Varenicline overdose in a teenager – a clinical pharmacology perspective

Varenicline overdose in a teenager – a clinical pharmacology perspective

To the Editor:

We comment here on the case report of varenicline overdosing in a teenager who ingested 30 tablets of 0.5 mg varenicline without serious adverse events and was dismissed from the hospital 8 h after admission.¹

Data from phase 1 clinical trials showed rapid vomiting responses after high doses of varenicline.^2,3 Maximum plasma concentrations after a single 10-mg dose, at which all subjects vomited, were found to range from 4.1 to 18 ng/mL, similar to those observed after a single 3-mg dose. Dose-escalating studies have consistently led to permanent discontinuation of subjects because of high incidence of early onset of vomiting. Analyses of plasma peak exposures observed following multiple days of high-dose regimens of up to 3 mg daily indicated that circulating concentrations never exceeded 28.3 ng/mL in any individual.

In this overdose case, it is reasonable to expect that after acute ingestion of a single 15-mg dose, the systemic exposure of varenicline would be considerably reduced following emesis, reaching levels near those observed in healthy volunteers administered 10 mg. The highest concentration observed after a 10-mg dose, 18 ng/mL, corresponds to free levels of varenicline of approximately 70 nM that are available for interactions with the target and other receptors. At that concentration, varenicline maintains good α4β2 selectivity and is unlikely to cause nicotine-like toxicity, because it has much higher affinity for α4β2 nAChRs (K_i = 0.15 nM) than for other nAChRs (K_i > 86 nM) or transmitter receptors and transporters (K_i > 350 nM) and lacks affinity for muscle-type α1β1δγε nAChRs (K_i > 10 μM) and smooth muscle-type muscarinic AChRs (K_i > 3 μM).⁴

The transient increases in blood pressure and heart rate that were described in the overdose case could be a consequence of the powerful autonomic response associated with vomiting. One possible mechanism of vomiting induced by high varenicline doses is activation of gastrointestinal 5-HT₃ receptors. As varenicline is a 5-HT_3A receptor agonist (EC₅₀ = 1 μM), it is conceivable that immediately after ingesting high doses, gut concentrations could be high enough to allow transient activation of local 5-HT₃ receptors. This mechanism would explain a rapid onset vomiting response that effectively limits systemic exposure.

In summary, the most frequent adverse events of varenicline, nausea and at high doses vomiting, can act as a protection mechanism that reduces risk of overexposure when patients either accidentally or intentionally overdose.