Bioavailability of just under 50 % in the pilot study showed that it was possible to administer a therapeutic dose of naloxone in 0.1 ml via a highly concentrated nasal spray. Absorption was also rapid, with serum concentrations after nasal administration remaining sufficiently high throughout the study. However, there was a need to confirm the findings in more comprehensive studies. Adjustment of the dose was also required to be able to offer a spray that would be equivalent to an intramuscular dose of 0.4–0.8 mg. The results for central pharmacokinetic variables were confirmed in subsequent studies.
Four different concentrations of the nasal spray were produced: 4, 8, 16 and 20 mg/ml. We chose to test the strongest solution of 20 mg/ml first, as previous reports on naloxone had indicated low bioavailability
(8). In order to determine absolute bioavailability, we chose in the initial studies to use intravenous naloxone as a comparator, as this is the recommended route of administration in the Summary of Product Characteristics for injectable naloxone. In subsequent studies, naloxone was administered via the intramuscular route, currently the most commonly used route of administration by the Norwegian ambulance service.
The bioavailability of 47 % was markedly higher than previously reported and corresponds well to the 47–54 % bioavailability in subsequent studies by ourselves and others
(12–14). Our results were thus a good reflection of the central tendency for absolute bioavailability. Variability was underestimated in the pilot study, where minimum–maximum values were 24–66 % (range 42) versus 23–83 % (range 60) and 30–105 % (range 75) for two different doses of nasal spray in the following study (12). This is illustrated in Figure 2 with a quartile-based box and whisker plot. A bioavailability of approximately 50 % means in practice that the dose must be doubled if naloxone is to be administered as a nasal spray rather than by injection.
Figure 2 Absolute bioavailability for three different doses of naloxone spray: 0.8 mg (N = 12), 1.6 mg (N = 11) and 2.0 mg (N = 5) in the current and following study ( 12). The horizontal lines in the middle of the boxes show the median, the upper and lower limits illustrate the upper and lower quartiles, and the ‘whiskers’ show the minimum and maximum values .
Intranasal and intramuscular naloxone have a relative bioavailability of about 44–54 % in healthy volunteers
(13–15). However, relative bioavailability was 75 % in individuals who received naloxone during ongoing infusion of the opioid remifentanil (16). There may therefore be a pharmacokinetic interaction between remifentanil and naloxone. If this is a general opioid effect, and not just specific to remifentanil, it may have an impact on the current approval processes for new naloxone formulations in opioid overdose.
Our maximum concentration (C
max) was 4.2 ng/ml after 2 mg intranasal naloxone. When the same dose (2 mg) was administered in a more dilute solution, the C max was 0.5 ng/ml. Our highly concentrated solution thus yielded a C max eight times higher than when the same dose was given in a more dilute solution, equivalent to that used until recently in the Norwegian Take Home Naloxone programme (9). Our C max was also four times higher than the standard regulatory comparison dose of 0.4 mg given intramuscularly (C max 1.1 ng/ml) (17). The 2 mg dose is therefore higher than that required for the nasal spray to be compatible with the 0.4 mg intramuscular comparison standard.
Intravenous administration of naloxone yields very high serum naloxone concentrations (22.7 ng/ml). The estimated time to maximum concentration (T
max) after intravenous administration of naloxone was 2.6 minutes in this study, compared to 16 minutes for the nasal spray. In later studies, we observed a somewhat higher T max (18–20 min), comparable with the 15–30 minutes reported for other high-concentration naloxone sprays (12–15) and with the T max of 10–23 minutes reported for intramuscular naloxone (13, 15, 17).
Rapid attainment of a high antidote concentration may be necessary in the minority of patients who cannot be ventilated. However, it comes at a cost of increased risk of withdrawal. Opioid withdrawal is not just an unpleasant adverse effect, but can also increase the risk of further overdoses and may cause patients to refuse follow-up or to discharge themselves from hospital
(18). In order to reduce acute withdrawal, many ambulance services have switched to intramuscular naloxone as first-line treatment, with intravenous naloxone administered only when necessary. Intranasal administration (Figure 1) results in a serum concentration time course similar to that seen following intramuscular injection. Our later studies in healthy volunteers showed a rapid onset and potent effect of intravenous naloxone (1 mg) measured in terms of pupillary size, while an intramuscular dose of 0.8 mg yielded less potent and slower onset effects (16, 19), consistent with a lower risk of withdrawal.
Little attention has been paid to the distribution volume and clearance of naloxone. The latter in particular is interesting. We confirmed previously reported clearance values of approximately 3500 ml/min
(20, 21), more than double the maximum capacity of the liver. This indicates extensive extrahepatic elimination of naloxone. In principle, all organs with demonstrable expression of drug-metabolising enzymes, including the nasal mucosa, may be involved in this process.
The U.S. Food and Drug Administration (FDA) has recommended that new naloxone products achieve serum concentrations comparable to those seen with 0.4 mg intramuscular naloxone, especially in the first few minutes after administration
(11). We have not performed this comparison in the current study, but our C max and T max were similar to those found for intramuscular naloxone, which also gave us a clear indication that we would be able to develop a commercial product.
The pilot study showed that our formulation could yield a serum concentration on a level with those achieved with established modes of administration. This was important knowledge early in the development process and laid the foundations for our subsequent studies
(12, 14, 16, 19). What at first glance appears to be a modest study with five men, initiated a process that has led to five further studies. From the birth of an idea at NTNU, we have progressed all the way to obtaining marketing authorisation of Ventizolve 1.26 mg naloxone through an industry collaboration with dne pharma as and Farma Industri AS. This demonstrates that small academic communities that receive funding and the freedom to conduct experimental research can deliver results amid fierce competition from the international pharmaceutical industry.