Available online 28 March 2024

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Tirosint-SOL bioavailability is not affected by the use of omeprazole

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This applies when omeprazole is given concomitantly or staggered by 12 hours

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Giving levothyroxine solution to people using PPIs may reduce extra monitoring

ABSTRACTObjective

This study evaluates the impact of a representative Proton Pump Inhibitor (PPI) (omeprazole), administered simultaneously or staggered, on the pharmacokinetics (PK) of levothyroxine (LT4) solution (Tirosint®-SOL).

Methods

This was a randomized, 3-way crossover, comparative bioavailability study in 36 healthy adults under fasting conditions.

Omeprazole 40 mg delayed-release capsule was administered once daily from Day 1 to 6 (mornings, Treatment-A; evenings, Treatment-B; none, Treatment-C) to increase and stabilize gastric pH. In the morning of Day 5, a single dose of LT4 solution 600 mcg was administered. Blood samples were collected 0-48 hours post-LT4 administration. Noncompartmental PK parameters were calculated for total serum thyroxine (TT4) using baseline-corrected data. Maximum concentration (Cmax) and area under the concentration-time curve (AUC0-48) were included in an analysis of variance to obtain geometric mean ratios (GMR) and 90% confidence intervals (CIs).

Results

For both comparisons (A/C and B/C), GMR and 90% CIs for all parameters were within the equivalence boundaries (80%-125%), indicating bioequivalence: for A/C, AUC0–48 98.98% [94-104%] and Cmax 91.68% [87-97%]; for B/C, AUC0–48 98.94% [95-103%] and Cmax 94.90% [90-100%]. Median Tmax was similar across treatments.

Conclusions

This study demonstrated that Tirosint®-SOL bioavailability is unaffected by coadministration of a representative PPI, given simultaneously or staggered by about 12 hours, compared to administration of LT4 solution alone. For hypothyroid patients on PPI therapy, administration of LT4 solution may reduce variations in TSH levels related to intermittent use of acid-reducing drugs and consequently the need for dose adjustments.

Section snippetsINTRODUCTION:

Hypothyroidism is a common health condition worldwide. In the United States (U.S.), 4.6% of Americans aged 12 years and older suffer from clinical or subclinical hypothyroidism.1 In Europe, the estimated prevalence in the general population is approximately 3%.2

Symptoms of hypothyroidism can range from mild to severe and can have a significant impact on quality of life.3 If left untreated, hypothyroidism can lead to organ damage. This can manifest itself as cardiovascular issues, metabolic

OBJECTIVES:

This study was conducted to evaluate the potential impact of a representative PPI (omeprazole) on the extent of absorption of LT4 solution administered to healthy subjects under fasting conditions. Omeprazole is preferably taken in the morning, although it may be ingested before dinner in patients suffering from nocturnal acid breakthrough,23, 24 therefore, both simultaneous (LT4 and omeprazole in the morning) and staggered (LT4 in the morning and omeprazole in the evening) administration of

Study Design

This randomized, open-label, 3-way crossover comparative bioavailability study of levothyroxine sodium oral solution included 36 healthy men and women. Levothyroxine solution (150 mcg/mL) was administered as a single oral dose of 600 mcg with (Treatment-A and -B) or without (Treatment-C) concomitant use of a representative PPI, omeprazole. The washout period between treatments was at least 35 days.

Ethics

All clinical work was conducted in compliance with Good Clinical Practices, as referenced in the

Population

A total of 36 healthy volunteers were included in the study (Table 1).

A total of 30 subjects received all 3 treatments and completed the study: 4 subjects voluntarily withdrew, 1 was discontinued due to positive COVID-19 test, and 1 subject was not dosed in Period 3 due to missing T3 lab results to confirm study eligibility (Figure 2), 2 subjects did not complete Period 2 (1 due to vomiting, 1 due to missing T3 lab results to confirm study eligibility) and 1 subject did not complete Period 3

DISCUSSION:

Tablets are the most commonly prescribed formulations of LT4 used to treat hypothyroidism, a chronic condition generally requiring life-long therapy. LT4 tablets require an acid gastric pH to undergo disintegration, deaggregation, and dissolution before becoming available for absorption by the intestine.26

Patients with gastrointestinal disorders (e.g., H. pylori infection, gastric atrophy, chronic gastritis) can often experience significant malabsorption of LT4 due to the underlying condition

CONCLUSION:

The results from this comparative bioavailability study indicated that the absorption of Tirosint®-SOL is not affected by the coadministration of a representative PPI given simultaneously or staggered by approximately 12 hours, compared to the administration of LT4 solution alone. For hypothyroid patients on PPI therapy, the use of LT4 solution may reduce variations in TSH levels related to intermittent use of the acid-reducing drug, and consequently the need for supplemental TSH monitoring and

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© 2024 Published by Elsevier Inc. on behalf of the AACE.