Once-Weekly Injectable Levothyroxine: A Future Hypothyroidism Treatment Option

A new form of thyroid hormone replacement therapy — once-weekly subcutaneous levothyroxine — is being studied as a simpler alternative to the traditional daily pill for hypothyroidism. Millions of people with hypothyroidism struggle to take levothyroxine consistently due to timing rules, food interactions, and absorption issues. Researchers hope that a single weekly injection could deliver more stable hormone levels, reduce daily stress, and improve adherence.

The leading investigational product, XP-8121, developed by Xeris Biopharma, uses a sustained-release liquid formulation injected just under the skin. Early clinical trials show that XP-8121 can maintain steady thyroid hormone levels using a weekly dose roughly four times higher than the daily oral dose. Participants in Phase 2 trials reported strong satisfaction and preference for the once-weekly approach, with mostly mild side effects such as fatigue or injection-site discomfort.

While the early results are promising, XP-8121 remains in the investigational stage and has not yet been approved for routine use. Researchers still need long-term safety data, Phase 3 confirmation, and evidence of cost-effectiveness in real-world patients. If proven effective, this innovation could represent a major shift in hypothyroidism management — offering greater convenience, steadier hormone control, and better quality of life for many patients.

In this article

Imagine never having to worry about taking your thyroid pill every single morning again. No more setting reminders, skipping breakfast, or stressing over whether that cup of coffee or glass of calcium-fortified orange juice will mess with your thyroid medication. For the millions of people living with hypothyroidism, this daily ritual can feel like a lifelong chore. But a new wave of research is reimagining what thyroid hormone replacement could look like — and it might be as simple as one small injection, once a week.

Once-weekly subcutaneous levothyroxine — a cutting-edge approach now in clinical trials — could soon transform how hypothyroidism is treated. Instead of juggling timing, meals, and absorption issues every day, you might be able to achieve stable hormone levels with a single weekly dose administered by injection just under the skin. It’s a concept that’s both simple and revolutionary — and one that’s already showing promise in improving convenience, consistency, and even quality of life.

In this article, we’ll explore the science behind once-weekly levothyroxine, the results of emerging studies (including new 2025 data from the American Thyroid Association meeting), and what this innovation could mean for the future of thyroid care.

Levothyroxine – synthetic thyroxine (T4) – has been the most common thyroid hormone replacement treatment for hypothyroidism and subclinical hypothyroidism for many decades. It is typically given as a daily oral dose, often in the morning on an empty stomach, because its absorption is sensitive to foods, other medications, gastrointestinal conditions, and adherence issues.

However, a substantial number of patients struggle to maintain stable target thyroid-stimulating hormone (TSH) levels, even with ongoing adjustment of their oral dose. This difficulty may result from:

• Variable absorption due to gastrointestinal (GI) disorders, drug interactions, or food

• Fluctuations in consistency, with better absorption some days compared to others

• Missed doses or imperfect adherence

• Differences between generic preparations or formulations

• Different pharmacokinetics (how fast a drug starts working, how long it lasts, how strong its effects are, and how often you need to take it)

Because of these challenges, clinicians sometimes refer to “refractory hypothyroidism” when TSH remains elevated (or free T4 low) despite what seems like an adequate oral dose. In such cases, clinicians have been interested in alternative approaches.

One such alternative is giving levothyroxine less frequently—for example, once weekly—in a way that ensures more stable exposure over time. The idea is that, with proper pharmacokinetics, you could “smooth out” the fluctuations, avoid day-to-day peaks and valleys, and bypass absorption issues related to your GI tract.

Sporadic case reports and small studies in the past have explored non-oral injectable routes of levothyroxine therapy with occasional success, especially in patients with malabsorption or difficulty with oral therapy. But a significant barrier has consistently been achieving predictable, safe, and stable dosing over a weekly schedule.

As a result, in recent years, more formal efforts have been launched to develop a formulated, once-weekly subcutaneous levothyroxine product—bypassing the GI tract and reducing fluctuations or absorption uncertainties.

The leading candidate being developed is XP-8121, a ready-to-use liquid subcutaneous formulation of levothyroxine developed by Xeris Biopharma.

The company claims that XP-8121 has several benefits, including:

• It bypasses the gastrointestinal route, thus avoiding absorption variability

• It has sustained-release characteristics suited for weekly dosing

• It offers predictable bioavailability over time

• XP-8121 reduces peaks and valleys compared to oral dosing

XP-8121 Phase 1 studies

In Phase 1 studies in healthy volunteers, XP-8121 was compared to oral levothyroxine dosing; the data showed that absorption is slower and more prolonged, with a lower peak concentration but extended exposure over days, and importantly, dose-proportional pharmacokinetics across a tested range.

Using modeling, researchers have simulated that a weekly subcutaneous dose of XP-8121 at about 4× the daily oral dose may produce comparable steady-state exposure to the same total weekly oral dose.

Encouragingly, safety in the Phase 1 single-dose studies was acceptable, with no serious adverse events attributable to the dosing. The treatment-emergent adverse events – known as TEAEs –  were mild to moderate.

Thus, XP-8121 laid the groundwork for moving into Phase 2 trials in actual hypothyroid patients.

XP-8121 Phase 2 results

One of the more recent and critical developments comes from a poster presented in 2025 (Poster 261, Clinical Thyroid Diseases & Cancer). The study, titled “A Phase 2 Study of XP-8121: Once-Weekly Subcutaneous Levothyroxine for Hypothyroidism,” focused on assessing the safety, tolerability, and the dose conversion factor from oral to weekly subcutaneous for adult hypothyroid participants.

This was a multicenter, non-randomized trial among hypothyroid participants who had been on stable oral levothyroxine therapy for at least three months, with normal TSH and free T4 at screening. They started at a levothyroxine dosage of XP-8121 that was cautiously set at 50% of the target weekly dose. The participants were checked, and the dose was titrated every two weeks over eight weeks. Once stable, the participants continued on the same dose for a four-week maintenance period.

The research had several significant findings:

• Roughly four times the daily oral dose was needed as a weekly injection to maintain comparable exposure and effectiveness

• By the end of the titration, the TSH and free T4 values had normalized in most participants

• These levels were largely stable through the maintenance period

• The most common complaints were fatigue and mild injection site pain

Perhaps most importantly, the study participants reported high satisfaction and preference for once-weekly injection compared to daily pills.

Overall, the Phase 2 data suggest that thyroid hormone therapy with XP-8121 is safe, tolerable, and capable of maintaining thyroid hormone levels in a stable way when dosed weekly, using about four times the daily oral equivalent.

These findings support continued development into Phase 3 trials to more definitively establish efficacy, safety, and long-term outcomes.

While XP-8121 is a leading candidate, other relevant research provides context on the promise and pitfalls of non-daily or non-oral levothyroxine.

Weekly (oral) levothyroxine

Before the subcutaneous formulation efforts, some investigators explored the idea of giving levothyroxine orally on a weekly basis, rather than daily. A few small trials in the past suggested this might be feasible in carefully selected patients, but with concerns about transient peaks, patient safety, and adherence. A 2021 meta-analysis (Indian Journal of Endocrinology & Metabolism) reviewed “Once Weekly Thyroxine vs Daily Thyroxine” and found that weekly dosing was associated with less efficient control of hypothyroidism (i.e., higher rates of TSH out-of-range) at 6 weeks compared with daily therapy.

One older report, “The Effect of Daily versus Weekly Levothyroxine Replacement,” suggested that weekly therapy could maintain euthyroidism (normal thyroid levels) in some patients, but with slightly less control.

In simple terms, taking a large weekly oral dose doesn’t work as well because the gut can only absorb so much at once—after a point, it stops absorbing the medicine efficiently.

Drug delivery/formulation reviews and other case reports

A 2023 mini-review, Drug delivery systems for thyroid disease treatment,  specifically mentions the use of “once-weekly subcutaneous levothyroxine injections in patients with a history of difficulty achieving desired thyroid levels” (i.e., in patients struggling with oral therapy). This suggests that beyond XP-8121, there is at least academic interest in off-label or investigational subcutaneous levothyroxine.

Also, in the 2025 article in Endocrine & Metabolic Case Reports, there is a case report of both subcutaneous and intramuscular levothyroxine injections in a patient, demonstrating safety and effectiveness in that context.

On a more general level, Liu et al.’s 2023 review “Levothyroxine: Conventional and Novel Drug Delivery” discusses how levothyroxine’s pharmacokinetics and challenges (absorption variability, adherence, formulation differences) provide clear motivation for novel delivery systems (including injectable forms).

While XP-8121 is the most advanced program, there is a modest but growing body of interest in alternative levothyroxine delivery systems for thyroid hormone therapy.

If fully validated and approved, once-weekly subcutaneous levothyroxine could offer several meaningful advantages over daily oral therapy:

Improved adherence/convenience

• Instead of remembering a pill every single day, one injection weekly may reduce the burden and likelihood of missed doses.
• Many participants in the Phase 2 XP-8121 trial expressed satisfaction and preference for the injection method (72% preference).

Reduced variability and more stable hormone levels

• Dosing of levothyroxine with pills can fluctuate due to food intake, variable GI absorption, and levothyroxine’s interactions with other drugs and foods.

• Bypassing the GI tract via subcutaneous delivery minimizes or eliminates absorption variability, which may allow more predictable hormone levels.

• The more prolonged, smoother pharmacokinetic profile may reduce peaks and valleys in thyroid levels.

Lower required total dose

• In the Phase 2 XP-8121 study, the weekly dose needed was 45% less than the equivalent of their former daily oral doses (i.e., an “efficiency” gain) This could translate to lower drug exposure, possibly fewer side effects, or cost savings, depending on pricing.

Better control in “difficult” patients

• Patients with malabsorption syndromes (celiac disease, atrophic gastritis, H. pylori infection, GI surgeries) or on interfering medications might benefit more from a non-GI-dependent route.

• For those whose TSH remains erratic despite adherence, injectable therapy might offer a clearer path to stability.

Patient satisfaction/quality of life

• Many patients strongly dislike managing pill regimens and worrying about food or drug interference. A weekly injection might improve peace of mind.

• As seen in the XP-8121 trial, the TSQM-9 (Treatment Satisfaction Questionnaire) scores for effectiveness, convenience, and global satisfaction were higher for XP-8121 versus oral therapy.

From a patient perspective, these potential benefits — fewer pills, more reliable control, and greater convenience — are strong motivators.

Of course, once-weekly subcutaneous levothyroxine is not yet a proven, approved standard of care. Several cautions and open questions remain:

Long-term safety and tolerability

• While the Phase 2 poster and prior Phase 1 trials report mostly mild to moderate TEAEs (fatigue, injection site pain, headaches, urinary tract infection), larger-scale and longer-term safety data are needed (e.g., over months to years).

• Injection site reactions over many weeks or months need careful monitoring (local irritation, lipodystrophy, fibrosis, pain).

• Potential for immunologic or hypersensitivity reactions as the formulation is novel.

Precision of titration and control

• Adjusting doses weekly (or every two weeks) might make fine-tuning harder compared to the daily oral approach, where minor adjustments can be made more incrementally.

• If a patient is over- or under-dosed, the consequence may last for days rather than being “corrected” by the next day’s pill.

Variability in pharmacokinetics among individuals

• Although modeling and early trials suggest a roughly 4× multiplier for many subjects, individual differences in body weight, distribution, clearance, metabolism, and comorbidities could lead to differences.

• In the Phase 1 PPK model, body weight was a factor that influenced the effectiveness of XP-8121 SC. (PMC)

Cost, insurance coverage, reimbursement

• New injectable therapies often come at a premium, and insurers might initially resist covering them over cheap generic oral levothyroxine.

• As a patient, you may face out-of-pocket costs, stigma, or logistical difficulties obtaining injections.

Patient acceptability of injections

• Some patients dislike needles or injections, and the question of self-administered subcutaneous injections (versus clinic-administered) introduces issues like training, comfort, and convenience.

• Although many participants preferred the once-weekly approach, that may reflect a trial selection bias (“enthusiastic early adopters”).

Regulatory and approval risk

• The path from Phase 2 to Phase 3, to regulatory submission, is long. Phase 3 trials may fail to confirm benefits, or they could reveal safety issues.

• If the therapy is approved, clinicians would need guidelines, dosing algorithms, and blood test and monitoring protocols.

Switching logistics and monitoring

• When switching a patient from daily oral to weekly subcutaneous treatment, healthcare providers will need to ensure safe cross-titration, frequent monitoring of TSH and other thyroid levels, and robust protocols to avoid over- or under-medicating patients.

• In real-world practice, lab testing might need to be timed carefully (e.g., just before the next dose) to interpret the lower valley levels.

Given these uncertainties, for now, once-weekly subcutaneous levothyroxine remains investigational, and patients should not self-convert without oversight.

From the perspective of a patient considering future options, here is a summary of what the current evidence suggests — and where gaps remain:

What we can say (with cautious optimism)

• The pharmacokinetics of XP-8121 appear suitable for weekly dosing, with slower absorption and sustained exposure, as demonstrated in Phase 1.

• Modeling supports a multiplier of about 4× the daily oral dose to achieve equivalent dosing results.

• The 2025 Phase 2 poster confirmed that in actual hypothyroid patients, TSH and free T4 levels could be maintained within normal ranges using XP-8121, with that approximate 4× multiplier, and with acceptable tolerability.

• Patient satisfaction and preference for the once-weekly subcutaneous thyroid hormone therapy route have been favorable in early trials.

• In at least one case report, subcutaneous or intramuscular levothyroxine injections have succeeded in patients who had difficulty with oral therapy.

What we cannot reliably say yet

• Long-term clinical outcomes (e.g., cardiovascular risk, osteoporosis, symptoms, quality of life) with weekly subcutaneous versus daily oral replacement.

• The complete safety profile over the years, across a diverse subset of patients (elderly, children, maternal hypothyroidism, and those with co-existing conditions).

• How well this works in patients with extremes of body weight, altered kidney or liver function, or other complicating factors.

• Real-world feasibility, cost-effectiveness, insurance uptake, and patient adherence outside trial settings.

• Fine-tuning strategies: how to adjust doses in subtle increments; how to respond to intercurrent illnesses or changes in body weight, hypothyroidism in pregnancy, or drug interactions.

• Whether you may still need supplemental T3 or other thyroid-related therapies in conjunction with weekly subcutaneous T4.

While the early data are promising, XP-8121 (or similar forms of levothyroxine) must still clear substantial hurdles before being ready for routine clinical use.

Let’s imagine how a future once-weekly subcutaneous levothyroxine therapy might play out from your point of view as a patient.

Would you be a good candidate?

You might be a good candidate for weekly subcutaneous levothyroxine if:

• You find that your TSH and free T4 remain unstable despite what seems like excellent adherence to oral therapy

• You have gastrointestinal absorption issues (celiac disease, inflammatory bowel disease, bariatric surgery, H. pylori infection, atrophic gastritis)

• You find daily pill routines burdensome, often forget doses, or dislike variability with food–drug interactions

• You’re willing to self-administer injections (or visit a clinic weekly)

• You have stable co-existing conditions and no contraindications to injections

How would switching work?

• Your provider would calculate your weekly subcutaneous starting dose (perhaps ~4× current daily dosage of oral medication, but possibly starting more conservatively, e.g., 2–3×)

• You would begin injections, with close monitoring (TSH, free T4) every 2–4 weeks during the titration phase

• Once stable, you would continue the same weekly dose, with periodic labs (perhaps every 3–6 months)

• If symptoms or lab deviations arise, adjustments would occur (which may take longer to “correct” given weekly treatment)

• You would need to document the injection day/time (to coordinate lab draws just before the next dose)

• You would also need access to injection supplies (syringes, alcohol pads, disposal) and education for safe self-injection

There are some potential downsides to subcutaneous levothyroxine treatment, including:

• Dealing with an injection once a week may be psychologically or physically undesirable

• If a dose is missed, the impact lasts for a week (i.e., skipping a dose is not trivial)

• Lab timing becomes more critical (ideally right before the next dose)

• If your clinical situation changes (e.g., weight gain/loss, new medications, pregnancy), adjustment delays might be more gradual

• Cost and insurance coverage are uncertain

• The potential for local injection site discomfort

Monitoring and safety concerns

Eventually, should the subcutaneous levothyroxine be approved, monitoring will be critical, including:

• Regular lab monitoring, particularly TSH and free T4, will be essential

• You and your provider will need to monitor for signs of hypo- or hyperthyroidism (e.g., fatigue, palpitations, weight changes)

• You’ll need to watch for injection site problems (pain, swelling, nodules, infection)

• In cases of illness or stress, your clinician may need a protocol for bridging (e.g., temporary oral supplementation)

• In caregivers or older patients, proper training and support for injection may be needed

If these challenges are managed, the potential upside—greater convenience, fewer absorption issues, more stable thyroid control—could make once-weekly subcutaneous therapy appealing to many patients.

Because once-weekly subcutaneous levothyroxine is not yet approved or standard, here’s what you should keep in mind now.

• Do not self-dose or “stretch out” your oral levothyroxine, for example, taking 7× your daily dose once a week. This is unsafe and not evidence-based.

• If you are struggling with absorption or lab instability, talk with your provider about investigating causes (e.g., GI issues, checking other drug interactions, vitamin D, anemia, GI infections).

• Some clinicians already use oral levothyroxine taken less frequently in occasional off-label cases (e.g., in noncompliant patients), but this is different from a validated injectable system.

• Stay current on clinical trial developments (e.g., via ClinicalTrials.gov NCT05823012)

• If a weekly subcutaneous therapy becomes available, ask about cost and insurance coverage, ensure your healthcare provider has access to dosing protocols, and that there is close follow-up and monitoring, especially initially.

To know whether once-weekly subcutaneous levothyroxine will become a practical, safe, and effective option, here are key milestones to observe:

Phase 3 trial results

• These will need to confirm non-inferiority (or superiority) in maintaining stable TSH/fT4, symptom control, safety, and adverse event profiles

• They should span longer durations (6–12 months or more) and include diverse populations

Regulatory approval and labeling

• FDA (or equivalent authorities) must approve it with clear labeling on dosing, switching protocols, contraindications, monitoring, and safety warnings

Real-world outcomes/registries

• After approval, usage in “real-world” patients (beyond trial populations) will reveal practical issues: adherence, injection logistics, provider comfort, cost, and insurance uptake

Economics, pricing, and insurance coverage

• The cost to patients and insurers will significantly influence whether this therapy becomes widely adopted

Comparison with other innovations in thyroid therapy

• Other alternative strategies (e.g., slow-release T3 + levothyroxine, new oral formulations with better absorption) will compete

• If T3-slow release or novel oral formulations gain traction, the injectable advantage must remain compelling

Guideline integration and provider education

• Endocrine societies will need to develop guidelines for patient selection, switching protocols, monitoring intervals, and adverse event management

For example, it is already known that patients often deviate from ideal pill-taking behavior; an easier alternative may shift standard practice. But much depends on demonstrating clear benefit in hard endpoints.

At Paloma Health, we continually monitor and report on the latest research to identify innovations that could improve life for people with hypothyroidism. The emerging research on once-weekly subcutaneous levothyroxine is an exciting example — early studies suggest that a simple weekly injection may one day offer patients a more convenient, consistent way to maintain healthy thyroid hormone levels.

While this treatment is still being studied and isn’t yet available for everyday use, it reflects the kind of forward-thinking science that inspires our work and nationwide practice. At Paloma, we stay up to date on the latest thyroid research so you can benefit from the most informed, personalized hypothyroidism care possible.

In the meantime, as a Paloma Health member, you’ll have access to a full range of clinically proven thyroid hormone replacement treatment options — including tailored levothyroxine dosing, combination T4/T3 therapy, natural desiccated thyroid, and ongoing support from our thyroid specialists — to help you feel your best every day.

• XP-8121 is a once-weekly injectable form of levothyroxine designed to bypass the digestive tract and deliver stable hormone levels.
• Clinical data show that a weekly dose of about four times the daily oral dose maintains normal thyroid levels (TSH and free T4).
• Phase 1 and 2 trials demonstrated predictable pharmacokinetics, good tolerability, and strong patient satisfaction.
• Weekly subcutaneous delivery may reduce variability, improve adherence, and help patients with absorption problems or inconsistent TSH control.
• Risks and challenges include long-term safety, cost, and insurance coverage, and the need for careful dose monitoring.
• The therapy is still investigational, with Phase 3 trials and FDA approval required before it can be used in standard clinical care.

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Optimizing your thyroid levels with thyroid hormone replacement medication is usually the first step in minimizing symptoms.

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