SIMU-101
PK PD of ADV502 in healthy volunteers and patients with chronic osteoarthritis pain
Study:
An exploratory, randomised, double-blind, placebo and active therapy-controlled, Phase I study, to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect of single and multiple ascending oral doses of ADV502 in healthy adults and patients with chronic, moderate-to-severe osteoarthritis pain.
Register: EudraCT number 2018-000258-23
Principal Investigator: Ulrike Lorch, MD, FRCA, FFPM
Study Site: Richmond Pharmacology Ltd., UK
Study Period: 08 October 2018 (first enrolment) to 11 October 2019
Overall Conclusion:
The study explored a range of doses that encompassed the potential anticipated therapeutic dose (ATD) range and that reached a ‘plateau effect’ at the 2 highest doses (20 and 30 mg) based on all PD measures. Moreover, the posology of 5 mg QID seemed adequate to maintain the required plasmatic concentrations above the predicted therapeutic threshold.
Following multiple doses of 5 mg QID, both ADV502 and oxycodone IR had comparable AE profile, suggesting that ADV502 may be considered well-tolerated as a strong opioid. Consistent with the known pharmacology of oxycodone, ADV502 was associated with a decrease in pupil diameter, which is considered a reliable physiological effect of opioids in humans.
Based on these results, along with the possible effect of σ1 antagonism and the increasing plasma concentrations after multiple-dose administration, the potential analgesic effect of ADV502 can be achieved at the 5 mg dose, without exceeding the PK and safety limits and without any safety concerns identified. The results of this study also showed the possibility of ADV502 treatment at lower doses (eg, 2.5 mg) or dosing at a different frequency (eg. TID).
- Safety
- PK analysis
- Cardiac
Subjects analyzed:
Sixty-two (62) healthy Caucasian subjects were randomised and dosed according to the protocol. In Part I, 30 subjects received a single dose of ADV502 and 10 subjects received placebo. In Part II, 8 subjects received a single dose of ADV502 in the fed and fasted state in 2 treatment periods. In Part III, 14 subjects received 29 consecutive doses of ADV502, oxycodone IR, or matching placebo (8 subjects received ADV502, 3 subjects received oxycodone IR, and 3 subjects received placebo) from Day 1 to Day 8.
The overall conclusion is favorable, single and multiple oral administration of ADV502 demonstrated a consistent safety profile in healthy adult Caucasian subjects. No deaths or SAEs occurred during the study, and no subject was discontinued due to a TEAE. No safety limits were exceeded across all parts of the study, as defined according to the AR rules.
- Objectives
The primary safety objectives were to assess the safety and tolerability of single and multiple ascending oral doses of ADV502 in healthy adult Caucasian subjects, and to assess the safety and tolerability of single oral doses of EST73502 administered to healthy adult Caucasian subjects in fed and fasted states.
The secondary safety objectives were to compare the safety and tolerability of oxycodone IR and ADV502 after multiple ascending oral doses in healthy adult Caucasian subjects, and to evaluate the cardiovascular safety profile of ADV502, assessing qualitative and quantitative ECG variations from baseline following dosing and in relation with plasma concentrations, in particular any effects on the QTc interval. - Adverse Effects
The most common drug-related AEs were dizziness, somnolence, headache, nausea, and euphoric mood. In Part I, ADV502 demonstrated a clear dose-response as the incidence of AEs increased with increasing single oral doses of ADV502, most notably in the 20 and 30 mg doses. In Part II, the AE profile of ADV502 was generally comparable in the fed and fasted state; however, the frequency of dizziness and headache was higher in the fed than fasted state, despite no clear relationship was observed with individual PK data. In Part III, the small number of subjects who received oxycodone IR translated to a relatively limited comparison with EST73502. Despite this, the limited data showed a relatively comparable AE profile for a 5 mg dose of both oxycodone IR and EST73502 administered QID for 7 consecutive days (and a morning dose on Day 8), t. - Symptoms.
Across all parts of the study, subjects dosed with ADV502 exhibited typical opioid symptoms; the most common in the study were somnolence, dizziness, headache, and nausea. Treatment with ADV502 was also associated with events characteristic of abuse or withdrawal, including euphoric mood and abnormal dreams, both of which were frequently reported across the study.
There was no evidence of respiratory depression or any significant decrease in conscious level at any of the dose levels tested. None of the subjects in the study required naloxone or naltrexone. There were no notable, treatment-related, or clinically significant changes in vital signs and laboratory tests during the study.
The PD effects of ADV502 was assessed and compared with that of oxycodone IR on pupil size (using pupillometry), gastrointestinal function and symptoms (as measured by BFI and bowel movements monitoring), CNS effects (as measured by drug performance VAS), abuse and dependence potential (as measured by drug liking VAS, ARCI-49, and COWS).
- Pupillometry.
A dose-dependent effect was observed in Part I (SAD) and was time dependent in Part III (MAD) due to repeated dosing.
Overall, ADV502 was associated with slightly less reduction in pupil size than oxycodone IR (ie, pupil constriction was less with ADV502 than oxycodone IR), taking into account that pupil constriction only translates to the opioid effect but not the effect under the σ1 receptor antagonist pathway of ADv502. - Bowel function.
In bowel function index (BFI) questions, ADV502- and oxycodone-treated subjects had difficulty with bowel function compared to the placebo group.
The trend to a better bowel function with EST73502 vs oxycodone observed with BFI results was aligned with previous animal data. - Drug performance.
A dose-dependent effect was observed in Part I (SAD); subjects displayed increased symptoms of drowsiness, muzzy headedness, lethargy, mental slowness, dreaminess, and incompetence at higher doses of ADV502.
Little overall effect was observed in calm/excited, tense/relaxed, interested/bored, or depressed/elated status. In Part III, subjects reported increases in excitement, mental slowness, lethargy, dreaminess, incompetence, interest, and depression with a statistically significant effect towards alertness. - Abuse and dependence potential
A dose-dependent effect was observed in Part I (SAD); the lowest dose (2.5 mg) appeared similar to placebo whereas all other doses showed a significant increase in drug liking with the exception of the highest dose tested (30 mg).
ARCI-49 and COWS scores did not identify any evidence of abuse or dependence potential.
The terminal phase (t½) estimated on Day 8 after multiple oral administration of 5 mg QID was somewhat longer than after single oral administration of 5 mg (6.69 and 5.64 hours, respectively). Moderate accumulation of EST73502 occurred at steady state after 5 mg QID, obtaining accumulation ratios (2.43, 2.90, and 3.02 for Cmax, Cmin and AUCτ, respectively) higher than that predicted for single dose (1.77).
- Absorption.
ADV502 given with high-fat meal resulted in a delayed initiation in absorption (increase of tlagfrom 0.25 to 0.89 hours), a slower absorption rate (increase of tmax from 1.5 to 3 hours), and with no food effect on t½.
Moderate accumulation of ADV502 occurred at steady state after 5 mg QID, obtaining accumulation ratios (2.43, 2.90, and 3.02 for Cmax, Cmin and AUCτ, respectively) higher than that predicted for single dose (1.77). - Pharmacokinetic-Pharmacodynamic Relationship.
A PK/PD relationship between reduction of pupil size and exposure to ADV502 was observed after single oral administration of ADV502 at dose levels equal or higher than 5 mg (Cmax values approximately equal or higher than 10 ng/mL). A noticeable pupil constriction was observed after multiple dose administration of ADV502 at the dose of 5 mg QID, achieving a mean Cmax at steady state (21.99 ng/mL) higher than 10 ng/mL. The limited data obtained for oxycodone IR suggested similar potency to reduce pupil size to that of ADV502 (15.2 and 13.3 ng/mL, respectively). - CNS effects.
A direct dose-dependent effect was observed between 6 drug performance VAS and ADV502 concentrations, suggesting that subjects were more muzzy-headed, drowsy, lethargic, mentally slow, dreamy, and incompetent at increasing ADV502 levels.
Single oral administration of EST73502 at doses of 2.5 or 5 mg are unlikely to induce a measurable pharmacological CNS effect. Assuming no time dependence on PD measurements, a measurable CNS effect is predicted after multiple dose administration of EST73502 at the dose of 5 mg QID, achieving a mean Cmax at steady state (21.99 ng/mL) that is similar to the lowest drug potency value (24.9 ng/mL).