Translational Modeling as a Tool to Evaluate the Effectiveness of Nalmefene in a Community Setting: A Critical Perspective

Chaturbedi et al.¹ used the validated translational model of synthetic opioid overdose from Mann et al.² to evaluate the effectiveness of two FDA-approved intranasal opioid antagonists, nalmefene and naloxone, in a community setting. Using formulations of intranasal nalmefene and naloxone with different pharmacokinetic profiles,¹ the authors emphasize the criticality of rapid absorption for an antagonist to reverse an overdose produced by potentially lethal doses of fentanyl and carfentanil. They also conclude that intranasal 4 mg naloxone hydrochloride and 3 mg nalmefene hydrochloride (2.7 mg base) are similarly effective based on predicted rates of cardiac arrest.¹ These findings differ substantially from previous work³ conducted using the same model² and demonstrating large and clinically meaningful reductions in the incidence of cardiac arrest with intranasal nalmefene compared to naloxone. This apparent discrepancy is explained by the source of pharmacokinetic data used to evaluate the FDA-approved formulation of nalmefene. While previous work³ utilized nalmefene plasma concentrations from subjects breathing room air, Chaturbedi et al.¹ used data (figure 2C) measured in subjects breathing a hypercapnic gas mixture during a pharmacodynamic study.⁴ Breathing a hypercapnic gas mixture markedly impacted the pharmacokinetics of intranasal nalmefene, with a 35% lower absorption rate³ manifested in a delayed and 50% lower peak concentration compared to subjects breathing room air^{4, 5} (Table 1). The pharmacokinetic profile in subjects breathing room air was replicated in independent study cohorts⁵ and constitutes the reference pharmacokinetic profile of intranasal nalmefene in the product label. These data were used to construct a robust population pharmacokinetic model of intranasal nalmefene in 153 subjects.³ Applying this pharmacokinetic model to the model of synthetic opioid overdose developed by Mann et al.,² large and clinically meaningful differences in the effectiveness of intranasal naloxone and nalmefene were observed across all dosing scenarios.³ For example, following a 1.63-mg intravenous fentanyl dose resulting in a cardiac arrest in 52.1% (95% confidence interval, 47.3–56.8) of simulated subjects absent intervention, intranasal naloxone, and nalmefene reduced this percentage to 19.2% (15.5–23.3) and 2.2% (1.0–3.8), respectively.³ The robust nature of these simulations is underscored by an incidence of cardiac arrest following intranasal naloxone³ similar to the value reported by Chaturbedi et al.¹ using an independent pharmacokinetic dataset. Overall, these findings raise issues about the interpretation and validity of results using pharmacokinetic data for intranasal nalmefene that do not mirror the conditions encountered in a “real world” overdose.