We used data from three randomized, placebo-controlled, double-blind trials of nortriptyline for smoking cessation to describe plasma nortriptyline concentrations and to evaluate their relationship to clinical outcomes. Increases in intended dosage yielded increases in plasma nortriptyline concentrations; however, marked variability in concentrations for fixed doses was seen. Amount of smoking showed a small but reliable association with normalized PNCs, but cessation did not result in marked increases in this quantity. In our sample, Asian and Black smokers had normalized PNCs significantly higher than Whites. Self-reported side effects bore little relationship to PNCs. End of treatment and long-term abstinence were significantly related to PNCs taken at 2-weeks post-cessation, after controlling for relevant covariates. No evidence for a curvilinear plasma nortriptyline response curve was observed.
The fact that fixed or mostly fixed dosages of nortriptyline yielded a broad range of PNCs is not surprising. Alexanderson[3
] showed that for a fixed dose of nortriptyline, plasma concentrations of the drug can range as much as 30-fold. The primary cause of this variability appears to be genetic, based on studies of monozygotic and dizygotic twins[22
], mostly due to differences in the polymorphic cytochrome P-450 enyzme, CPY2D6[23
]. Even including only subjects with self-reported full compliance in the week preceding sampling, we still observed some test concentrations falling below the concentration of detectability (e.g., at week 6, 7% were < 20 ng/mL). The most likely explanation for these observations is medication non-compliance. However, it is also possible some of these subjects were ultra-rapid nortriptyline metabolizers[24
In our sample, we observed significantly higher normalized plasma nortriptyline concentrations in Asians and Blacks compared to Whites (see ). Ethnic differences in the metabolism of tricyclic antidepressants have been observed in Asians as well as in Africans and African-Americans[25
]. Data specific to nortriptyline are few but are concordant with our findings[15
]. Kishimoto and Hollister[27
] found that after a single 100 mg dose of nortriptyline in 20 males (Japanese, N
= 10; American, N
= 10 [race not specified]), Japanese participants achieved numerically superior maximum plasma concentrations (39.3 vs. 32.0 ng/mL) and significantly higher exposure, as assessed by area-under-the curve (1150 vs. 730 ng/hour/mL). Evidence of slower metabolism or clearance for another tricyclic antidepressant, desipramine, has been seen in Chinese or mixed Asian samples compared to Caucasians[28
]. Ziegler et al., (1977)
observed that nortriptyline concentrations were nearly 50% higher in African-Americans than Whites (113.5 vs.75.7 ng/mL). The potential genetic basis for ethnic differences in PNCs likely relates to differences in the frequency of defective CPY2D6 alleles (i.e., so-called “poor metabolizers”), with a higher rate of defective alleles for this enzyme generally, but not always, observed in Asians and those of African ancestry[30
]. For a given dose of nortriptyline, higher plasma concentrations of the drug will be achieved due to slower metabolism.
Smokers have been observed to have lower concentrations of nortriptyline than non-smokers[36
], although not always[38
]. In our sample, greater smoking was associated with smaller nortriptyline concentrations, although this effect was slight. Several potential mechanisms may account for this relationship. Nortriptyline is primarily metabolized by CYP2D6 (90%), while the balance of metabolism is accomplished by CYP1A2 and CYP2C19[39
]. Since CYP2D6 has generally not been shown to be inducible [40
], this enzyme is unlikely to be involved in reduced PNC with greater smoking. Cigarette smoking has been shown to induce CYP1A2 [42
] while the inductive effects of cigarette smoke on CYP2C19 await further evaluation [43
]. Overall, the role of smoking on nortriptyline concentrations in our sample appeared modest.
Side effects from nortriptyline and other tricyclic antidepressants can play a major role in medication non-compliance and discontinuation in depressed patients[44
]. Rates of nortriptyline discontinuation have been significantly elevated compared to placebo in some smoking cessation trials[8
], while others have found shown no difference[5
], or a greater rate for placebo[7
]. However, the current report showed little association between PNCs and endorsement of side effects. Two previous studies have evaluated the relationship between PNCs and self-reported side effects[47
]. Asberg and colleagues[47
] evaluated the association between total side effects and plasma nortriptyline concentrations in a sample of depressed patients over the first 4 weeks of treatment. They observed a steady abatement in side effects over time such that by week 4, no association between side effects and PNCs was seen. Ziegler et al., [48
] found that two individual side effects bore a consistent relationship to PNCs: dry mouth and perspiration. Perspiration was not assessed in any of the present studies. However, the persistence of dry mouth in the present studies does confirm Ziegler and coworkers' [48
] observation, at least in the pre-cessation induction phase. Overall, the nortriptyline concentrations achieved in this multistudy analysis are on the low end of the range recommended for treatment for depression (i.e., 50 to 150 ng/mL), and this may also account for the weak associations seen with side effects. Finally, side effects were measured on a dichotomous scale, and the use of a continuous side effects scale would likely have better informed the foregoing analyses[e.g., 49
Guidelines for the dosing of nortriptyline in depression have been available for over thirty years[4
]. Beginning with an early report[14
], evidence of a curvilinear relationship, an inverted u-shape function, between PNCs and depressive remission began to accumulate. When we evaluated PNCs as a continuous predictor of abstinence, we found evidence of a significant linear but not a quadratic (i.e., curvilinear) effect (see ). Given the lack of side effects seen in the current range of plasma nortriptyline concentrations and the relatively stable abstinence rates with concentrations above 40 ng/mL, the utility of achieving PNCs consistent with depression therapy seems unnecessary. However, in order to offer definitive recommendations on a therapeutic range for nortriptyline in smoking cessation, the current findings require replication in a prospective design where smokers are randomized to specific ranges of PNC. Moreover, formal pharmacokinetic-pharmacodynamic modeling of plasma nortriptyline concentrations will be needed to obtain more accurate estimates of a smoking cessation specific therapeutic range.
Ultimately, the generation of smoking-cessation specific guidelines for therapeutic drug monitoring of nortriptyline is most important for the more than 1 billion smokers without access to other smoking cessation aids [50
]. However, as Ozdemir and colleagues[51
] recently noted with respect to off-patent medications, lower medication cost does not guarantee greater access and improved treatment outcomes. In the case of nortriptyline, the costs of TDM may limit access in some settings. The possibility of rapid genotyping of CYP2D6 could allow for genotype-specific dosing, eliminating or reducing the need for TDM. Nevertheless, compared to existing smoking cessation medications, nortriptyline is several times less expensive, requires only once-a-dosing, and has an excellent safety profile.
The current study has limitations. First, only total plasma nortriptyline concentrations were evaluated. Free nortriptyline concentrations might have shown a clearer dose response relationship to side effects and abstinence from smoking[52
]. Second, we did not conduct phenotypic or genotypic tests of the CYP2D6 gene or enzyme. Third, although we had self-reported data on medication compliance, such data are prone to error and bias. More complete and accurate knowledge of differences in amount of medication taken would have been an important explanatory variable in our analyses, particularly to determine if those with undetectable or elevated medication concentrations were non-compliant or instead were ultra-rapid or poor metabolizers as a function of the CPY2D6 enzyme.
In conclusion, wide variability in plasma nortriptyline concentrations was seen in a pooled sample of cigarette smokers given a narrow range of doses. Therapeutic drug monitoring continues to be important in ensuring that patients receive clinically effective nortriptyline exposure, however, the effective range of PNCs appears lower for smokers than for those with depression. Consideration of racial status, particularly among Asian and African-Americans, may be important in initial dosing. Future research is needed to prospectively confirm the possible optimum therapeutic range of nortriptyline in smoking cessation.