A Long-acting Naltrexone Implant (iSTEP-N) for Opioid Use Disorder

Abstract

Objectives:

iSTEP-N is a novel, bioresorbable, subcutaneous implant designed to release naltrexone for 6–12 months after a single procedure and improve adherence. This first-in-human study evaluated the safety and pharmacokinetics of iSTEP-N.

Methods:

This was a single-center, randomized, double-blind, placebo-controlled, single-ascending-dose trial. Sixteen healthy adults (10 females and 6 males) were assigned to receive either 1 implant (4.8 g naltrexone), 2 implants (9.6 g naltrexone), or placebo implants. Participants were followed for 12 weeks, after which implants were removed per regulatory requirement. Plasma naltrexone concentrations and safety outcomes were assessed throughout.

Results:

All participants completed the study. The 9.6 g cohort maintained mean plasma naltrexone concentrations above the 2.0 ng/mL opioid blockade threshold from Tmax at 10 hours through the end of the study at 12 weeks; no mean value fell below 2.8 ng/mL during this time. The 4.8 g cohort maintained therapeutic levels of naltrexone through week 6 but dropped below threshold thereafter. In both cohorts, ∼22% of implant drug content was released over 12 weeks, based on plasma exposure and estimated clearance, indicating potential for extended coverage. In the 9.6 g group, seroma formation was observed in 3 of 6 participants (50%) and resolved without intervention. No serious adverse events occurred.

Conclusions:

At the 9.6 g dose, iSTEP-N provided sustained therapeutic naltrexone exposure for 12 weeks with a favorable safety profile, while releasing less than one-fourth of its drug content. Further studies will evaluate longer-term exposure, safety, and clinical feasibility in individuals with opioid use disorder.

The opioid crisis represents one of the most significant public health challenges of our time. In 2022, there were 82,136 opioid-related deaths in the United States, a 10-fold increase from the 8050 deaths in 1999.¹ In 2024, the number of deaths decreased to 48,422, but is still unacceptably high with overdose remaining the leading cause of death for Americans aged 18 to 44 years.²

Current medications for opioid use disorder (MOUD) are hampered by 2 critical factors, poor utilization (secondary to regulatory limitations, insurance coverage, and stigma)³ and poor adherence. Unfortunately, only 25% of the 9 million Americans who would benefit from MOUD receive the recommended medications.⁴ Among the 25% of people with OUD who receive MOUD, ∼74% receive opioid agonists (buprenorphine or methadone), while 26% receive antagonists (naltrexone).⁵ In addition to poor utilization, both agonist and antagonist therapy have major problems with adherence.

Adherence to agonist therapy is adversely affected by several factors. Some people distrust agonist therapies, viewing them as replacing one addictive substance with another; others dislike the cognitive and emotional side effects they can cause; and others are deterred by the stigma surrounding these treatments.^6–8 Adherence to buprenorphine varies widely depending on formulation, dosing schedule, and treatment setting. While real-world studies reported a 6-month adherence rate of 27% for daily oral buprenorphine, other studies have shown moderate retention, with approximately 40%–50% of patients remaining in treatment at 6 months, particularly in structured primary care or higher-dose settings.^9–12 Long-acting injectable formulations may improve retention but remain underutilized.¹³

Adherence to antagonist therapy also faces several challenges. Extended-release intramuscular naltrexone (XR-naltrexone, 380 mg every 4 wk) was approved in 2010 after demonstrating reduced relapse in individuals with OUD compared with placebo in a phase 3 trial.¹⁴ Unfortunately, induction to XR-naltrexone is limited by the need for a 7–14-day opioid-free interval before initiation to avoid precipitating withdrawal.¹⁵ In addition, the already modest 6-month adherence rate of 36% reported in the XR-naltrexone registration trial has not been replicated in real-world practice, where adherence falls to only about 10%.¹⁶ There are several reasons for poor adherence. First, injection-site pain and anxiety associated with monthly intramuscular administration can reduce willingness to continue treatment. In addition, the declining plasma concentrations toward the end of the dosing interval with XR-naltrexone (<2.0 ng/mL between days 21 and 28)¹⁷ can leave patients with suboptimal opioid receptor blockade and increased susceptibility to cravings, relapse, and overdose.

Because of the problems with monthly naltrexone, several long-acting subcutaneous naltrexone implant formulations have been used in Australia, Russia, and the United States. These systems (eg, O’Neil, Prodetoxone, Wedgewood) typically consist of compressed naltrexone tablets or pellets in magnesium stearate or polymer matrices inserted into the subcutaneous tissue.^18,19 Although clinical trials and observational studies have shown that these implants can sustain therapeutic naltrexone concentrations for several months,²⁰ they have generally been used under unapproved or compassionate access pathways and have not undergone the regulatory evaluation required for approved medicines and devices.¹⁸ Clinical experience has also highlighted limitations, including variable pharmacokinetics and significant complications, such as wound infections, abscesses, necrosis, and wound dehiscence.^19,21,22 These implant systems therefore demonstrate proof-of-concept for long-acting opioid antagonist delivery but underscore the need for rigorously evaluated, bioresorbable formulations manufactured under standardized conditions, with predictable release profiles, and developed in accordance with established FDA regulatory pathways.

To address these limitations—including adherence challenges, safety concerns, and the absence of rigorously evaluated, bioresorbable long-acting formulations developed under regulatory oversight—we developed iSTEP-N, an Implantable, subcutaneous, Tunable, Extended-release, fully bioresorbable, Polymeric device designed to release Naltrexone for 6–12 months following a single administration. Here, we report the results of the first-in-human phase 1 clinical trial evaluating the pharmacokinetics (PK) and safety of iSTEP-N over 3 months.

METHODS

Study Design

This was a single-center, randomized, double-blind, placebo-controlled, single-ascending-dose study conducted in 2 sequential cohorts of healthy volunteers.

Participants

Healthy men and women aged 18–55 years were eligible if they were in good general health based on medical history, physical examination, vital signs, 12-lead electrocardiogram (ECG), and clinical laboratory testing. Body mass index (BMI) was required to be 18–32 kg/m² with a minimum weight of 50 kg. Liver function tests (alanine aminotransferase, aspartate aminotransferase, total bilirubin, albumin, gamma-glutamyl transferase), kidney function tests (creatinine, blood urea nitrogen), and reticulocyte counts were required to be within 25% of normal limits.

Key exclusion criteria included: clinically significant abnormalities on physical examination, ECG, or laboratory tests; current or past opioid use disorder or alcohol use disorder as defined by DSM-5; positive urine drug screen for amphetamines, barbiturates, benzodiazepines, cocaine, opiates, cannabinoids, phencyclidine, propoxyphene, methadone or breath alcohol test; physical dependence on opioids as determined by naloxone challenge; elevated suicide risk by Columbia Suicide Severity Rating Scale or Hamilton Depression-17 score >10; and known hypersensitivity to naltrexone or the polymeric excipients. Women of childbearing potential were required to have a negative pregnancy test before dosing and to use effective contraception throughout the study.

Interventions

iSTEP-N

The investigational product, iSTEP-N, is a solid, bioresorbable, extended-release subcutaneous implant formulated as a polymeric matrix containing naltrexone base dispersed within a proprietary blend of 2 bioresorbable polymers. Physically, each iSTEP-N is an asymmetric disc measuring 4.0×5.6×0.56 cm with rounded edges. The naltrexone loading in each implant is 40% by weight, which means that one 10 mL iSTEP-N contains 4.8 g of naltrexone.

Treatment

Participants received either a single subcutaneous abdominal wall iSTEP-N containing 4.8 g of naltrexone (dose level 1) or 2 iSTEP-Ns containing a total of 9.6 g of naltrexone (dose level 2), or matching placebo implant(s), all placed by a surgeon in the left upper quadrant of the abdomen (ratio 6:2 per cohort) deep to the subcutaneous fat. This cohort size of 6 subjects per group is standard for early-phase exploratory PK studies

Active and placebo implants differed slightly in physical appearance due to the presence or absence of naltrexone, although both were packaged in identical sterile containers and labeled only with blinded treatment codes maintained by unblinded pharmacy staff. All other staff remained blinded to treatment allocation throughout the study. Implants were placed under local anesthesia with conscious sedation during a brief inpatient stay (day –1 to day 3), during which serial PK samples were collected up to 72 hours post dose.

Participants were followed as outpatients with weekly visits through week 12 for safety monitoring and PK sampling. Although iSTEP-N is designed to be completely bioresorbable, implants were removed at week 12 because regulatory approval for this first-in-human study was based on 12-week preclinical safety data. During removal, the condition of the surrounding capsule and tissue was documented, and PK sampling continued for 96 hours post explantation.

Clinical Assessments

Pharmacokinetic Procedures

Sample collection: Venous blood samples for plasma naltrexone and 6β-naltrexol concentrations were collected according to the protocol-defined PK schedule: before implant; and 1, 3, 6, 12, 24, 48 and 72 hours, days 7 and 10, and weeks 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11 after implant. Blood was also collected for plasma levels preexplantation (ie, at 12 wk post implantation); and at 1, 3, 6, 12, and 24, 48, 72, and 96-hours post explantation to assess how fast the drugs were cleared from the circulation after the implant was removed.

Samples were collected into prechilled K₂-EDTA tubes, immediately placed on wet ice, and centrifuged at ∼1500 g for 10 minutes at 4 °C within 30 minutes of collection. Plasma was aliquoted into prelabeled cryovials and stored at ≤−70 °C until shipment on dry ice to Aliri Bioanalysis, Inc. (Hudson, MA) for LC–MS/MS analysis.

Bioanalysis: Plasma concentrations of naltrexone and 6β-naltrexol were quantified using a validated liquid chromatography–tandem mass spectrometry method (Aliri Bioanalysis, Inc).

Tolerability and Safety

Subjects were seen in clinic weekly from implantation through explantation. At each visit, implant site reactions, systemic adverse events, and concomitant medications were assessed. The HAM-D test was administered every other week; the CSSR, clinical chemistries, and hematology were assessed at weeks 4 and 8. All safety parameters were again assessed preexplant. Data were team-reviewed including by an Independent Medical Monitor every 2 weeks. The final safety check was 2 weeks after explantation, which was 14 weeks after implantation.

Local implant site reactions, including pain, tenderness, edema, erythema, and induration, were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.²³ Subjective symptoms such as pain and tenderness were classified as mild (grade 1) if they did not interfere with routine activities and were associated with minimal discomfort, and as moderate (grade 2) if they interfered with routine activities and were associated with a moderate level of discomfort. Higher grades (grade 3 and above) reflect increasing severity requiring medical intervention.

Analyses

Pharmacokinetic Analysis

Noncompartmental pharmacokinetic analysis (NCA) was utilized to obtain parameters and performed with the software Phoenix WinNonLin Ver 8.5 (Certara LP). Actual times were used for plotting individual plasma concentrations profiles and pharmacokinetic analysis. The time of maximum plasma concentration (Tmax) and its value (Cmax) were obtained for each profile. Half-lives (T1/2’s) were estimated as ln(2)/ λz, where λz is the elimination rate constant post explantation. Estimates of AUCs and partial AUCs were calculated by the linear trapezoidal and linear interpolation methods. In the case of AUC to infinity (AUC∞), the AUC from the last concentration (Ct) to infinity was obtained as Ct// λz.

Tolerability/Safety Analysis

Safety endpoints were implant site reactions, vital signs, blood chemistries and hematology, urine drug tests, systemic AEs/SAEs, ECG, suicidality, and depression.

Statistical Procedures

Plasma concentrations, PK parameters, and tolerability were analyzed by descriptive statistics: mean, geometric mean, SD, coefficient of variation, median, minimum, and maximum. Analyses were exploratory; no formal hypothesis testing was performed.

Ethical Review

The study protocol was approved by Advarra Institutional Review Board, and all participants provided written informed consent. The study was approved by the US FDA (IND# 152157). Protocol details are available at ClinicalTrials.gov (NCT06216132).

RESULTS

Participant Disposition and Baseline Characteristics

A total of 38 individuals provided informed consent and were screened for eligibility. Of these, 22 did not meet eligibility criteria, most commonly due to laboratory abnormalities outside protocol-defined limits or positive urine drug screens. Sixteen participants were randomized and implanted across 2 dose levels (Fig. 1). Each cohort consisted of 8 participants: 6 of whom received active iSTEP-N and 2 of whom received matching placebo implants. In cohort 1, participants received a single iSTEP-N containing 4.8 g naltrexone or a placebo implant; in cohort 2, participants received 2 iSTEP-Ns containing a total of 9.6 g naltrexone or 2 placebo implants. All participants completed the planned in-clinic assessments through the scheduled end of the study. Baseline demographics and clinical characteristics were generally balanced between groups, with mean age 32.4 years (range: 21–49) and mean BMI 28.1 kg/m² (range: 20.3–31.9; Table 1).

FIGURE 1.

Disposition of participants. A total of 38 individuals were screened for eligibility. Of these, 22 did not meet eligibility criteria, most commonly due to laboratory abnormalities or positive drug screens. Sixteen participants were randomized into 2 sequential cohorts. In cohort 1, six participants received a single iSTEP-N containing 4.8 g of naltrexone and 2 received placebo. In cohort 2, six participants received two iSTEP-N, 9.6 g total naltrexone, and 2 received placebo. All randomized participants completed study treatment, scheduled pharmacokinetic assessments, and protocol-mandated implant removal at 12 weeks.

TABLE 1.

Summary of Demographic and Other Baseline Characteristics

Characteristic	iSTEP-N 1 Implant N=6	iSTEP-N 2 Implants N=6	Placebo 1 or 2 Implants N=4	All Subjects N=16
Sex; n (%)
Male	2 (33.3)	4 (66.7)	0	6 (37.5)
Female	4 (66.7)	2 (33.3)	4 (100)	10 (62.5)
Age (y)
Mean (SD)	32.0 (4.2)	30.2 (2.5)	36.5 (11.0)	32.4 (6.2)
Height (cm)
Mean (SD)	165.5 (8.4)	175.8 (12.0)	166.2 (5.1)	169.5 (10.1)
Weight (kg)
Mean (SD)	73.0 (7.9)	92.3 (8.5)	76.0 (13.5)	80.97 (12.8)
BMI (kg/m2)
Mean (SD)	26.8 (3.7)	29.9 (2.2)	27.4 (3.6)	28.1 (3.3)

Tolerability/Safety

Implant Site Reactions

No participants (0/16) experienced wound infection, wound dehiscence, or bleeding at the implant site. Transient seroma formation was observed in 5 of 16 participants (31%): 2 of 6 (33%) in the 4.8 g group and 3 of 6 (50%) in the 9.6 g group, with onset between days 4 and 11 and spontaneous resolution without intervention within 8–64 days. No seromas or other local reactions occurred in any of the 4 placebo recipients. All seromas were mild (CTCAE grade 1), asymptomatic, and detected only on clinical examinations.²³ Because placebo implants contained the same bioresorbable polymer matrix as the active implants, these findings suggest that seroma formation was more likely related to naltrexone exposure or release rather than to the polymers. Transient, mild pain or tenderness at the implant site was reported by 3 participants in the 4.8 g group, but not in the higher-dose group. No erythema, itching, or clinically significant inflammation was observed.

Implant removal was straightforward and easily accomplished. The original implantation incision was reused in all cases, and each implant was encapsulated. Following an incision of the capsule, the implants were grasped with forceps and slid out intact, without difficulty.

Serious adverse events (SAEs): There were no SAEs, severe (grade 3) AEs, or discontinuations. Vital signs, ECGs, and laboratory parameters remained within protocol-defined normal limits. One iSTEP-N participant had mildly elevated values of AST, uric acid, and cholesterol that reverted to normal upon retesting. No adverse psychiatric effects, including depressive symptoms or suicidal ideation, were reported.

Among participants in the 4.8 g cohort who reported AEs possibly attributable to drug, there was 1 participant who reported moderate (grade 2) dizziness, 2 participants who reported mild (grade 1) headache, and one participant who reported each of mild nausea, abdominal pain, dizziness, and muscle stiffness. These adverse events are consistent with the expected safety profile of naltrexone.²⁴ There were no participants in the 9.6 g cohort who had moderate AEs attributed to drug, and only 1 participant who reported each of mild headache and nausea attributed to drug. Ondansetron was given as prophylaxis of nausea in 2 participants in the low-dose group and 2 participants in the higher-dose group.

Pharmacokinetics

For each dose level, there were 29 blood draws per participant for each of 6 participants: a total of 174 draws. In cohort 1, 173 draws were accomplished. For cohort 2, all 174 planned draws were accomplished.

For naltrexone, T_max occurred between 9 hours and 13 hours for both cohorts (Fig. 2, Table 2). After 72 hours, plasma naltrexone concentration declined gradually until approximately week 8, after which levels stabilized through week 12 (Fig. 3). Following explantation, plasma concentrations fell rapidly, reaching <0.5 ng/mL within 6 hours.

FIGURE 2.

Early mean plasma naltrexone. Mean plasma naltrexone concentrations (±SE) following implantation of iSTEP-N for the first 72 hours. The squares represent cohort 1 (single 4.8 g iSTEP-N implant) and the circles represent cohort 2 (two 4.8 g iSTEP-N implants; 9.6 g total).

TABLE 2.

Naltrexone Pharmacokinetic Parameters

PK Parameter	Cohort 1: 4.8 g iSTEP-N 6				Cohort 2: 9.6 g iSTEP-N 6
	Mean	SD	CV%	GeoM	Mean	SD	CV%	GeoM
Cmax
(ng/mL)	15.9	5.7	35.8	15.0	26.9	9.1	34	25.6
Tmax
(h)	13.46	4.8	35.7	12.9	9.7	3.2	32.6	9.2
AUC(0 –last)
(h*ng/mL)	4962	732.2	14.8	4918	10,060	1060	10.5	10,010
AUC(0 –∞)
(h*ng/mL)	4964	732.1	14.8	4919	10,060	1060	10.5	10,020
AUC (2–12 wk)
(h*ng/mL)	3262	545.3	16.7	3222	6862	877.2	12.8	6813
T1/2 (postexplantation)
(h)	3.10	1.06	34.2	2.98	2.16	0.43	20.1	2.12
Cave 2–12 wk
(ng/mL)	1.94	0.32	16.7	1.92	4.08	0.52	12.8	4.06
Cmax/dose
(ng/mL/g)	3.31	1.19	35.8	3.12	2.80	0.95	34.0	2.67
AUC(0 –∞)/dose
(h*ng/mL/g)	1034	152.5	14.8	1025	1048	110.5	10.5	1043

FIGURE 3.

Late mean plasma naltrexone. Mean plasma naltrexone concentrations (±SE) following implantation of iSTEP-N from 72 hours to week 12. The squares represent cohort 1 (single 4.8 g iSTEP-N implant) and the circles represent cohort 2 (two 4.8 g iSTEP-N implants; 9.6 g total). While implants remained in place, mean concentrations in the 9.6 g cohort consistently exceeded the 2.0 ng/mL opioid blockade threshold, whereas concentrations in the 4.8 g cohort fell below this threshold beginning at week 7.

Geometric means closely matched arithmetic means for all PK parameters, suggesting a normal distribution of individual values, and coefficients of variation were small despite the limited sample size (n = 6 per group). Dose proportionality was evident: for 9.6 g versus 4.8 g, mean C_max values were 26.9 versus 15.9 ng/mL (ratio = 1.7) and mean AUC_0-last values were 10,060 versus 4962 h*ng/mL (ratio = 2.03). Dose-normalized C_max (2.8 vs 3.3 ng/mL/g) and AUC_0-last (1048 vs 1034 h*ng·/mL/g) were nearly identical.

The clinically relevant threshold for opioid blockade is generally considered to be 2.0 ng/mL.^25,26 For the 4.8 g dose, mean concentrations during weeks 7–12 were <2.0 ng/mL, with an average concentration of 1.9 ng/mL for weeks 2–12 (Fig. 3, Table 2). In contrast, the 9.6 g dose maintained mean concentrations >2.0 ng/mL at all post-Cmax time points through week 12, with mean values exceeding 2.5 ng/mL from 13-hour post-dose to explantation at 12 weeks (Fig. 3). At only one time point in the study did any participant have a plasma naltrexone <2.0 ng/mL. That was participant 3 at week 10 when the plasma naltrexone level was 1.8 ng/mL (Fig. 4).

FIGURE 4.

Individual plasma naltrexone levels in cohort 2 (9.6 g naltrexone). Plasma naltrexone concentrations in the high dose cohort (9.6 g) following implantation of two 10 mL iSTEP-N from week 1 through week 12. At week 10, participant 3 had a plasma naltrexone of 1.8 ng/mL. At all other time points, all participants' plasma naltrexone level was ≥2 ng/mL.

The metabolite 6β-naltrexol, which is 12–56-fold less potent than naltrexone in animal models,²⁷ is presented for completeness (Table 3). Exposure profiles were dose proportional (AUC _0-last ratio = 2.1), and the 6-β-naltrexol/naltrexone exposure ratio based on AUCs was identical for both dose levels (2.5).

TABLE 3.

6β-Naltrexol Pharmacokinetic Parameters

PK Parameter	Cohort 1: 4.8 g iSTEP-N 6				Cohort 2: 9.6 g iSTEP-N 6
	Mean	SD	CV%	GeoM	Mean	SD	CV%	GeoM
Cmax
(ng/mL)	23.7	5.8	24.3	23.1	40.9	14.0	34.1	38.6
Tmax
(h)	21.7	14.2	65.4	18.7	19.9	14.7	73.6	16.8
AUC(0 –last)
(hr*ng/mL)	12,300	1936	15.7	12,160	25,620	2866	11.2	25,480
AUC(0 –∞)
(h*ng/mL)	12,310	1941	15.8	12,170	25,630	2865	11.2	25,490
AUC (2–12 wk)
(h*ng/mL)	8159	1313	16.1	8062	17,500	1485	8.5	17,450
T1/2 (postexplantation)
(hr)	15.8	4.44	28.0	15.4	16.4	3.52	21.4	16.1
Cave 2–12 wk
(ng/mL)	4.86	0.78	16.1	4.80	10.4	0.88	8.5	10.4
Cmax/dose
(ng/mL/g)	4.93	1.20	24.3	4.81	4.26	1.45	34.1	4.02
AUC(0 –∞)/dose
(h*ng/mL/g)	2564	404.4	15.8	2536	2670	298.4	11.2	2656

DISCUSSION

Adherence remains a critical limitation of current MOUDs. Both agonist therapies (methadone, buprenorphine) and antagonist therapy with intramuscular XR-naltrexone suffer from poor long-term adherence, leading to high rates of relapse and overdose.^1,2,11,16 For XR-naltrexone, adherence is a critical issue. Real-world 6-month adherence is as low as 10%, hindered by the need for monthly injections, injection-site pain, and waning plasma concentrations that often fall below therapeutic levels near the end of the dosing cycle.^16,17 A longer-acting formulation of naltrexone capable of maintaining exposure well above the 2.0 ng/mL opioid blockade threshold for many months after a single administration could substantially improve adherence and clinical outcomes. The goal of the iSTEP-N program is to develop an ultra-long–acting naltrexone implant that is well-tolerated and maintains therapeutic naltrexone levels for 6–12 months following a single administration.

This first-in-human study of iSTEP-N evaluated the pharmacokinetics and safety of 2 dose levels of naltrexone, 4.8 g and 9.6 g, implanted for 12 weeks, after which explantation of the completely bioabsorbable implant occurred per protocol. Therapeutic plasma naltrexone concentrations were achieved rapidly following implantation, within 1–3 hours in all participants. In participants with a single iSTEP-N (4.8 g naltrexone) from week 7 to week 12, mean plasma naltrexone levels fell to subtherapeutic levels (<2.0 ng/mL; Figs. 2 and 3). In participants with 2 iSTEP-Ns (9.6 g naltrexone) individual plasma naltrexone levels were therapeutic throughout the 12-week study, except for one participant at week 10 when a single plasma naltrexone was 1.8 ng/mL (Fig. 4).

Importantly, tolerability was favorable at both dose levels, with no serious adverse events, no severe (grade 3) adverse reactions, and no moderate (grade 2) systemic reactions in the 9.6 g group.

The mean Cmax of 26.9 ng/mL observed in the 9.6 g implant cohort was higher than peak concentrations reported after administration of 380 mg intramuscular extended-release naltrexone, which range from approximately 25 to 28 ng/mL.¹⁷ However, no dose-related systemic toxicity, hepatotoxicity, or clinically significant laboratory abnormalities were observed at these exposure levels in our study.

The consistently high naltrexone exposures (Fig. 4) observed with the 9.6 g implant may be contrasted with XR-naltrexone, which produces trough concentrations at days 21–28 that are often close to or below the 2.0 ng/mL blockade threshold.^17,25,26 The data supporting the pharmacodynamic relevance of 2 ng/mL for opioid blockade derives from the work of Verebey.²⁵ After the administration of 100 mg oral naltrexone in detoxified individuals with OUD, mean naltrexone plasma levels were found to be 2.4 ng/mL at 24 hours and 2.0 ng/mL at 48 hours. These participants were then administered 25 mg intravenous heroin challenges and evaluated for both pleasurable subjective (liking) and deleterious objective (respiratory depression) responses at those times. The 100 mg naltrexone dose provided 96% blockade of all responses at 24 hours and 86.5% blockade of all responses at 48 hours. These data, along with the more recent work of Castillo et al,²⁶ show that plasma naltrexone levels of ≥2.0 ng/mL, the ∼90% blockade level, should be effective in maintaining opioid receptor blockade and reducing the risk of relapse in OUD.

The PK advantage of the 9.6 g iSTEP-N, being ≥2.0 ng/mL each week, will mitigate the end-of-cycle vulnerability seen with monthly XR-naltrexone injections. Moreover, the total amount of drug released from the iSTEP-Ns could be estimated using the product of AUC and systemic clearance (3.5 L/min).²⁴ For both dose levels, ∼22% of the implant’s naltrexone content was released over 12 weeks, indicating that a substantial proportion of the drug remained available in the implant. Whether the release rate observed during this initial period will be maintained over longer durations remains to be determined. Future registration trials of iSTEP-N will comprise studies of one year or more to characterize sustained pharmacokinetics, release kinetics, and safety over the intended duration of use. In addition, since this study was conducted in healthy volunteers, its findings may not translate to individuals with OUD, who often have comorbidities such as impaired hepatic function or metabolic disturbances. These factors can alter naltrexone metabolism, systemic exposure, and implant tolerability. Therefore, confirmatory studies in OUD patients are planned.²⁸

In summary, iSTEP-N achieved durable naltrexone exposure and a favorable safety profile in this 12-week first-in-human evaluation. This fully bioresorbable implant is designed to provide sustained naltrexone exposure following a single administration. With more than three-quarters of the implant’s naltrexone content remaining at explantation, we anticipate therapeutic action well beyond 12 weeks. Next steps include a 3-year extended phase 1b study in healthy volunteers to determine the duration of therapeutic exposure and to characterize long-term safety and tolerability of the implant, and a phase 2 study in individuals with opioid use disorder to further evaluate pharmacokinetics and efficacy, and to support later-phase development.