Proton Pump Inhibitors Do Not Affect the Bioavailability of a Novel Liquid Formulation of Levothyroxine.

OBJECTIVE: This study evaluates the impact of a representative proton pump inhibitor (PPI) (omeprazole), administered simultaneously or staggered, on the pharmacokinetics 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 to 48 hours post-LT4 administration. Noncompartmental pharmacokinetic parameters were calculated for total serum thyroxine 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 and 90% confidence intervals. RESULTS: For both comparisons (A/C and B/C), geometric mean ratios and 90% confidence intervals 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 (time associated with Cmax) was similar across treatments. CONCLUSION: 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 thyroid stimulating hormone levels related to intermittent use of acid-reducing drugs and consequently the need for dose adjustments.

Levothyroxine soft capsules demonstrate bioequivalent pharmacokinetic exposure with the European reference tablets in healthy volunteers under fasting conditions.

OBJECTIVE: To assess the bioequivalence (BE) potential under fasting conditions between levothyroxine soft capsules and the European reference tablet formulation. METHODS: Two studies were conducted to assess the BE potential as per European regulations. Study 1 was a two-way crossover BE study comparing a high strength of levothyroxine soft capsules versus levothyroxine tablets (200 µg), while study 2 was a three-way crossover dosage form proportionality study between low, medium, and high strengths of soft capsules. 70 healthy adult subjects participated in the two studies. Each treatment consisted of a 600-µg dose of levothyroxine sodium, administered under fasting conditions. Blood samples were collected for levothyroxine (T4) assay prior to dosing and up to 72 hours post dose. A washout of 35 days separated treatments in each study. Pharmacokinetics was assessed using noncompartmental methods. RESULTS: A total of 61 subjects completed the studies. Baseline-adjusted total T4 ratios (test/reference) and 90% confidence intervals (CIs) between soft capsules and tablets were within 80.00 - 125.00%. Comparison of the three strengths of soft capsules indicated pharmacokinetic equivalence between them (ratios and 90% CIs were contained within 80.00 - 125.00%). Overall, levothyroxine sodium was well tolerated with all products when given as single oral doses of 600 µg, except for 1 serious adverse event of secondary bacteremia reported in study 2, deemed not to be related to treatment. CONCLUSION: Levothyroxine soft capsules meet BE criteria in terms of systemic exposure when compared to a European reference tablet under fasting conditions in healthy volunteers.

When Bioequivalence in Healthy Volunteers May not Translate to Bioequivalence in Patients: Differential Effects of Increased Gastric pH on the Pharmacokinetics of Levothyroxine Capsules and Tablets.

PURPOSE: Clinical studies have suggested that proton pump inhibitors may decrease levothyroxine absorption and an in vitro study suggested that the effect of pH on dissolution may differ with formulation. To determine the impact of formulation on the pharmacokinetics of levothyroxine in altered gastric pH conditions, this study compared the pharmacokinetics of levothyroxine capsules and tablets, two formulations deemed bioequivalent in healthy volunteers under fasting conditions, when taken with or without esomeprazole. METHODS: Two clinical studies were conducted in healthy volunteers given single dose levothyroxine (600 mg) with a 45-day washout period. In Study 1 (parallel-design/two-way crossover), 16 subjects received either levothyroxine capsules or tablets, each group with or without prior administration of intravenous esomeprazole (maximum dose of 80 mg). In Study 2 (two-way crossover), 16 subjects received both capsules or tablets after intravenous esomeprazole. Blood samples were collected pre-dose and up to 24 hours post-dose. Baseline-adjusted pharmacokinetic parameters were calculated: Cmax (maximal concentration), Tmax (time to Cmax), AUC0-t (area under the concentration-time curve from 0 to the last detectable concentration), AUC0-6 and AUC0-12 (areas under the curve from 0 to 6 and 12 hours, respectively). Analyses of variance were conducted to compare ln-transformed Cmax and AUC. Non-parametric Tmax analyses were done. RESULTS: In Study 1, esomeprazole caused a greater decrease in overall levothyroxine exposure of tablets vs. capsules (13% vs 6% for Cmax, 18% vs. 14% for AUC(0-6), 17% vs. 5% for AUC(0-12) and 10% vs. 8% for AUC(0-t)). In Study 2 esomeprazole administration resulted in a 16% smaller levothyroxine exposure with tablets vs. capsules. No statistically significant differences in Tmax were found. CONCLUSIONS: Although both formulations are considered "bioequivalent" in healthy volunteers, they may not necessarily be bioequivalent in patients with impaired gastric pH conditions. Levothyroxine capsules may therefore be more appropriate for patients with decreased gastric acidity.

Efficacy of Levothyroxine Sodium Soft Gelatin Capsules in Thyroidectomized Patients Taking Proton Pump Inhibitors: An Open-Label Study.

Background: Treatment with proton pump inhibitors (PPIs) and antacids affects the gastrointestinal absorption of levothyroxine sodium (LT4) tablets. Patients with hypothyroidism taking LT4 and PPIs or antacids, thus, require appropriate monitoring. The objective of this study was to determine whether a soft gelatin capsule of LT4 (Tirosint®) would obviate the effect of PPIs on LT4 absorption. The objective was achieved by assessing the effects of a switch from a conventional LT4 tablet form to the same dose as soft capsules in thyroidectomized patients on treatment with LT4 and PPIs. Methods: Patients with history of hypothyroidism due to total thyroidectomy on stable treatment with LT4 tablets, and with gastrointestinal disease treated with PPIs, were switched to a 12-week treatment with Tirosint at the same dose of the LT4 tablets, while maintaining treatment with PPIs. Serum thyrotropin (TSH) levels were the primary endpoint of the study. Secondary efficacy endpoints were: serum levels of free thyroxine (fT4), total thyroxine (TT4), free triiodothyronine (fT3), total triiodothyronine (TT3), creatine-phosphokinase (CPK), sex-hormone binding globulin, ferritin, angiotensin converting enzyme, and a lipid panel. Results: Forty-seven patients (36 females and 11 males, mean age 55.4 years) were enrolled and 45 of them completed the study (2 patients withdrew consent). During treatment with Tirosint, mean TSH levels demonstrated a statistically significant decrease (mean changes from baseline: -0.32 mIU/L at week 6 and -0.68 mIU/L at week 12) and concomitant increases in thyroid hormone (TH) levels from baseline to week 12, which were statistically significant for fT3 and TT3 (mean changes from baseline: 0.26 pmol/L and 0.10 nmol/L, respectively). Significant decreases of serum low-density lipoprotein, total cholesterol, and CPK levels were observed at week 12. No signs/symptoms arose during the study that could be specifically correlated to either hypo- or hyperthyroidism. Conclusions: In thyroidectomized patients taking PPIs and replacement LT4, a switch from conventional LT4 tablets to LT4 soft capsules at the same dose was associated with a significant decrease in TSH and increase in TH, indicating that LT4 absorption may be less affected by PPIs when given in the form of soft capsules. Clinical Trial Registration: NCT03094416.

A Novel Levothyroxine Solution Results in Similar Bioavailability Whether Taken 30 or Just 15 Minutes Before a High-Fat High-Calorie Meal.

Background: Levothyroxine (LT4) sodium is a standard treatment for hypothyroidism. Its absorption and bioavailability when taken as a tablet have been shown to be significantly decreased with concomitant food ingestion. Therefore, LT4 formulations are recommended to be taken on an empty stomach, at least 30, ideally 60, minutes before breakfast, potentially affecting adherence to therapy. A novel LT4 solution (Tirosint®-SOL) has been shown to result in a faster absorption process than tablets or soft-gel capsule formulations. The objective of this trial was to evaluate the bioavailability of this preparation taken 15 minutes before a high-fat high-calorie meal in comparison with the minimally recommended 30-minute interval. Methods: Thirty-six (33 completers, 24 males and 9 females) healthy volunteers participating in the randomized study took 600 mcg of LT4 oral solution, single doses after a 10-hour fast, 15 or 30 minutes before a high-fat, high-calorie, FDA-approved standardized meal in a controlled research setting. We measured serum total thyroxine using Liquid Chromatography with Tandem Mass Spectrometry at baseline and multiple time points up to 72 hours after LT4 administration. The predefined equivalence boundaries for the extent of exposure reflected by the area under the curve (AUC) were 80-125%. The washout period was at least 35 days. Results: The geometric mean ratios and confidence intervals (CIs) for the baseline-adjusted extent of exposure represented by AUCs truncated at both 48 and 72 hours after dosing (AUC0-48: 90% [90% CI 86-94]; and AUC0-72: 92% [90% CI 87-97]) were within the prespecified equivalence boundaries. The baseline-adjusted peak concentration was also clinically similar (Cmax: 85% [90% CI 80-90]). The median tmax was 1.5 hours in each group. The rate of adverse events was similar between groups. Conclusions: We observed no significant difference in the pharmacokinetic properties of a novel LT4 solution administered 15 and 30 minutes before a high-fat high-calorie meal in normal subjects. Further research is needed to evaluate (a) the differences in overall bioavailability at other time points (including immediately premeal) and (b) the real-world effectiveness of this preparation in newly proposed administration conditions to optimize treatment outcomes in hypothyroid patients.

Pharmacokinetic equivalence of a levothyroxine sodium soft capsule manufactured using the new food and drug administration potency guidelines in healthy volunteers under fasting conditions.

OBJECTIVE: To assess the pharmacokinetic equivalence of a new soft capsule formulation of levothyroxine versus a marketed reference product and to assess the soft capsule formulated with stricter potency guidelines versus the capsule before the implementation of the new potency rule. METHOD: Two single-dose randomized two-way crossover pharmacokinetic equivalence studies and one dosage form proportionality single-dose study comparing low, medium, and high strengths of the new formulation. All three studies were performed in a clinical setting. Participants were healthy male and female adult subjects with normal levothyroxine levels. A total of 90 subjects participated in the three studies. RESULTS: Pharmacokinetic parameters were calculated on baseline- adjusted concentrations. The first pharmacokinetic equivalence study compared the levothyroxine sodium soft capsule formulation (Tirosint) with the reference Synthroid tablets and the two products were considered bioequivalent. The dosage form proportionality study compared the 50-, 100-, and 150-µg test capsules strengths dosed at the same level (600 µg) and all three strengths were considered equivalent when given at the same dosage. The last study compared the test capsule used in the first two studies with a new capsule formulation following the new potency guideline (±5%) set forward by the Food and Drug Administration and the two capsules were considered bioequivalent. Doses were well tolerated by subjects in all three studies with no serious adverse events reported. CONCLUSIONS: The levothyroxine soft capsule formulated with the stricter new potency guideline set forward by the Food and Drug Administration met equivalence criteria in terms of rate and extent of exposure under fasting conditions to the reference tablet formulation. Clinical doses of the capsule formulation can be given using any combination of the commercialized strengths.

Relative bioavailability and pharmacokinetics of two oral formulations of docosahexaenoic acid/eicosapentaenoic acid after multiple-dose administration in healthy volunteers.

OBJECTIVES: To assess the comparative pharmacokinetic profile and bioavailability of docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) after multiple-dose administration of a new oral formulation (test formulation) and a commercially available reference formulation in healthy subjects. METHODS: Forty-eight healthy subjects received a 28-day oral treatment with DHA/EPA in the form of either the test or the reference product according to an open-label, randomized, parallel-group design. Both formulations were given t.i.d. at 8-h intervals at a dose of 3.0 g/day. Steady-state DHA and EPA concentrations in plasma and lysed whole blood were measured by gas-liquid chromatography at baseline and after 7, 14, 21 and 28 days of treatment. Kinetic parameters were compared both after subtraction of baseline concentrations and by using baseline concentrations as a covariate. RESULTS: For both DHA and EPA, plasma and RBC concentrations measured from day 7 to day 28 were significantly higher than at baseline and did not differ significantly between the two products. On day 28 the plasma DHA concentration on average doubled the baseline level after administration of test and reference product, while there was a 10-fold increase in EPA plasma concentration. When the assessment was performed using baseline values as covariate, test-to-reference ratios for area under the curve (AUCss(0-8)) and for peak concentration (Css(max)) after the last administration on day 28 met bioequivalence criteria (i.e., 90% confidence intervals within 0.80-1.25 for AUCss(0-8) ratios, and within 0.75-1.33 for Css(max) ratios). When the assessment was conducted after subtraction of baseline values, the 90% confidence intervals for Css(max) ratios were within the bioequivalence range, whereas the intervals for AUCss(0-8) ratio were borderline for bioequivalence. CONCLUSION: The two formulations tested were similarly effective in increasing DHA and EPA concentrations in plasma and lysed whole blood, and showed comparable bioavailability for both active components.

Pharmacokinetics and Comparative Bioavailability of a Levothyroxine Sodium Oral Solution and Soft Capsule.

A new formulation of levothyroxine sodium has been developed in the form of an oral solution contained in unit-dose ampules. A study has been conducted to compare the bioavailability of levothyroxine sodium oral solution and levothyroxine sodium soft capsule in healthy volunteers under fasting conditions. The rate and extent of absorption of the new levothyroxine solution were also evaluated when administered on dilution in water or directly into the mouth without water. In each period, according to the randomization scheme, subjects were administered single oral doses of either test, as 4 × 150-µg unit-dose ampules, with or without water, or reference, as 4 × 150-µg capsules in a crossover design. Thirty-six subjects were randomized and dosed in this study; of these, 31 completed all study periods. When comparing the solution with the capsule (both products administered with water), the 90% confidence intervals for the ratio of log-transformed values of AUC0-48 and Cmax were within 90.00% and 111.11%, respectively, for baseline-corrected levothyroxine. Moreover, the administration of levothyroxine oral solution without water did not affect the rate and extent of its absorption. In conclusion, levothyroxine oral solution unit-dose ampules were bioequivalent to the levothyroxine capsule when administered with or without water. All formulations were well tolerated, with no major side effects.

Topical ketoprofen patch (100 mg) for the treatment of ankle sprain: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Topical nonsteroidal anti-inflammatory drugs offer the advantage of enhanced drug delivery to local affected tissues with low plasma levels and an expected reduced incidence of systemic adverse events (mainly peptic ulcer disease and gastrointestinal hemorrhage). HYPOTHESIS: To test the efficacy and tolerability of a 100-mg patch of ketoprofen applied once a day. STUDY DESIGN: Randomized controlled clinical trial; Level of evidence, 1. METHODS: The 2-week trial included patients suffering painful (spontaneous pain >or=50 mm on a 0- to 100-mm visual analog scale), benign (grade I or II), recent (<2 days) ankle sprains as a model of general traumatic soft tissue injuries. The primary efficacy criterion was spontaneous pain change after 7 days of treatment in the intention-to-treat population. One hundred sixty-three patients were randomized (ketoprofen, 81; placebo, 82). RESULTS: After 1 week of treatment, the decrease in spontaneous pain was -50+/-20 mm for ketoprofen and -38+/-24 mm for the placebo, showing a statistically significant intergroup difference (P=.0007). The majority of the secondary criteria were also statistically significant in favor of the ketoprofen patch. Tolerance was good in both groups, adverse events being mostly local. CONCLUSION: This trial suggested that a 7-day course of treatment with a ketoprofen patch is useful in benign ankle sprain, without revealing unexpected adverse events.

The free fractions of circulating docosahexaenoic acid and eicosapentenoic acid as optimal end-point of measure in bioavailability studies on n-3 fatty acids.

The high complexity of n-3 fatty acids absorption process, along with the huge amount of endogenous fraction, makes bioavailability studies with these agents very challenging and deserving special consideration. In this paper we report the results of a bioequivalence study between a new formulation of EPA+DHA ethyl esters developed by IBSA Institut Biochimique and reference medicinal product present on the Italian market. Bioequivalence was demonstrated according to the criteria established by the EMA Guideline on the Investigation of Bioequivalence. We found that the free fractions represent a better and more sensitive end-point for bioequivalence investigations on n-3 fatty acids, since: (i) the overall and intra-subject variability of PK parameters was markedly lower compared to the same variability calculated on the total DHA and EPA fractions; (ii) the absorption process was completed within 4h, and the whole PK profile could be drawn within 12-15 h from drug administration.

Pharmacodynamics and pharmacokinetics of a novel, low-dose, soft-gel capsule of acetylsalicylic acid in comparison with an oral solution after single-dose administration to healthy volunteers: a phase I, two-way crossover study.

BACKGROUND: Low-dose acetylsalicylic acid (ASA; aspirin) is well-established as a platelet anti-aggregating agent for the secondary prevention of cardiovascular events. OBJECTIVES: The objective of this study was to investigate the non-inferiority of a novel ASA 75 mg soft-gel capsule formulation compared with a marketed powder for oral solution in terms of reduction in serum thromboxane B2 (TXB2), a surrogate for platelet aggregation. Pharmacokinetics and tolerability of the products were also investigated. METHODS: In this randomised, two-way crossover study, 46 male and female healthy subjects received a single dose of the investigational products in two periods separated by a 14-day washout. Serum TXB2 and plasma ASA were determined up to 24 h post-dose. Maximum percentage of TXB2 inhibition (I max) and area under the inhibition-time curve (AUICt) were calculated. Non-inferiority was assumed if the lower limits of the 95 % confidence intervals (CIs) for the two pharmacodynamic parameters were above 85 %. RESULTS: The 95 % CI lower limits were 95.35 % for I max and 86.12 % for AUICt, i.e. within the pre-specified delta. Time to achieve I max did not differ between treatments (p = 0.88). The two formulations were bioequivalent as regards the extent of ASA exposure (area under the plasma concentration-time curve from zero to time t [AUCt] 90 % CIs 96.67-113.37); a delayed ASA absorption (later time to reach maximum plasma concentration [t max], lower maximum plasma concentration [C max]) was observed for the test product. No treatment-related adverse events were reported. CONCLUSIONS: In healthy subjects, the 75 mg soft-gel capsules were not inferior to the oral solution in terms of serum TXB2 inhibition, indicating that the novel formulation could be an effective alternative in the secondary prevention of cardiovascular events.

Topical ketoprofen patch in the treatment of tendinitis: a randomized, double blind, placebo controlled study.

OBJECTIVE: To evaluate the efficacy and tolerability of ketoprofen patch in the treatment of tendinitis. METHODS: A multicenter, 14 day, randomized, double blind placebo controlled trial of a once-a-day ketoprofen 100 mg patch in symptomatic tendinitis of recent onset, not requiring orthopedic or surgical treatment. Pain on daily activities scored on a 100 mm visual analog scale was the primary efficacy criterion. Other criteria were spontaneous pain at rest, pain on full passive motion, pain relief, and pain intensity assessed twice daily by the patient (calculation of total pain relief and summed time-weighted pain intensity difference). Statistical analysis was performed on the differences between the 2 groups in the intention-to-treat population. RESULTS: One hundred seventy-two patients were included. Good compliance was obtained in 98% of patients. Twenty-six patients (15%) discontinued the study mainly because of adverse events, inefficacy, or cure. Decrease in pain after one week of treatment (primary criterion) was -38.4 +/- 25.6 mm (56%) and -25.8 +/- 24.5 mm (37%) in the ketoprofen and placebo groups, respectively (p = 0.0013). The differences of the secondary criteria during the trial between the 2 groups were significant more often than not. Tolerance was considered satisfactory in both groups, most adverse events reported being local reactions: 47 versus 44 were possibly or probably related to treatment in the ketoprofen and placebo groups, respectively. These local skin reactions resolved spontaneously and rarely led to premature termination of treatment. CONCLUSION: This trial suggested that a 3-14 day course of treatment by ketoprofen patch is useful in nonarticular rheumatisms, the duration of treatment depending on the results obtained. The safety profile revealed no unexpected adverse events.