to have an effect on bioavailability, sex and disease status impacting absorption duration, and disease status influencing CL/F.

For the PK/PD model, an indirect turnover effect compartment was found suitable to characterize the relationship between BH4 and blood Phe reduction in patients with PKU. Based on the covariate analysis, the following covariate relationships were retained: increase of synthesis rate of Phe and maximum BH4 effect for patients with BH4 responsiveness and female patients, while classical PKU decreased those parameters.

Monte-Carlo simulations showed that BH4 exposures were about 30% higher in Asians compared to non-Asian patients across age groups. However, the increase was moderate and did not necessitate any dose adjustments. Overall, the PD response at steady state was comparable across age groups when the body weight adjusted dose was administered.

Conclusions: PK and PK/PD models demonstrated reliable predictive capacity for describing plasma BH4 concentrations and blood Phe response in adult and pediatric patients of all ages with PKU during sepiapterin treatment. The robustness and stability of the models were evaluated through goodness-of-fit analyses across various population groups. Results from this modeling and simulation analysis support the recommended optimal dosage of sepiapterin for the treatment of PKU.

Citations: No citation

Keywords: Sepiapterin, Tetrahydrobiopterin, Phenylalanine, Pediatric, Phenylketonuria, Population PK/PD Modeling