Objective: To develop population pharmacokinetic (PK) models for levodopa (LD) and carbidopa (CD) following subcutaneous (SC) infusion, including adjunct oral LD/CD administration.

Background: ND0612 is in development as the first drug-device combination delivering liquid LD/CD via continuous SC infusion to reduce motor complications in patients with Parkinson’s disease (PD). Previous PK studies in patients and healthy subjects have confirmed stable LD and CD plasma levels following ND0612 administration.

Method: Two separate population PK models (for levodopa and for carbidopa) were developed using data from two Phase I studies of ND0612 (NCT04006210, NCT02604914), accounting for combined zero- and first-order absorption processes (representing SC infusion and oral + SC absorption, respectively). Population PK models were developed by using non-linear mixed-effects modelling techniques. The predictive performance of each model was then tested using data from a third study (Study 114). Model refinement was performed using aggregated data from the 3 studies and will be continually updated as more PK data from ND0612 studies becomes available.

Results: LD and CD population PK were adequately described by one-compartment disposition models with first-order oral and SC absorption. CD was characterized by linear elimination, while the LD model had two parallel elimination pathways accounting for the dopa decarboxylase (DDC) and catechol-O-methyltransferase mediated biotransformation routes, where the DDC-mediated clearance was inhibited by CD plasma levels. Body weight was included as a structural predictor of the disposition parameters for both compounds based on allometry principles; entacapone coadministration was also a structural covariate on LD bioavailability which was increased under a combination treatment setting. Due to the small sample size available in the present analysis, covariates modelling was done in an exploratory fashion, and revealed that age had a significant effect on apparent clearance and volume of distribution for both LD and CD.

Conclusion: Model diagnostics for the LD and CD population PK models indicated a satisfactory predictive performance, supporting their usability to derive individual predictions of exposure to be used in future PK-pharmacodynamic analyses.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/population-pharmacokinetic-analysis-of-levodopa-and-carbidopa-after-subcutaneous-administration-with-and-without-adjunct-oral-therapy/