Naloxone nasal spray - bioavailability and absorption pattern in a phase 1 study. / Naloksonnesespray ­ biotilgjengelighet og opptaksmønster i en fase 1-studie.

BACKGROUND: Bystander administration with naloxone nasal spray can prevent deaths from opioid overdose. To achieve optimal nasal absorption of naloxone, the spray must be administered at low volume with high concentration of the drug. The study aimed to investigate the bioavailability and absorption pattern for a new naloxone nasal spray. MATERIAL AND METHOD: In an open, randomised, two-way crossover study undertaken in five healthy men, naloxone 2 mg (20 mg/ml) in nasal spray was compared with 1 mg intravenously administered naloxone. A total of 15 blood samples were taken over a period of six hours after administration. The drug concentration was determined using liquid chromatography tandem-mass spectrometry. Pharmacokinetic variables were calculated using non-compartmental analysis. RESULTS: Bioavailability for intranasal naloxone was 47 % (minimum-maximum values 24-66 %). Maximum concentration (Cmax) was 4.2 (1.5-7.1) ng/ml, and this was achieved (Tmax ) after 16 (5-25) minutes. INTERPRETATION: The nasal spray resulted in a rapid systemic absorption with higher serum concentrations than intravenous naloxone 10-240 minutes after intake. The pilot study indicated that the highly concentrated nasal spray may provide a therapeutic dose of naloxone with a single spray actuation. The findings led to further commercial development of the medication.

Pharmacodynamics and arteriovenous difference of intravenous naloxone in healthy volunteers exposed to remifentanil.

PURPOSE: Pharmacodynamic studies of naloxone require opioid agonism. Steady state condition may be achieved by remifentanil TCI (target controlled infusion). Opioid agonism can be measured by pupillometry. It is not known whether there are arteriovenous concentration differences for naloxone. The aim was thus to further develop a model for studying pharmacokinetic/pharmacodynamic aspects of naloxone and to explore whether a significant arteriovenous concentration difference for naloxone in humans was present. METHODS: Relevant authorities approved this study. Healthy volunteers (n = 12) were given 1.0 mg intravenous (IV) naloxone after steady state opioid agonism was obtained by TCI of remifentanil (1.3 ng/ml). Opioid effect was measured by pupillometry. Arterial and venous samples were collected simultaneously before and for 2 h after naloxone administration for quantification of naloxone and remifentanil. RESULTS: Arterial remifentanil was in steady state at 12 min. One milligram IV naloxone reversed the effect of remifentanil to 93% of pre-opioid pupil-size within 4 min. The estimated duration of antagonism was 118 min. At that time, the concentration of naloxone was 0.51 ng/ml. The time course of arterial and venous serum concentrations for naloxone was similar, although arterial AUC (area under the curve) was slightly lower (94%) than the venous AUC (p = 0.03). There were no serious adverse events. CONCLUSION: Onset of reversal by IV naloxone was rapid and lasted 118 min. The minimum effective concentration was 0.5 ng/ml. Using TCI remifentanil to obtain a steady-state opioid agonism may be a useful tool to compare new naloxone products.

Pharmacokinetics and -dynamics of intramuscular and intranasal naloxone: an explorative study in healthy volunteers.

PURPOSE: This study aimed to develop a model for pharmacodynamic and pharmacokinetic studies of naloxone antagonism under steady-state opioid agonism and to compare a high-concentration/low-volume intranasal naloxone formulation 8 mg/ml to intramuscular 0.8 mg. METHODS: Two-way crossover in 12 healthy volunteers receiving naloxone while receiving remifentanil by a target-controlled infusion for 102 min. The group were subdivided into three different doses of remifentanil. Blood samples for serum naloxone concentrations, pupillometry and heat pain threshold were measured. RESULTS: The relative bioavailability of intranasal to intramuscular naloxone was 0.75. Pupillometry showed difference in antagonism; the effect was significant in the data set as a whole (p < 0.001) and in all three subgroups (p < 0.02-p < 0.001). Heat pain threshold showed no statistical difference. CONCLUSIONS: A target-controlled infusion of remifentanil provides good conditions for studying the pharmacodynamics of naloxone, and pupillometry was a better modality than heat pain threshold. Intranasal naloxone 0.8 mg is inferior for a similar dose intramuscular. Our design may help to bridge the gap between studies in healthy volunteers and the patient population in need of naloxone for opioid overdose. TRIAL REGISTRATION: clinicaltrials.gov : NCT02307721.

Pharmacokinetics of a new, nasal formulation of naloxone.

PURPOSE: Nasal naloxone is wanted for bystander administration in opioid overdose and as a needle-free alternative for emergency medical personnel. Epidemiologic studies have indicated a therapeutic effect of bystander administration of low-concentration/high-volume formulations. The objective for this study was to describe the nasal pharmacokinetics of a new high-concentration/low-volume nasal formulation of naloxone. METHODS: This was an open, randomized triple crossover trial in healthy, human volunteers (n = 12) where two doses of nasal naloxone (0.8 and 1.6 mg) and one intravenous dose (1.0 mg) were compared. Fifteen serum samples were collected before and until 6 h after naloxone administration. Quantification of naloxone was performed by a validated liquid chromatography-tandem mass spectrometry method. RESULTS: Bioavailability was 0.54 (0.45-0.63) for the 0.8 mg and 0.52 (0.37-0.67) for the 1.6 mg nasal naloxone formulation. Maximum concentration levels (C max) were 1.45 ng/ml (1.07-1.84) for 0.8 mg and 2.57 ng/ml (1.49-3.66) for the 1.6 mg. Time to maximum concentrations (T max) were reached at 17.9 min (11.4-24.5) and 18.6 min (14.4-22.9) for the 0.8 mg and the 1.6 mg doses, respectively. CONCLUSION: This nasal naloxone formulation had a rapid, systemic uptake and higher bioavailability than naloxone formulations not designed for IN use. This indicates that an optimized high-concentration/low-volume nasal spray formulation may deliver a therapeutic dose. The 1.6 mg nasal dose provided serum concentrations that surpassed those of 1.0 mg IV after 15-20 min and stayed above for the rest of the study period.

Effects of hypothermia on the disposition of morphine, midazolam, fentanyl, and propofol in intensive care unit patients.

Therapeutic hypothermia (TH) may induce pharmacokinetic changes that may affect the level of sedation. We have compared the disposition of morphine, midazolam, fentanyl, and propofol in TH with normothermia in man. Fourteen patients treated with TH following cardiac arrest (33-34°C) were compared with eight matched critically ill patients (36-38°C). Continuous infusions of morphine and midazolam were stopped and replaced with infusions of fentanyl and propofol to describe elimination and start of infusion pharmacokinetics, respectively. Serial serum and urine samples were collected for 6-8 hours for validated quantification and subsequent pharmacokinetic analysis. During TH, morphine elimination half-life (t(1/2)) was significantly higher, while total clearance (CL(tot)) was significantly lower (median [semi-interquartile range (s-iqr)]): t(1/2), 266 (43) versus 168 (11) minutes, P < 0.01; CL(tot), 1201 (283) versus 1687 (200) ml/min, P < 0.01. No significant differences were seen for midazolam. CL(tot) of fentanyl and propofol was significantly lower in hypothermic patients [median (s-iqr)]: fentanyl, 726 (230) versus 1331 (678) ml/min, P < 0.05; propofol, 2046 (305) versus 2665 (223) ml/min, P < 0.05. Compared with the matched, normothermic intensive care unit patients, t(1/2) of morphine was significantly higher during TH. CL(tot) was lower during TH for morphine, fentanyl, and propofol but not for midazolam. Reducing the infusion rates of morphine, fentanyl, and propofol during TH is encouraged.

Early pharmacokinetics of nasal fentanyl: is there a significant arterio-venous difference?

OBJECTIVE: We have investigated the arterio-venous difference in the pharmacokinetics of 50 microg fentanyl during the first hour following nasal administration and documented its tolerability in opioid-naïve middle-aged to elderly patients. METHODS: Twelve male patients (range in age 47-84 years) scheduled for transurethral resection of the prostate gland received a 100-microl dose of 50 microg fentanyl base as a fentanyl citrate formulation in one nostril. Simultaneous arterial and venous blood samples for analyses of fentanyl were drawn at baseline and at 1, 3, 5, 7, 9, 13, 15, 20, 25, 35, 45 and 60 min after drug administration. Vital signs, sedation and symptoms of local irritation were recorded. RESULTS: The arterial C(max) (maximum serum concentration) of 0.83 ng/ml was nearly twofold higher than the venous C(max) of 0.47 ng/ml, and the arterial T(max) (time to maximum serum concentration) of 7.0 min was about 5 min shorter than the venous T(max) of 11.6 min. The arterial AUC(0-60) (area under the curve from 0 to 60 min after administration) of 21 min*ng/ml was approximately 30% larger than the venous AUC(0-60) of 15 min*ng/ml (all p values < or = 0.005). Venous T(max) and C(max) did not predict the corresponding arterial values. No significant adverse events were observed. CONCLUSION: A significant arterio-venous difference was present after intranasal administration of fentanyl. The short arterial T(max) complies with its rapid onset of action. The use of venous concentrations for the prediction of onset time of analgesia should be discouraged. A 50-microg dose of nasal fentanyl was well tolerated by opioid-naïve middle-aged to elderly male patients.

Intranasal midazolam: a comparison of two delivery devices in human volunteers.

Bidirectional nasal drug delivery is a new administration principle with improved deposition pattern that may increase nasal drug uptake. Twelve healthy subjects were included in this open, non-randomized 3-way crossover study: midazolam (3.4 mg) intravenously (1 mg mL (-1)), or nasally by bidirectional or traditional spray (2 x100 microL of a 17 mg mL(-1) nasal midazolam formulation). The primary outcome was bioavailability. Blood samples were drawn for 6 h for determination (gas-chromatography-mass-spectrometry) of midazolam and 1-OH-midazolam. Pharmacokinetic calculations were based on non-compartmental modelling, sedation assessed by a subjective 0-10 NRS-scale, and nasal dimensions by non-invasive acoustic rhinometry. Mean bioavailabilities were 0.68-0.71, and Tmax 15 min for the sprays, which also were bioequivalent (ratio geometric means (90%) CI: 97.6% (90% CI 83.5; 113.9)). Sedation after bidirectional spray followed intravenous sedation closely, while sedation after the traditional spray was less pronounced. A negative correlation between Cmax and smallest cross-sectional area was seen. Adverse effects such as local irritation did not differ significantly between the sprays. Apparently bidirectional delivery did not increase systemic bioavailability of midazolam. We cannot disregard that only the traditional spray caused less sedation than intravenous administration. This finding needs to be confirmed in trials designed for this purpose.

Transepithelial transport of morphine and mannitol in Caco-2 cells: the influence of chitosans of different molecular weights and degrees of acetylation.

The object of this study was to compare the effect of chitosans of different number-average molecular weights (MWs) and degrees of acetylation (F(A)) on transepithelial transport of morphine in Caco-2 cells. Caco-2 monolayers on polycarbonate (PC) membranes (0.5 cm(2)) were incubated with morphine (10 microM) or mannitol (55 microM) for 180 min. Samples for analysis of morphine (LCMSMS) and mannitol (liquid scintillation) were drawn at 45, 90, 120 and 180 min. Transepithelial electrical resistance (TEER) and transmission electron microscopy were used to monitor cell integrity. In controls, morphine transport was half that of mannitol. Chitosans affected the transport of morphine and mannitol similarly. For chitosans with similar F(A) (0.32-0.43) and varying MWs (7-200 kD), transport was increased at MWs of 29 kD or more. Among chitosans of similar MWs (180-300 kD) and varying F(A) (0.01-0.61), those with the highest F(A) (0.61) had the least effect, while chitosans with F(A)/MW 0.01/250 and 0.17/300 promoted the greatest transport. An F(A)/MW of 0.32/200 and 0.43/170 induced a high and stable transport rate. Chitosans may enhance transepithelial transport of morphine by the same mechanism as for mannitol. Chitosans with F(A) of 0.3-0.4 and MW of approx. 200 kD seem favourable in this respect.

A validated method for rapid analysis of ethane in breath and its application in kinetic studies in human volunteers.

Oxidative stress may initiate lipid peroxidation that generates ethane. Ethane, at low concentrations, is eliminated by pulmonary exhalation. Previous methods have not allowed frequent sampling, thus ethane kinetics has not been studied in man. A validated method over the range 3.8-100,000 ppb with a limit of quantitation of 3.8 ppb (CV 9.3%) based on cryofocusing technique of a 60 ml breath sample allowed frequent sampling. Due to a rapid analytical procedure batches of more than 100 samples may be analyzed. In human volunteers (24-55 years) uptake was studied for up to 23 min (n = 9), elimination was studied for 210 min (n = 9). Ethane was inhaled (concentrations varied from 16 to 29 ppm (parts per million)) through a non-rebreathing system; sampling was performed with short intervals from the expiratory limb. Samples were also drawn from the inhalatory limb. Ninety-five percent of steady state (inspired) concentration was reached within 1.75 min. Five percent of the initially inhaled concentrations was found in exhaled air 1.5 min after termination of inhalation. A terminal mean half life of 31 min for ethane was also observed. The data indicate that frequent sampling will be necessary to capture relevant changes in breath ethane.

Effects of food on the pharmacokinetics of levodopa in a dual-release formulation.

The objective was to assess the effect of food on the pharmacokinetics of levodopa and 3-O-methyldopa after administration of a new levodopa/benserazide formulation with a dual-release drug delivery profile (Madopar DR). In an open-label, two-way cross-over study, 19 healthy volunteers who had fasted overnight were randomized to receive a single oral dose of levodopa/benserazide (200/50 mg) in the absence or presence of a standardized, high-fat breakfast, administered 30 min before drug administration. The treatment periods (fasting, non-fasting) were preceded by a baseline regimen of levodopa/benserazide (100/25 mg t.i.d. for 6 or 7 days). Blood samples were taken at specific times over a 12-hour period. Plasma concentrations of levodopa and 3-O-methyldopa were determined by high-performance liquid chromatography for pharmacokinetic evaluation. The parameter C(max) of levodopa was significantly lower and t(max) longer under postprandial conditions than under fasting conditions (mean C(max) 1.41 vs. 2.09 mg l(-1); mean t(max) 3.1 vs. 1.0 h). With food, the area under the curve (AUC) of levodopa was equivalent to that following an overnight fast. Compared with volunteers who had fasted, food did not alter t(1/2). Estimates of C(max), t(max) and AUC of 3-O-methyldopa under non-fasting conditions were not significantly different from those under fasting conditions. In conclusion, food decreases the rate of levodopa absorption, but had no effect on the systemic exposure to levodopa and the degree of 3-O-methyldopa formation. Standardization of levodopa/benserazide administration with respect to meal times is recommended.

Chronic exposure to carbon monoxide and nicotine: endothelin ET(A) receptor antagonism attenuates carbon monoxide-induced myocardial hypertrophy in rat.

The aims of the present study were to determine the effects of endothelin ET(A) receptor antagonism on carbon monoxide (CO)-induced cardiac hypertrophy and endothelin-1 (ET-1) expression and to compare myocardial effects of chronic nicotine with CO exposure. Female Sprague-Dawley rats (n = 84) were randomized to three groups exposed 20 h/day to CO (200 ppm), nicotine (500 microg/m3), or air for 14 consecutive days. In each exposure group, animals were randomized to ET(A) receptor antagonist LU 135252 in drinking water (0.5 mg/ml) or placebo. Myocardial ET-1 and atrial natriuretic peptide (ANP) expression was measured by competitive RT-PCR and plasma ET-1 by immunoassay. Carboxyhemoglobin was 22.1 +/- 0.3% in CO-exposed animals and 2.8 +/- 0.3% in controls. Plasma nicotine was 57 +/- 7 ng/ml and plasma cotinine was 590 +/- 23 ng/ml in nicotine-exposed animals and below detection levels in controls. CO exposure induced a 21% increase in right ventricular hypertrophy (p < 0.01), a 7% increase in left ventricular hypertrophy (p < 0.01), a 25% increase in right ventricular ET-1 expression (p < 0.05), and an eightfold increase in ANP expression (p = 0.08). ET(A) receptor antagonism reduced right ventricular hypertrophy by 60% (p < 0.05) with no significant effect on left ventricular hypertrophy or myocardial ET-1 expression. Chronic nicotine exposure did not significantly affect cardiac weights or ANP and ET-1 expression. We conclude that ET(A) receptor antagonism reduces right ventricular hypertrophy induced by chronic CO exposure, whereas CO-induced myocardial ET-1 expression remains unchanged.