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.

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.

Comparative Bioavailability Study of a New Vitamin D3 Orodispersible Film Versus a Marketed Oral Solution in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: An orally disintegrating film (ODF) formulation of vitamin D3 that dissolves rapidly in the mouth without drinking or chewing may be a worthwhile alternative to currently available drug products for therapeutic vitamin D supplementation. This study aimed to compare the bioavailability of a single dose of a vitamin D3 25000 I.U. ODF with those of a marketed oral vitamin D3 preparation in healthy subjects. METHODS: This Phase 1, randomised, parallel-group, open-label study compared the pharmacokinetics of calcifediol [25(OH)D3], the precursor of bioactive vitamin D3, after a single dose of a new vitamin D3 25,000 I.U. ODF with those of a Reference formulation (vitamin D3 25000 I.U./2.5 mL oral solution) in healthy adult subjects using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. The primary objective was bioavailability under fed conditions, defined as maximum plasma concentration (Cmax) of 25(OH)D3 and area under the concentration-time curve from time zero to time t, the last quantifiable concentration (AUC0-t). The pharmacokinetics of 25(OH)D3 were also evaluated following the ODF administration under fasting conditions. Subjects were randomised to receive a single dose of the vitamin D3 25000 I.U. ODF or the Reference oral solution under fed conditions or the vitamin D3 ODF under fasting conditions. RESULTS: Forty-eight healthy subjects were randomised and completed the study. Overall, the pharmacokinetic profile was very similar across the three treatment groups, and bioavailability did not significantly differ among treatments. Under fed conditions, mean 25(OH)D3 plasma values for Cmax were 6.68 ± 2.03 versus 6.61 ± 2.62 ng/mL for the Test versus Reference formulations. Corresponding values for AUC0-t were 2364.80 ± 1336.97 versus 2150.52 ± 1622.76 ng/mL × h. Mean Cmax was slightly lower (6.68 ± 2.03 vs 7.23 ± 1.48 ng/mL) and the time to reach peak concentration was delayed (144 h [36-312] versus 42 h (2-480]) with the ODF under fed versus fasting conditions (p = 0.0371). The point estimates and 90 % CIs of the Testfed/Referencefed ratios of the geometric means showed that the bioavailability of exogenous 25(OH)D3 was, both in rate and extent of absorption, slightly higher with the vitamin D3 ODF than the vitamin D3 oral solution under the administration conditions recommended for the vitamin D3 oral solution. Palatability and ease of use of the ODF were satisfactory. CONCLUSION: The new ODF 25000 I.U. formulation provided a valuable alternative to the marketed oral solution for therapeutic vitamin D supplementation, with a bioavailability that was slightly higher than that of the vitamin D3 oral solution administered under the same conditions. TRIAL REGISTRATION: The study was retrospectively registered with the ISRCTN Registry (Registry code: ISRCTN13208948) on 27 November 2020.

Increasing Concentration of Sinovial: Effect on Cartilage Protection in a Rabbit ACLT Model.

OBJECTIVE: This study aimed to test the hypothesis that administration of increasing doses of Sinovial (hyaluronic acid [HA]), would exhibit a dose-dependent effect on the prevention of cartilage degradation, without local and systemic toxicity. METHODS: Twenty-seven adult rabbits were subjected to anterior cruciate ligament transection (ACLT). Two Sinovial products containing HA concentrations of 1.6% and 2.4% were used as active treatment, and 0.9% saline was used as control and injected intra-articularly 7 days post ACLT. Radiographs were taken prior to surgery, at injection and sacrifice times. After euthanasia, 8 weeks postsurgery, knee joints were observed macroscopically using India ink staining with OARSI (Osteoarthritis Research Society International) scoring and histologically using modified Mankin scoring. The synovial membranes were analyzed using Cake classification. RESULTS: No intraoperative complications were observed. One week postinjection, 4 animals in the HA 2.4% group developed subcutaneous nodules that disappeared spontaneously. No inflammation of the synovial membrane was ever observed. The control group exhibited the maximum uptake of India ink 2.22 ± 0.14. HA groups exhibited a dose-dependent (P = 0.02) reduction in India ink uptake: 1.75 ± 0.17 for HA 1.6% and 1.58 ± 0.14 for HA 2.4%. The most marked dose-dependent effect of this study was a reduction of modified Mankin score for HA groups, with the 2.4% treatment achieving a statistically significant improvement as compared with the control group (7.19 ± 0.85 for saline, 4.65 ± 0.66 for HA 1.6%, and 3.53 ± 0.59 for HA 2.4%; P = 0.005). CONCLUSIONS: A dose-dependent protective effect on cartilage was observed after injection of both HA solutions.

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.

Can We Identify Patients with High Risk of Osteoarthritis Progression Who Will Respond to Treatment? A Focus on Biomarkers and Frailty.

Osteoarthritis (OA), a disease affecting different patient phenotypes, appears as an optimal candidate for personalized healthcare. The aim of the discussions of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) working group was to explore the value of markers of different sources in defining different phenotypes of patients with OA. The ESCEO organized a series of meetings to explore the possibility of identifying patients who would most benefit from treatment for OA, on the basis of recent data and expert opinion. In the first meeting, patient phenotypes were identified according to the number of affected joints, biomechanical factors, and the presence of lesions in the subchondral bone. In the second meeting, summarized in the present article, the working group explored other markers involved in OA. Profiles of patients may be defined according to their level of pain, functional limitation, and presence of coexistent chronic conditions including frailty status. A considerable amount of data suggests that magnetic resonance imaging may also assist in delineating different phenotypes of patients with OA. Among multiple biochemical biomarkers identified, none is sufficiently validated and recognized to identify patients who should be treated. Considerable efforts are also being made to identify genetic and epigenetic factors involved in OA, but results are still limited. The many potential biomarkers that could be used as potential stratifiers are promising, but more research is needed to characterize and qualify the existing biomarkers and to identify new candidates.

An exploratory microdialysis study investigating the effect of repeated application of a diclofenac epolamine medicated plaster on prostaglandin concentrations in skeletal muscle after standardized physical exercise.

AIM: Muscle injuries and extensive exercise are associated with cyclo-oxygenase dependent formation of inflammatory prostaglandins. Since the effect of topical administration of non-steroidal anti-inflammatory drugs (NSAIDs) on local cyclo-oxygenase is unknown, the present exploratory, open label, non-randomized study set out to measure exercise induced release of prostaglandins before and after epicutaneous administration of diclofenac. METHODS: Microdialysis was used to determine the local interstitial concentration of PGE2 and 8-iso-PGF2α as well as diclofenac concentrations in the vastus lateralis under rest, dynamic exercise and during recovery in 12 healthy subjects at baseline and after a treatment phase applying a total of seven plasters medicated with 180 mg of diclofenac epolamine over 4 days. RESULTS: At baseline PGE2 concentrations were 1169 ± 780 pg ml(-1) at rest and 1287 ± 459 pg ml(-1) during dynamic exercise and increased to 2005 ± 1126 pg ml(-1) during recovery. After treatment average PGE2 concentrations were 997 ± 588 pg ml(-1) at rest and 1339 ± 892 pg ml(-1) during exercise. In contrast with the baseline phase no increase in PGE2 concentrations was recorded during the recovery period after treatment (PGE2 1134 ± 874 pg ml(-1)). 8-iso-PGF2α was neither affected by exercise nor by treatment with diclofenac. Local and systemic concentrations of diclofenac were highly variable but comparable with previous clinical pharmacokinetic studies. CONCLUSIONS: We can hypothesize an effect of topical diclofenac epolamine plaster on limiting the increase of local concentrations of the pro-inflammatory prostaglandin PGE2 induced in the muscle of healthy human subjects following standardized physical exercise. No effect of diclofenac treatment on 8-iso-PGF2α concentrations was observed, mainly since isoprostane is produced by a free radical-catalyzed lipid peroxidation mechanism independent of cyclo-oxygenases.

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.

Efficacy and safety of the Betamethasone valerate 0.1% plaster in mild-to-moderate chronic plaque psoriasis: a randomized, parallel-group, active-controlled, phase III study.

BACKGROUND: Corticosteroids are a versatile option for the treatment of mild-to-moderate psoriasis due to their availability in a wide range of potencies and formulations. Occlusion of the corticosteroid is a widely accepted procedure to enhance the penetration of the medication, thereby improving its effectiveness. Betamethasone valerate (BMV) is a moderately potent corticosteroid that is available as a cream, ointment, and lotion. A ready-to-use occlusive dressing, which provides a continuous sustained release of BMV, has been developed for the treatment of psoriasis. OBJECTIVE: To evaluate the efficacy and safety of a new BMV 0.1% plaster compared with a BMV 0.1% cream in patients with mild-to-moderate chronic plaque psoriasis. METHODS: This was a prospective, randomized, assessor-blind, parallel-group, active-controlled, multicenter, phase III study. Eligible outpatients (aged ≥18 years) with a diagnosis of stable, chronic plaque psoriasis vulgaris with two to four plaques on extensor surfaces of limbs were randomized to receive BMV 0.1% plaster or BMV 0.1% cream for 3-5 weeks; patients with resolution of target plaques then entered a 3-month, treatment-free, follow-up period. The number of patients showing clearing of plaques (remission) at 3 weeks (primary endpoint) and at 5 weeks was independently evaluated from digitized images of target plaques by two blinded assessors, and also assessed by the investigator and patient. Additional endpoints were (i) change from baseline in target plaque size and in Psoriasis Global Assessment (PGA) score, as evaluated by the blinded assessors, investigator, and patient; (ii) change from baseline in symptom (itching, soreness) severity; (iii) treatment satisfaction and ease of use; (iv) clearing and relapse during the follow-up period; and (v) adverse events (AEs). RESULTS: Patients (n = 231) were screened and randomized to treatment with BMV 0.1% plaster (n = 116) and BMV 0.1% cream (n = 115). Significantly more patients achieved clearing after 3 weeks' treatment with BMV plaster than with BMV cream (Cochran-Mantel-Haenszel test, p < 0.001); this difference was maintained at 5 weeks. The total plaque area decreased to a larger extent for the BMV plaster group compared with the BMV cream group (analysis of covariance [ANCOVA] model, p = 0.017 at week 5). PGA scores were significantly lower after 3 and 5 weeks' treatment with BMV plaster (ANCOVA model, all p ≤ 0.016 vs BMV cream). Both treatments reduced itching and soreness to a similar degree, and the incidences of relapse during the follow-up period were comparable between treatment groups. There were no significant differences in AEs between treatment groups. CONCLUSIONS: BMV 0.1% plaster is more efficacious than BMV 0.1% cream in the treatment of patients with mild-to-moderate chronic plaque psoriasis in a clinical setting resembling daily clinical practice.

Diclofenac epolamine plus heparin plaster versus diclofenac epolamine plaster in mild to moderate ankle sprain: a randomized, double-blind, parallel-group, placebo-controlled, multicentre, phase III trial.

BACKGROUND: In general sports, ankle sprain is the most frequently reported ankle injury and can cause chronic lateral ankle pain and tenderness. Treatment with NSAIDs is preferred, and several topical NSAID formulations are now available, helping to avoid the systemic adverse events typically associated with oral preparations. OBJECTIVE: To compare the efficacy and tolerability of a newly developed fixed-dose diclofenac epolamine (diclofenac hydroxyethylpyrrolidine, DHEP)/heparin plaster (Flectoparin® Tissugel) with that of a DHEP (Flector EP Tissugel®) or placebo plaster in the treatment of mild to moderate ankle sprain in adults. METHODS: This was a randomized, double-blind, parallel-group, placebo-controlled, multicentre, phase III study conducted in the emergency medical centres of hospitals or private clinics in Europe. Outpatients aged 18-65 years who had suffered an acute ankle sprain (O'Donoghue grade I or II in severity, with external lateral ligament involvement) within the previous 48 hours and had peri-malleolar oedema were eligible for inclusion. A total of 430 patients were randomized to receive a DHEP/heparin 1.3%/5600 IU (n = 142), DHEP 1.3% (n = 146) or placebo (n = 142) plaster, applied once daily to the injured ankle for a total of 7 days. The primary endpoint was the mean change from baseline in pain on movement on day 3, as measured by a visual analogue scale (VAS). RESULTS: The DHEP/heparin plaster was associated with a significantly (p = 0.002) greater mean reduction from baseline in pain on movement after 3 days of treatment than the DHEP plaster (-24.2 vs -18.8 mm VAS), with each active treatment providing significantly (p ≤ 0.005) greater pain relief than placebo (-13.7 mm VAS). Both DHEP/heparin and DHEP were also effective in relieving other measures of pain, with DHEP/heparin recipients experiencing significantly less daily pain while leaning on the injured limb than DHEP recipients (p < 0.001). In addition, oedema was reduced to a significantly greater extent with DHEP/heparin than with placebo (day 7 only; p = 0.012). The DHEP/heparin plaster and DHEP plaster were both well tolerated, with adverse event profiles similar to that of placebo. Local adverse events were infrequent and generally mild in severity and there were no systemic adverse effects. CONCLUSION: The fixed-dose DHEP/heparin plaster is effective and has advantages over the DHEP plaster in relieving pain, and possibly also swelling, associated with mild to moderate acute ankle sprains with oedema in adults.