Objective: To characterize the pharmacokinetics (PK) of carbidopa (CD) and levodopa (LD) from delayed-release (DR) tablets intended for bedtime administration and to correlate systemic exposure with gastrointestinal (GI) transit and timing of drug release using scintigraphic imaging in healthy volunteers (HVs) and patients with Parkinson’s disease (PPD).

Background: Sleep disturbance and early morning motor symptoms in PPD are associated with low nocturnal and early morning LD plasma concentrations. A delayed-release CD/LD formulation designed to initiate GI drug release several hours after bedtime dosing may provide LD exposure during the early morning period.

Method: Two phase 1 open-label, randomized, crossover, three treatment period studies evaluated two DR CD/LD formulations targeting release delays of 4 and 6 h in 19 HVs and 14 PPD. In HVs, DR formulations were compared with a marketed controlled-release (CR) formulation. In PPD, DR tablets were co-administered with an immediate-release (IR) CD/LD formulation and compared with IR alone. DR tablets were radiolabeled to assess GI transit and onset of release, and scintigraphic findings were correlated with plasma PK parameters.

Results: In HVs, DR formulations demonstrated delayed absorption compared with CR, with median LD T_max of 6.0 h and 7.0 h, versus 2.5 h for CR. Scintigraphy confirmed delayed radiolabel release (median 5.25 h and 6.25 h post-dose), occurring in the stomach or small intestine depending on gastric emptying [table1].

In PPD, DR plus IR CD/LD resulted in later median LD T_max (5.30 h and 5.76 h) compared with IR alone (0.97 h). Scintigraphy confirmed similar radiolabel release behavior in terms of onset of release [table1].

At 16 h post dose 93-100% of PPD and 37-43 % of HVs receiving DR formulations had quantifiable levels of LD plasma concentrations, compared with 43% of PDP and 5% of HVs receiving comparator treatments [table1].

Representative subjects illustrate the relationship between scintigraphy and levodopa PK [figure1].

No clinically relevant safety concerns were identified.

Conclusion: Delayed-release CD/LD tablets demonstrated GI release and PK profiles consistent with delayed drug delivery following bedtime administration. These findings support further clinical evaluation of bedtime dosing to target early morning motor fluctuations in Parkinson’s disease.

Table 1: Key pharmacoscintigraphic data

Figure 1: Example pharmacoscintigraphic data

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MDS Abstracts - https://www.mdsabstracts.org/abstract/pharmacoscintigraphic-evaluation-and-safety-of-a-novel-dual-pulse-delayed-release-carbidopa-levodopa-tablet-for-bedtime-dosing/