Background Inhalation of apomorphine could be a faster‐acting and more user‐friendly alternative to subcutaneous injection for treating off periods in Parkinson's disease (PD). Objective The aim of this study was to compare the safety and pharmacokinetics of inhaled apomorphine (AZ‐009) with subcutaneous apomorphine (APO‐go PEN) in healthy volunteers (HVs) and to examine the safety, pharmacokinetics, and efficacy of AZ‐009 in patients with PD. Methods In part A of this study, eight HVs received 1 mg AZ‐009 and 2 mg subcutaneous apomorphine in a randomized crossover manner. In the subsequent single ascending dose parts in HVs (part B, n = 16) and patients with PD (part C, n = 25), participants were randomized to placebo or AZ‐009 up to 4 mg. In patients, after medication withdrawal, Movement Disorder Society‐Unified Parkinson's Disease Rating Scale part III and on/off states were assessed predose and postdose. Results AZ‐009 was rapidly absorbed with peak plasma concentrations at 2 minutes, as compared to 30 minutes for subcutaneous apomorphine. Adverse events for AZ‐009 were comparable to subcutaneous apomorphine, except for mild and transient throat irritation. Adverse events limited AZ‐009 dose escalation in HVs to 3 mg. Patients tolerated up to 4 mg. In patients with PD, 2, 3, and 4 mg AZ‐009 reduced mean Movement Disorder Society‐Unified Parkinson's Disease Rating Scale part III score (standard deviation) by 10.7 (13.6), 12.8 (7.9), and 10.3 (3.7) points, respectively, compared to 4.8 (4.9) after placebo at 10 minutes postdose. The percentage of patients achieving full on within 45 minutes postdose increased dose dependently: 0% (placebo), 17% (2 mg), 50% (3 mg), and 83% (4 mg). Conclusions AZ‐009 appears to be a rapid‐acting and reasonably well‐tolerated formulation for treating off periods. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

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The bioavailability of an active substance might be altered when a solid oral dosage form (SODF) is crushed or disintegrated and mixed with fluids or food in order to assist swallowing. In consequence, the current European Medicines Agency (EMA) practice is to request comparative bioavailability testing for bridging safety and efficacy data from a formulation administered whole to the same product administered crushed. Specific criteria for waiving in vivo testing of crushed products are available only for BCS Class I and Class III drugs. Since rivaroxaban is a Class II drug which can be administered crushed and mixed with fluids, any generic formulation has to be tested against the originator in this setting. Therefore, an open label, randomized, single dose, two-period, two-sequence, crossover bioequivalence study with administration of rivaroxaban 10 mg crushed tablets suspended in apple puree was conducted in 24 fasting healthy volunteers. Both rivaroxaban treatments were well tolerated by the study subjects. A standardized, dose efficient and fully reproducible protocol for grinding, mixing and administering investigational medicinal products was developed and applied. Assessment of bioequivalence was based on plasma concentrations of parent rivaroxaban, quantified using a validated HPLC/MS/MS method. The 90% confidence intervals for C max and AUC 0-t least square mean T/R ratios were within the bioequivalence acceptance range of 80% to 125%. Results from the present study reinforced the bioequivalence conclusion reached for the same test and reference products following administration of whole tablets in fasting state. No notable changes in bioavailability occurred when rivaroxaban tablets were crushed, immediately dispensed in 70 mL apple puree and quantitatively (entire dose recovered) administered to fasting volunteers.