Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Drug used in nicotine dependence.

ATC code: N07B A01
Nicotine is an agonist at nicotine receptors in the peripheral and central nervous system and has pronounced CNS and cardiovascular effects.
Clinical studies have shown that nicotine replacement products can help smokers abstain from use by relieving these withdrawal symptoms.
A parallel, double-blind, placebo-controlled, randomised pharmacodynamic study conducted in solus, regular vapers has shown that the mouth spray is effective in relieving momentary urges to vape (cravings) following ad lib use of the spray over 11 hours. A significantly higher proportion of subjects (p<0.001) in the mouth spray group (82.6%) had a maximum reduction of at least 50% vs. baseline in momentary urges-to-vape scores during the two hours follow-up compared to the placebo group (55.1%).
Compared to nicotine gum or nicotine lozenge, the absorption of nicotine from the mouth spray is more rapid (section 5.2) and based on prior experience with nicotine replacement therapy, this will result in a faster onset of relief of cravings and other symptoms.
Increased appetite is a recognised symptom of nicotine withdrawal and post-cessation weight gain is common. Clinical trials have demonstrated that Nicotine Replacement Therapy can help control weight following a quit attempt.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
The pharmacokinetics of nicotine has been extensively studied, and variations in delivery format have been found to have significant effects on rate and extent of absorption.

The pharmacokinetics of the mouth spray has been studied in 4 studies. The studies included 141 subjects.

Absorption
The oral spray form means that the nicotine dose is administered instantaneously, and as a result the absorption of nicotine from the mouth spray is rapid: In trials, nicotine uptake from the oral nicotine spray was detected at 2 minutes, the first timepoint tested.


A maximum concentration of 5.3 ng/mL is reached within 13 minutes after administration of a 2 mg dose. The nicotine AUCs over the first 10 minutes after administration of the mouth spray at a dose of 1 and 2 mg exceeds those of nicotine gum as well as nicotine lozenge at doses of 4 mg (0.48 and 0.64 h*ng/mL vs. 0.33 and 0.33 h*ng/mL).

AUC∞ estimates show the bioavailability of nicotine administered by mouth spray is somewhat higher than that of nicotine gum or lozenge. The AUC∞ of the mouth spray 2 mg measured 18.9 h*ng/mL as compared with 16.2 h*ng/mL for nicotine gum 2 mg. Allowing for differences in administered dose, bioavailability was also higher in a second study. The nicotine AUC∞ of the mouth spray 2 mg measured 14.0 h*ng/mL in comparison with 23.0 h*ng/mL and 26.7 h*ng/mL for and nicotine gum 4 mg and nicotine lozenge 4 mg, respectively.

Steady-state average nicotine plasma concentrations achieved after administration of the maximum dose (i.e. 2 sprays of the mouth spray 1 mg every 30 minutes) are approximately 28.8 ng/mL as compared with 23.3 ng/mL for nicotine gum 4 mg (1 gum, hourly) and 25.5 ng/mL for nicotine lozenge 4 mg (1 lozenge, hourly).

Given the rapid absorption and the similar, high relative bioavailability, the majority of the nicotine released from the mouth spray is apparently absorbed through the buccal mucosa.

Distribution
The volume of distribution following intravenous administration of nicotine is about 2 to 3 l/kg.


Plasma protein binding of nicotine is less than 5%. Therefore, changes in nicotine binding from use of concomitant drugs or alterations of plasma proteins by disease states would not be expected to have any significant effects on the nicotine pharmacokinetics.


Biotransformation
Nicotine metabolism and elimination are independent of the choice of nicotine formulation, and thus results from studies with intravenous administration of nicotine are used to describe biotransformation and elimination.


The major nicotine-eliminating organ is the liver, although the kidney and lung also metabolise nicotine. More than 20 metabolites of nicotine have been identified, all of which are believed to be less active than the parent compound.


The primary metabolite of nicotine in plasma, cotinine, has a half-life of 15 to 20 hours and concentrations that exceed nicotine by 10-fold.
Elimination
The average plasma clearance of nicotine is 70 l/hour and the half-life is 2-3 hours.
The primary urinary metabolites are cotinine (12% of the dose) and trans-3-hydroxy- cotinine (37% of the dose). About 10% of nicotine is excreted unchanged in the urine.
As much as 30% of nicotine may be excreted unchanged in the urine with high flow rates and acidification of the urine below pH 5.


Linearity/non-linearity
There is only a small deviation from dose-linearity of AUC∞ and Cmax as shown when single doses of 1, 2, 3 and 4 sprays of the 1 mg mouth spray are given.


Characteristics in specific groups of subjects:

Renal Impairment
Progressive severity of renal impairment is associated with decreased total clearance of nicotine. Nicotine clearance was on average decreased by 50%, in subjects with severe renal impairment. Raised nicotine levels have been seen in smokers undergoing hemodialysis.


Hepatic Impairment
In smokers with liver cirrhosis but only mild liver impairment (Child-Pugh score 5) the pharmacokinetics of nicotine is unaffected. However, in smokers with moderately impaired liver (Child-Pugh score 7) total clearance has been reported to be reduced by 40-50%. There is no information available in subjects with a Child-Pugh score > 7.


Elderly
A minor reduction in total clearance of nicotine, not justifying adjustment of dosage, has been demonstrated in healthy elderly patients.