Pharmacokinetics of a novel nasal spray in development in Europe Take-home naloxone: Pharmacokinetics of a novel nasal spray in development in Europe  Rebecca McDonald Addictions Department Take-home naloxone: pharmacokinetics of a novel nasal spray in development in Europe. 

Declarations of Interest Since October 2013: Involvement in development in buccal naloxone tablet formulation on which King’s College London has applied to register intellectual property. Since June 2016: Consultant for the United Nations Office on Drugs and Crime (UNODC), supporting a feasibility study of community-based opioid overdose prevention strategies in the framework of the UNODC-WHO Programme on Drug Dependence Treatment and Care (GLOK32). October – December 2016: Unpaid student industry placement with Mundipharma Research Ltd. (Cambridge, UK), with focus on the analysis of naloxone nasal spray formulations. This study was sponsored by Mundipharma Research Ltd. “These are my disclosures. I had the opportunity to undertake an unpaid , where I analyzed the pharmacokinetics of new nasal NLX formulations”

Overview Background: Opioid overdose deaths and the need for non-injectable naloxone PK study of concentrated nasal naloxone: Methods PK study of concentrated nasal naloxone: Key findings Implications for clinical practice Conclusions

1 | Overdose deaths in the EU Source: EMCDDA (2017)

1 | UK opioid overdose deaths: 2011-2015 England/Wales: 1,201 heroin/morphine deaths in 2015 (up from 596 in 2011) Scotland: 349 heroin/morphine deaths in 2015 (up from 207 in 2011) England & Wales: ↑ 102% (ONS, 2016) Scotland: ↑ 68% (NRS, 2016)

1 | Take-home Naloxone: Systematic Review We know that take-home naloxone is an effective intervention for reducing opioid OD mortality.

1 | Why is non-injectable naloxone needed? Injectable naloxone not well-suited for take-home naloxone use: More training required Risk of needle-stick-injury Low carriage rates (5-16%; McAuley et al., 2016 ) However, injectable formulations are not well suited for layperson use, Administering injections can be intimidating, requires training; Injections bear the risk of needle-stick-injury and blood-borne virus transmission (HIV, HBV, HCV) Carriage rates well below 20%, meaning that only 1 in 5 kits is being carried Source: goo.gl/QxHcRJ Strang, J.*, McDonald, R.*, Alqurshi, A., Royall, P., Taylor, D., & Forbes, B. (2016). Naloxone without the needle− systematic review of candidate routes for non-injectable naloxone for opioid overdose reversal. Drug and Alcohol Dependence, 163, 16-23. (* joint first authors)

1 | Naloxone nasal spray: what is required? Easy to use: must not require medical training Small volume  concentrated solution Good early absorption (similar to IM) Dose adequate, but not excessive there has been increasing investment in the development of naloxone nasal spray. Nasal spray needs to meet at least 4 criteria Source: goo.gl/5t1XlA Strang, J.*, McDonald, R.*, Alqurshi, A., Royall, P., Taylor, D., & Forbes, B. (2016). Naloxone without the needle− systematic review of candidate routes for non-injectable naloxone for opioid overdose reversal. Drug and Alcohol Dependence, 163, 16-23. (* joint first authors)

1 | Naloxone nasal spray: Feasibility

1 | Naloxone nasal spray: Feasibility (May 2017)

Pharmacokinetic study in healthy volunteers Naloxone nasal spray Pharmacokinetic study in healthy volunteers

2.1 | Pharmacokinetic study Rationale: Naloxone has no pharmacological effect in healthy volunteers Aim 1: Compare early exposure: IN vs. IM Aim 2: Assess IN naloxone pharmacokinetics, incl. bioavailability Design: Open-label, randomized 5-way crossover (n=38) Three intranasal (IN) vs. two parenteral doses IN 1mg/0.1mL vs. IN 2mg/0.1mL vs. IN 4mg/0.2mL vs. IV 0.4mg/mL vs. IM 0.4mg/mL (reference) Methods: IN spray as 0.1ml from Aptar device Intense early blood sampling 0-15 min (+1, 2, 3, 4, 6, 8, 10, 12.5, 15 min) A Phase-I crossover design study was conducted in healthy volunteers, with the aims to… The nasal doses tested were 1, 2, 4mg, and this is interesting because it reflects the range of concentrated spray formulations already used in clinical practice, with the 4mg spray approved in North America, and a 1mg formulation recently introduced in France.

3.1 | Key findings: Naloxone mean PK profile IV was characterised by an extremely rapid spike of plasma concentration, reaching peak at 2 minutes (Tmax), followed by rapid decay over the next 10 minutes and gradual decay thereafter.

3.1 | Key findings: Naloxone mean PK profile IM was characterised by peak plasma levels at a median of 10 minutes (Tmax), with gradual decay thereafter. ”not huge value to the spike”

3.1 | Key findings: Naloxone mean PK profile The 1mg IN is slower than the IM reference, which may delay OD reversal

3.1 | Key findings: Naloxone mean PK profile The 4mg dose exceeds the IM reference in naloxone exposure, with elevated Cmax. We know that Cmax is typically where adverse reactions occur Good early uptake, but Cmax similar to IV

3.1 | Key findings: Naloxone mean PK profile The 2mg dose comes in in the middle, between 1 and 4 mg, and closely follows the early curve of IM. IN reached maximum plasma levels at 15-30 minutes (Tmax). Maintains blood levels for

3.1 | Key findings: Early naloxone exposure The 2mg dose comes in in the middle, between 1 and 4 mg, and closely follows the early curve of IM. IN reached maximum plasma levels at 15-30 minutes (Tmax) and rapidly achieved plasma levels >50% of peak concentrations (T50%) at 9-10 minutes (slightly slower than with IM and IV).

3.1 | Key findings: Early naloxone exposure (AUCp) Roughly a min behind

3.1 | Key findings: Early naloxone exposure (AUCp) AUCp (h*ng/mL) Mean (CV%) 1mg IN 0.05 (112.2) 2mg IN 0.11 (105.1) 4mg IN 0.27 (98.6) 0.4mg IM 0.11 (67.9)

3.1 | Key findings: Early naloxone exposure (AUCp) AUCp (h*ng/mL) Mean (CV%) 1mg IN 0.05 (112.2) 2mg IN 0.11 (105.1) 4mg IN 0.27 (98.6) 0.4mg IM 0.11 (67.9) Within 10 minutes post-dosing, the 2mg IN dose most closely followed the 0.4mg IM curve, and the Area under the curve was roughly equivalent (AUCp = 0.11ng/ml)

3.2 | Key findings: Bioavailability Ratio (%) 90% CI (lower, upper) IN 1 mg IN 2 mg IN 4 mg Absolute Bioavailability IN : IV* 50 (44.6, 56.6) 47 (41.7, 52.6) 48 (43.3, 53.5) Relative Bioavailability IN : IM** 51 (45.2, 57.1) 47 (41.7, 53.5) 48 (43.2, 54.1) *IV 0.4 mg used as the reference treatment for the dose-adjusted comparison **IM 0.4 mg used as the reference treatment for the dose-adjusted comparison

4 | Implications for clinical practice ‘Nyxoid contains 1.8 mg naloxone, which is equivalent to 2 mg naloxone hydrochloride'. IMPORTANT: “No marketing authorization has yet been granted for the product in Europe”

4 | Implications for clinical practice Likely implementation advantages for take-home naloxone distribution Advantages and disadvantages of IN and IM curves: 0-10 minutes: 2mg IN = 0.4mg IM 10 minutes-2 hours: 2mg IN > 0.4mg IM dose Is IN dose titration possible, similar to IM? The extra factor: Time to naloxone administration? Higher acceptability and carriage rates of nasal spray? A central limitation of this study: Phase 1 trial: unclear what impact

Questions? Email: rebecca.s.mcdonald@kcl.ac.uk