Pharmacokinetic Properties of Intranasal and Injectable Formulations of Naloxone for Community use: a Systematic Review

Figures & data

Figure 1. Flow chart of study selection.

^†One study was initially included in the systematic review based on information presented as a poster [37]; however, this study was published after the search was performed [35].

iv.: Intravenous; PI: Prescribing information; PK: Pharmacokinetic.

Table 1. Summary of included studies.

Naloxone formulation	Study (year)	Naloxone dose(s)	Comparator product(s)	Study design	N	Ref.
US FDA-approved formulations for community use
im./sc. auto-injector (EVZIO^®)	Edwards et al. (2015)	0.4 mg (midanterolateral thigh)	0.4-mg im. standard syringe and needle (midanterolateral thigh)	R, single-blind, single-dose, 2-period, 2-sequence, crossover	30 healthy adult volunteers	[31]
im./sc. auto-injector (EVZIO^®)	Product PI	0.4 mg (1 injection) 0.8 mg (2 injections of 0.4 mg administered 2 min apart) 2 mg (1 injection)	–	Crossover (other design details not specified)	24 healthy volunteers (age not specified)	[24]
Approved intranasal (NARCAN^®)	Krieter et al. (2016)	2 mg (1 spray of 2 mg/0.1 ml) 4 mg (1 spray of 4 mg/0.1 ml) 4 mg (1 spray of 2 mg/0.1 ml in each nostril) 8 mg (1 spray of 4 mg/0.1 ml in each nostril)	0.4-mg im. standard syringe and needle (0.4 mg/1 ml, gluteus maximus)	R, OL, 5-period, 5-treatment, 5-sequence, crossover	30 healthy adult volunteers	[32]
Unapproved intranasal kits
Unapproved intranasal (LMA^® MAD Nasal^™)^†	Edwards et al. (2016)	2 mg (1 mg/ml in each nostril)	2-mg im. standard syringe and needle (1 mg/1 ml in each thigh)	R, OL, single-dose, 3-period, crossover	36 adults with chronic rhinitis but no significant nasal abnormalities, surgery, polyps or trauma	[33]
Unapproved intranasal (MAD)^‡	Dowling et al. (2008)	0.8 mg (1 spray of 0.4 mg/1 ml in each nostril) 2 mg (1 spray of 1 mg/2.5 ml in each nostril)	0.8-mg iv. 2-mg iv. 0.8-mg im. standard syringe and needle (gluteus maximus)	OL, crossover	6 healthy adult volunteers	[34]
Community-use formulations in development
Intranasal in development (Mundipharma)	McDonald et al. (2017)	1 mg (1 spray of 1 mg/0.1 ml) 2 mg (1 spray of 2 mg/0.1 ml) 4 mg (2 sprays of 2 mg/0.1 ml)	0.4-mg im. standard syringe and needle (primary reference; deltoid muscle) 0.4-mg iv.	R, OL, 5-way, crossover	38 healthy adult volunteers	[35]
Intranasal in development (dne pharma)	Tylleskar et al. (2017)	0.8 mg (1 spray of 0.8 mg/0.1 ml) 1.6 mg (2 sprays of 0.8 mg/0.1 ml)	1.0-mg iv.	R, OL, 3-way crossover	12 healthy adult volunteers	[36]

† Teleflex, Inc. NC, USA.

‡ Wolf-Tory Medical, UT, USA.

im.: Intramuscular; iv.: Intravenous; LMA: Laryngeal mask airway; MAD: Mucosal atomizer device; OL: Open label; PI: Prescribing information; R: Randomized; sc.: Subcutaneous.

Table 2. Pharmacokinetic parameters for community-use formulations of naloxone.

Naloxone formulation	N	Mean (%CV) Cmax, ng/ml	Mean (%CV) AUC0-∞, ng•h/ml	Median (range) tmax, h	Mean (%CV) t1/2, h	Bioavailability, %
US FDA-approved formulations for community use
im./sc. auto-injector naloxone
0.4-mg dose [31]	30	1.2 (51.4)	1.9 (23.4)	0.25 (0.08–1.23)	1.3 (38.0)	98.3^†
0.4-mg dose [24]	24	1.3 (62.9)	2.0 (16.3)	0.25 (0.09–0.84)	1.6 (28.9)	NA
0.8-mg (two 0.4-mg) dose [24]	24	2.2 (47.4)	3.8 (19.1)	0.21 (0.09–0.85)	1.5 (23.7)	NA
2-mg dose [24]	24	7.9 (45.8)	10.3 (15.2)	0.25 (0.13–0.67)	1.5 (25.0)	NA
Approved intranasal spray [32]
2 mg (1 spray of 2 mg/0.1 ml)	29	3.1 (36.1)	4.7 (29.8)	0.3 (0.3–1.0)	1.9 (34.6)	51.9^†
4 mg (1 spray of 4 mg/0.1 ml)	29	5.3 (44.6)	8.5 (39.0)	0.5 (0.2–1.0)	2.2 (29.1)	46.2^†
4 mg (2 sprays of 2 mg/0.1 ml)	29	6.5 (32.3)	9.7 (26.7)	0.3 (0.2–0.6)	2.4 (31.7)	53.5^†
8 mg (2 sprays of 4 mg/0.1 ml)	29	10.3 (38.1)	15.8 (23.1)	0.3 (0.2–1.0)	2.2 (39.0)	43.9^†
Unapproved intranasal kits
Unapproved intranasal [33]
2 mg/2 ml^‡	36^§	1.3 (48.3)	1.5 (31.6)	0.25 (0.07–0.68)	1.5 (18.5)	14.6^¶
2 mg/2 ml^‡ + vasoconstrictor^#	36^§	0.7 (52.0)	1.1 (35.1)	0.33 (0.08–1.00)	1.5 (22.9)	11.1^¶
Community-use formulations in development
Intranasal in development (Mundipharma) [35]
1 mg (1 spray of 1 mg/0.1 ml)	32	1.5^†† (50.2)	2.7^†† (40.5)	0.25 (0.2–1.0)	1.3 (NA)	50.8^†
2 mg (1 spray of 2 mg/0.1 ml)	32	2.9^†† (49.6)	5.0^†† (38.5)	0.5 (0.1–1.0)	1.4 (NA)	47.1^†
4 mg (2 sprays of 2 mg/0.1 ml)	32	6.0^†† (54.5)	10.1^†† (35.8)	0.25 (0.2–1.0)	1.7 (NA)	48.3^†
Intranasal in development (dne pharma) [36]
0.8 mg (1 spray of 0.8 mg/ml)	12	1.4 (1.1–1.8)^‡‡	1.6 (1.3–2.0)^‡‡^§§	0.3 (0.2–0.4)^††	1.5 (1.3–1.7)^††	54^¶¶
1.6 mg (2 sprays of 0.8 mg/ml)	11	2.6 (1.5–3.7)^‡‡	3.1 (2.0–4.1)^‡‡^§§	0.3 (0.2–0.4)^††	1.3 (1.1–1.5)^††	52^¶¶

† Relative to 0.4-mg im. standard syringe/needle.

‡ 1 mg/ml in each nostril using the LMA^® MAD Nasal™ atomizer.

§ Adults with chronic rhinitis; all other studies were of healthy adults.

¶ Relative to 2-mg im. standard syringe/needle (1 mg in each thigh).

# Oxymetazoline HCl 0.05% nasal solution (Afrin^®).

†† Geometric mean.

‡‡ Data shown as mean (95% CI).

§§ AUC_0-t.

¶¶ Relative to 1.0-mg iv., based on AUC_0-t.

%CV: Percent coefficient of variation; AUC_0-∞: Area under the plasma concentration–time curve from baseline extrapolated to infinity; AUC_0-t: Area under the plasma concentration–time curve from baseline to the last measurable concentration; C_max: Time concentration; im.: Intramuscular; iv.: Intravenous; LMA: Laryngeal mask airway; MAD: Mucosal atomizer device; NA: Not available; sc.: Subcutaneous; t_1/2: Terminal elimination half-life; t_max: Time to maximum plasma concentration.

Figure 2. Mean naloxone plasma concentration–time curves for approved intranasal spray versus intramuscular standard syringe: overall.

im.: Intramuscular.

Reprinted with permission from [32] © John Wiley & Sons, Inc. (2016).

Figure 3. Mean naloxone plasma concentration–time curves for approved intranasal spray versus intramuscular standard syringe: early-stage (0–1 h).

Error bars represent standard deviation.

im.: Intramuscular.

Reprinted with permission from [25] © Adapt Pharma, Inc. (2017).

Figure 4. Mean naloxone plasma concentration–time curves for intranasal formulation in-development, intramuscular standard syringe and intravenous administration: overall (2 h).

Error bars represent standard deviation.

im.: Intramuscular; iv.: Intravenous.

Adapted with permission from [35] (2018) via a CreativeCommons Attribution-NonCommercial license.

Figure 5. Mean naloxone plasma concentration–time curves for intranasal formulation in-development, intramuscular standard syringe and intravenous administration: early stage (20 min).

Error bars represent standard deviation.

im.: Intramuscular; iv.: Intravenous.

Adapted with permission from [35] (2018) via a CreativeCommons Attribution-NonCommercial license.

Figure 6. Time course of plasma concentrations (mean [error bars 95% confidence interval]) of naloxone after intravenous (1.0 mg) and intranasal (0.8 and 1.6 mg) administration in healthy human volunteers (n = 12 for intravenous and intranasal 0.8 mg, n = 11 for intranasal 1.6 mg).

Squares are the 0.8 mg intranasal, dots are the 1.6 mg intranasal and triangles are the 1.0 mg iv. [36].

CI: Confidence interval; iv.: Intravenous.

Adapted with permission from [36] © Springer (2017).

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