Sources of variability in nicotine and cotinine levels with use of nicotine nasal spray, transdermal nicotine, and cigarette smoking

Abstract

Aims Nicotine nasal spray and transdermal nicotine are effective aids to smoking cessation, and are being evaluated for treatment of other medical diseases. Wide variation in levels of nicotine and its metabolite, cotinine, have been observed with such therapies. This study aimed primarily to assess sources of individual variability in nicotine and metabolite plasma levels from these dosing systems and from cigarette smoking. Methods Twelve cigarette smokers, studied on a clinical research ward, received four treatments of 5 days duration each, including (1) cigarette smoking, 16 cigarettes/day; (2) transdermal nicotine, 15 mg/day; (3) nicotine nasal spray, 24-1 mg doses/day; (4) placebo nicotine nasal spray, 24 doses/day. On a different occasion, the disposition kinetics of nicotine and cotinine were determined via infusion of deuterium-labeled nicotine and cotinine. Plasma levels of nicotine, cotinine, and 3∞-hydroxycotinine and daily intake of nicotine during various treatments were examined, as well as pharmacokinetic factors that determined plasma nicotine and cotinine levels. Results There was considerable individual variation in plasma nicotine and cotinine levels and in the daily dose of nicotine absorbed from various delivery systems, with most variability with nicotine nasal spray (fivefold) and least for transdermal nicotine (two-to threefold). Plasma nicotine levels were determined most strongly by nicotine clearance. Cotinine levels were determined most strongly by dose of nicotine and, to a lesser extent, the clearance of cotinine and fractional conversion of nicotine to cotinine. Conclusions Plasma levels of nicotine and cotinine produced by nicotine therapies are highly variable, due to both wide variability in individual pharmacokinetics and in dose delivery from the products. To compensate for individual differences in clearance, individualization of nicotine dosing based on therapeutic drug monitoring with comparison to nicotine or cotinine levels during cigarette smoking prior to treatment may be necessary to optimize nicotine therapy. This study also validates a recently proposed method for estimating absolute bioavailability of a drug using drug and metabolite pharmacokinetic data, and presents novel data on plasma levels of the metabolite trans-3∞-hydroxycotinine in people.

A therapeutic vaccine for nicotine dependence: preclinical efficacy, and phase I safety and immunogenicity

“…The nicotine concentration in the serum of control mice was found to be 20 ng/ml (Fig. 3), similar to the peak concentrations seen in humans when smoking up to 31 cigarettes/ day [18,19]. Immunized mice had increased concentrations of nicotine in serum (50-70 ng/ml) reflecting both free and antibody-bound nicotine.…”

“…it may be necessary to block or delay the distribution of only a fraction of nicotine into the brain inhaled during smoking of a cigarette. Smoking one cigarette increases arterial nicotine content to about 20 ng/ml, whereas one puff increases nicotine concentration by about 7 ng/ml [19,23]. Encouragingly, in an ongoing phase II study, we have seen that additional booster injections further increase antibody titers (P. Maurer et al, unpublished).…”

Impact of CYP2A6 genotype on pretreatment smoking behaviour and nicotine levels from and usage of nicotine replacement therapy

“…In contrast, the majority of the variability in plasma cotinine from these delivery systems could be explained by the dose of nicotine (64-77% of variance), followed by cotinine clearance (15-30% of the variance). 28 In our study, among those subjects randomized to the nicotine patch, where usage, and likely the absorbed dose of nicotine, was similar between the two genotype groups, slow metabolizers had greater plasma nicotine concentrations consistent with reduced rates of nicotine clearance (Figure 4), but similar plasma cotinine concentrations. The fact that cotinine levels were similar in slow and normal metabolizers is most likely explained by balanced effects of a smaller percentage conversion of nicotine to cotinine and slower clearance of cotinine in slow metabolizers.…”

“…66 Likewise, when controlling for similar doses of nicotine delivered from smoking (16 cigarettes evenly spaced over 16 h), from the nicotine patch (15 mg/ 16 h) and from the nicotine spray (24 Â 1 mg doses/ day), clearance and dose accounted for the majority of this variability. 28 Specifically, individual nicotine clearance accounted for 45-57% of the variance and was the best predictor of plasma nicotine levels from cigarettes, nicotine patch or nicotine spray, whereas dose accounted for only 9-20% of the variance. In contrast, the majority of the variability in plasma cotinine from these delivery systems could be explained by the dose of nicotine (64-77% of variance), followed by cotinine clearance (15-30% of the variance).…”

“…under-dosing) compared to levels obtained with smoking. [28][29][30] Although several studies have shown that CYP2A6 genetic variation alters the rate of nicotine metabolism, 6,8,11,31,32 the effect of these variants on plasma nicotine levels obtained with NRT in a clinical trial setting has not been determined. This is important to study as increasing the amount of nicotine replaced by NRT has been shown to improve abstinence rates and alleviate withdrawal symptoms, particularly on the nicotine patch.…”