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 work ³ conducted using the same model ² 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 work ³ 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 rate ³ 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 cohorts ⁵ 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 naloxone ³ 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.

Table 1.

Effect of breathing a hypercapnic gas mixture on the pharmacokinetics of intranasal nalmefene

Pharmacokinetic parameter	Subjects breathing room aira	Subjects breathing a hypercapnic gas mixtureb
C max (ng/mL)	12.2 (55.2)	6.78 (40.0)
T max (h)	0.25 (0.0833, 2.00)	0.50 (0.04, 2.00)
C 5 min (ng/mL)	4.43 (109)	2.66 (131)
C 10 min (ng/mL)	10.0 (74.4)	3.97 (69.4)
C 20 min (ng/mL)	8.23 (48.9)	5.37 (49.1)
AUC0‐20 min (h.ng/mL)	2.34 (63.5)	1.18 (59.3)

Values represent mean (% coefficient of variation) except for T _max, summarized using median (range). C _max, maximum plasma concentration; T _max, time of C _max; C _{x min}, plasma concentration at x minutes; AUC_{0‐20 min}: area under the plasma concentration–time curve from 0 to 20 minutes post dose.

^a Data from Crystal et al. ⁵ in 66 healthy subjects. Values were replicated in a separate study ⁵ and constitute the reference pharmacokinetic data for intranasal nalmefene in the product label.

^b Data from Ellison et al. ⁴ in 61 healthy subjects breathing a hypercapnic (7% CO₂/43% N₂/50% O₂) gas mixture through a face mask. These data, used in Chaturbedi et al., ¹ show a marked decrease in peak and early nalmefene plasma exposures compared to subjects breathing room air.