Graduate Student Seoul National University College of Medicine and Hospital, Seoul-t'ukpyolsi, Republic of Korea
Disclosure(s):
Hyunwook Ryu, Pharm.D: No financial relationships to disclose
Objectives: DA-8010 is a novel muscarinic receptor 3 (M3) antagonist with extended-release formulation for the treatment of overactive bladder (OAB). The pharmacokinetics of DA-8010 present complexity during the absorption phase, characterized by multiple "shoulders", which cannot be adequately described by conventional first- or zero-order absorption models. The objective of this study was to develop a population pharmacokinetic (PK) model capable of characterizing the PK profile of DA-8010, incorporating various absorption PK models.
Methods: A total of 2581 plasma DA-8010 concentration-time data from 137 healthy subjects participated in three phase 1 clinical studies (NCT02821312, NCT05991401 and NCT05992428) were pooled for population PK analysis. Population PK modeling was performed using NONMEM® version 7.4, and first-order conditional estimation(FOCE) method was implemented. Model diagnostics included a log-likelihood ratio test, goodness-of-fit (GOF) plots and visual predictive check (VPC) plots.
Results: The PK profile of DA-8010 was best described by a two-compartment model with first-order absorption followed by zero-order absorption incorporating an enterohepatic recirculation (EHR) component. The typical values of absorption-related population parameters included an absorption rate constant (KA) of 0.319 h-1, absorption lag time for first-order absorption(ALAG1) of 0.458 h, duration of zero-order absorption (D1) of 1.53 h, absorption lag time for the zero-order absorption (ALAG2) of 3.6 h, and fraction absorbed as zero-order absorption (F2) of 0.388. Disposition-related parameters were estimated as follows; apparent clearance (CL/F) of 539 L/h, apparent central volume of distribution (Vc/F) of 6340 L, apparent peripheral volume of distribution (Vp/F) of 1470 L, and apparent inter-compartmental clearance (Q/F) of 135 L/h. The typical parameter estimate value related to EHR included an input rate constant into the gallbladder (K24) of 0.0751 h-1, while enterohepatic reabsorption time (T42) was fixed at 0.5 h.
Conclusion: The final population PK model, comprising a two-compartment with first-order absorption followed by zero-order absorption incorporating an EHR component, effectively captured the observed PK properties of DA-8010.
