1. 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. 

2. 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”

3. 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

4. 1 | Overdose deaths in the EU
Source: EMCDDA (2017)

5. 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)

6. 1 | Take-home Naloxone: Systematic Review
We know that take-home naloxone is an effective intervention for reducing opioid OD mortality.

7. 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, (* joint first authors)

8. 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, (* joint first authors)

9. 1 | Naloxone nasal spray: Feasibility

10. 1 | Naloxone nasal spray: Feasibility
(May 2017)

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

12. 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.

13. 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.

14. 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”

15. 3.1 | Key findings: Naloxone mean PK profile
The 1mg IN is slower than the IM reference, which may delay OD reversal

16. 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

17. 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 minutes (Tmax). Maintains blood levels for

18. 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 minutes (Tmax) and rapidly achieved plasma levels >50% of peak concentrations (T50%) at 9-10 minutes (slightly slower than with IM and IV).

19. 3.1 | Key findings: Early naloxone exposure (AUCp)
Roughly a min behind

20. 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)

21. 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)

22. 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

23. 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”

24. 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

25. Questions?