Pharmacokinetic studies in women of 2 novel oral formulations of tranexamic acid therapy for heavy menstrual bleeding.

Two randomized, open-label clinical studies involving healthy female volunteers aged 18-45 years (study 1, N = 32; study 2, N = 40) are described, which characterize the pharmacokinetics and steady-state dosage regimen performance of 2 novel, modified-release tranexamic acid tablet formulations. The objective of these studies was to identify the optimum product formulation to advance into late-phase clinical trials for heavy menstrual bleeding. For study 1, participants received single 1.3-g doses (2 650-mg tablets) of tranexamic acid modified-immediate-release (MIR) and tranexamic acid delayed-release (DR) formulations under fasting conditions compared with nonfasting conditions (after breakfast). For study 2, participants received tranexamic acid MIR or tranexamic acid DR as a single 1.3-g dose followed by a dosage regimen of 1.3 g every 8 hours for 5 days. Plasma tranexamic acid concentrations reached minimum effective levels (≥5 µg/mL) within 1.5 hours and within 3 hours after a 1.3-g tranexamic acid MIR and tranexamic acid DR dose, respectively. Food did not appreciably influence tranexamic acid MIR pharmacokinetics, whereas a high-fat meal significantly lowered the maximum concentration produced with tranexamic acid DR. Peak systemic exposure and maintenance of plasma tranexamic acid concentrations within the therapeutic range (5-15 µg/mL) were optimally achieved with 1.3 g of the MIR formulation dosed every 8 hours. The MIR and DR formulations were well tolerated. Peak-to-trough steady-state performance of the tranexamic acid MIR 1.3-g product (dosed every 8 hours, or 3 times daily, for up to 5 days) supported its advancement to late-phase clinical trials in women with heavy menstrual bleeding.

Tranexamic acid: a novel oral formulation for the treatment of heavy menstrual bleeding.

Tranexamic acid, a synthetic lysine derivative, is an antifibrinolytic drug that prevents the breakdown of fibrin by competitively blocking binding sites of plasminogen. Tranexamic acid is often considered a first-line treatment for the management of heavy menstrual bleeding (HMB). A new oral formulation of tranexamic acid provides a nonhormonal HMB therapy that is safe, effective and well tolerated; is administered only during menstruation; addresses the excessive fibrinolysis implicated in many cases of HMB; and improves women's health-related quality of life by reducing limitations on physical, social and leisure activities. This article provides a summary of the clinical development, therapeutic efficacy and tolerability profile of this novel formulation of tranexamic acid for the treatment of HMB.

Menorrhagia Impact Questionnaire: assessing the influence of heavy menstrual bleeding on quality of life.

OBJECTIVE: Menorrhagia, or heavy menstrual bleeding (HMB), has a negative impact on women's quality of life (QOL). The objective was to develop, validate, and assess the performance of a disease-specific patient-reported outcome (PRO) measurement instrument for HMB (the Menorrhagia Impact Questionnaire [MIQ]). RESEARCH DESIGN AND METHODS: The MIQ was designed to measure the effect of HMB on a woman's self-assessment of menstrual blood loss (MBL), limitations in social/leisure activities, physical activities, and ability to work. Meaningfulness of these observed MBL changes were also measured. The development and psychometric validation of the MIQ was performed utilizing data from a long-term safety study of tranexamic acid (Lysteda * *Lysteda is a registered trade name of Ferring Pharmaceuticals Inc., Parsippany, NJ, USA. ), with comparison to an age-matched normal control group recruited from the general population. Performance of the MIQ was also evaluated using data from a six-cycle, randomized, double-blind, clinical study of tranexamic acid for the treatment of HMB. Correlations and sensitivity of each pertinent MIQ item to the treatment-induced changes in MBL were assessed, and the minimally important differences (MID) for the individual MIQ items were determined. RESULTS: The psychometric properties of the MIQ were fully validated. Correlations between individual MIQ items and changes in MBL were statistically significant (p < 0.001). A clear differentiation between tranexamic acid and placebo groups confirmed sensitivity of the MIQ and its ability to detect treatment-induced changes in MBL. MIDs were estimated for the individual MIQ items, with sensitivities and specificities in the 64-79% and 63-82% ranges using receiver operating characteristic (ROC) curve analyses, respectively. MIDs were found to be equal to or greater than 0.5. Statistically significant treatment differences were also observed for the proportions of subjects achieving at least 1-point improvement in MIQ scores. CONCLUSION: The MIQ contains validated constructs important to women with HMB. CLINICAL TRIAL REGISTRATION: NCT00113568 and NCT00386308 (ClinicalTrials.gov ID).

Estimating a meaningful reduction in menstrual blood loss for women with heavy menstrual bleeding.

OBJECTIVE: A dichotomy exists within the treatment of heavy menstrual bleeding (HMB); guidelines and expert opinion recommend that clinical management be guided by subjective, patient-centered measures, yet clinical trials often describe treatment efficacy in terms of objective reductions in menstrual blood loss (MBL). The purpose of this investigation was to correlate subjective and objective aspects of HMB treatment by identifying the minimum change in MBL that would be considered meaningful to women. RESEARCH DESIGN AND METHODS: Receiver operating characteristic (ROC) curve analyses were performed using data from a multicenter, randomized, double-blind, placebo-controlled, parallel-group study of a novel, oral formulation of tranexamic acid (Lysteda). The study enrolled women ages 18-49 years with a history of cyclic HMB. Menstrual blood loss was measured objectively using the alkaline hematin method and subjectively using the Menorrhagia Impact Questionnaire (MIQ), a patient-reported outcome instrument previously validated in an HMB population. Additional subgroup analyses were performed after stratification by low (80-160 mL/cycle) or high (> 160 mL/cycle) baseline MBL. CLINICAL TRIAL REGISTRATION: NCT00401193 (NIH Clinical Trials Registry) RESULTS: A total of 278 women were included in the ROC analyses. The best balance of sensitivity and specificity was achieved for predicting a patient-perceived meaningful improvement in MBL, at a cut point of 36 mL/cycle. Absolute reductions in MBL that were considered meaningful were more modest in women with lower baseline MBL (22 mL/cycle) and greater in women with higher baseline MBL (47 mL/cycle). However, an approximately 22% MBL reduction was meaningful to the majority of women in either the low or high baseline MBL subgroups. CONCLUSIONS: Reducing measurable MBL by 36 mL/cycle, or approximately 22%, was considered to be a meaningful improvement for the majority of women with HMB in this study population.

Tranexamic acid treatment for heavy menstrual bleeding: a randomized controlled trial.

OBJECTIVE: To assess the efficacy and safety of an oral formulation of tranexamic acid for the treatment of heavy menstrual bleeding. METHODS: Adult women with heavy menstrual bleeding (mean menstrual blood loss 80 mL or more per cycle) were enrolled in a double-blind, placebo-controlled study. After two pretreatment menstrual cycles, women were randomized to receive tranexamic acid 3.9 g/d or placebo for up to 5 days per menstrual cycle through six cycles. To meet the prespecified three-component primary efficacy end point, mean reduction in menstrual blood loss from baseline with tranexamic acid treatment needed to be 1) significantly greater than placebo, 2) greater than 50 mL, and 3) greater than a predetermined meaningful threshold (36 mL or higher). Health-related quality of life was measured using a validated patient-reported outcome instrument. RESULTS: Women who received tranexamic acid (n=115) met all three primary efficacy end points: first, a significantly greater reduction in menstrual blood loss of -69.6 mL (40.4%) compared with -12.6 mL (8.2%) in the 72 women who received placebo (P<.001); reduction of menstrual blood loss exceeding a prespecified 50 mL; and last, reduction of menstrual blood loss considered meaningful to women. Compared with women receiving placebo, women treated with tranexamic acid experienced significant improvements in limitations in social or leisure and physical activities, work inside and outside the home, and self-perceived menstrual blood loss (P<.01). The majority of adverse events were mild to moderate in severity, and the incidence of gastrointestinal adverse events was comparable with placebo. CONCLUSION: In this study, a new oral tranexamic acid treatment was well tolerated and significantly improved both menstrual blood loss and health-related quality of life in women with heavy menstrual bleeding. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00386308. LEVEL OF EVIDENCE: I.

Thorough cardiac QTc interval conductance assessment of a novel oral tranexamic acid treatment for heavy menstrual bleeding.

OBJECTIVE: To assess the effect of a novel oral tranexamic acid treatment on cardiac repolarization in a randomized, double-blind, positive- and placebo-controlled, four-treatment single-dose cross-over inpatient study. METHODS: QTc interval and drug exposure relationship analyses were performed using triplicate digital electrocardiographs (ECGs) collected from 12-lead Holter monitors from healthy females (n = 48) with plasma drug concentrations and pharmacokinetics simultaneously evaluated over 24 h post-dose. Therapeutic (1.3 g) and supratherapeutic (3.9 g) tranexamic acid modified immediate-release doses, a positive-control 0.4 g moxifloxacin dose, and a placebo-control were administered at each period. RESULTS: All post-dose, time-matched, baseline-adjusted, mean QTcF (Fridericia's heart rate correction, QT/RR(1/3)) treatment-placebo differences (DeltaDeltaQTcF), were less than 5 milliseconds (ms) for the 1.3 g and 3.9 g tranexamic acid doses. Upper limits of the 95% confidence interval (CI) for all tranexamic acid-placebo DeltaDeltaQTcF doses were < 10 ms for all time points. Lower limits of the 95% CI for the positive-control (moxifloxacin-placebo) DeltaDeltaQTcF were > 5 ms at multiple time points demonstrating assay sensitivity. No correlation between tranexamic acid plasma concentrations and adjusted QTc intervals was observed. A positive linear relationship was observed for moxifloxacin (p < 0.01). CONCLUSION: Cardiac repolarization is not influenced by tranexamic acid at the doses studied.

A pharmacokinetic analysis of diclofenac potassium soft-gelatin capsule in patients after bunionectomy.

The clinical utility of diclofenac potassium, a nonsteroidal anti-inflammatory drug, may be lessened by inconsistent gastrointestinal absorption. Diclofenac potassium liquid filled soft-gelatin capsule (DPSGC) is an investigational formulation that uses ProSorb dispersion technology to facilitate rapid and consistent gastrointestinal absorption. In this study, the pharmacokinetic (PK) properties of DPSGC are investigated and compared with a commercially available oral diclofenac potassium tablet in patients after primary unilateral first metatarsal bunionectomy. In an open-label, randomized study, 53 patients received ProSorb-D 12.5 mg (the liquid equivalent of DPSGC), DPSGC 25 mg, DPSGC 50 mg, or immediate-release diclofenac potassium 50-mg tablet administered every 8 hours for a 24-hour inpatient period followed by 7 days of outpatient dosing. Diclofenac steady-state PK was evaluated over an 8-hour sampling period 4 days after surgery. Delayed and/or multiple peaks in the diclofenac plasma concentration-time course profiles occurred more frequently with the commercially available oral diclofenac potassium 50-mg tablet than with the other DPSGC formulations. PK data for ProSorb-D 12.5-mg liquid, DPSGC 25 mg, DPSGC 50 mg, and diclofenac potassium 50-mg tablet revealed mean peak plasma concentrations (Cmax) of 302, 749, 1006, and 902 ng/mL, respectively, whereas area under the plasma concentration curve values were 316, 595, 1029, and 1166 ng-hour/mL, respectively. Mean times to Cmax (tmax) were 0.49, 0.63, 0.95, and 1.26 h, respectively. When compared with absorption characteristics of diclofenac potassium 50-mg tablet, DPSGC was more rapidly and consistently absorbed after bunionectomy. These characteristics should be advantageous when rapid pain relief is desired.

Effects of food intake on the pharmacokinetics of diclofenac potassium soft gelatin capsules: a single-dose, randomized, two-way crossover study.

BACKGROUND: Diclofenac potassium liquid-filled soft gelatin capsule (DPSGC) is an investigational formulation that uses dispersing agents designed to facilitate rapid and consistent absorption of this NSAID. OBJECTIVE: The aim of this study was to characterize the effects of food intake on the pharmacokinetic (PK) profile of oral DPSGC at doses of 25 and 50 mg. METHODS: In this open-label, randomized, single-dose (2 distinct doses), 2-way crossover bioavailability study, healthy adult volunteers were randomly assigned to receive a single dose of DPSGC 25 or 50 mg after an overnight fast (fasted condition) or high-fat breakfast (fed condition) (period 1). After 7 days, the participants received the same dose under the opposite fed/fasted condition (period 2). Serial blood samples were obtained before and through 6 hours after study drug administration. Concentrations of diclofenac in plasma were determined using HPLC, and PK profiles were studied using ANCOVA. Adverse events (AEs) were monitored and recorded on each in-clinic day. RESULTS: Of 47 participants included in the study, 24 received the 25-mg dose of DPSGC and 23 received the 50-mg dose. The majority of participants were male (80.9%), and the mean age was 28.6 years. The mean (SD) AUC values for the fasted and fed states were 691 (195) and 680 (184) ng x h/mL, respectively, with the 25-mg dose, and 1521 (377) and 1416 (366) ng . h/mL, respectively, with the 50-mg dose, suggesting that the extent of absorption was similar with both dietary conditions at each dose. Food intake was associated with decreases in C(max) by nearly half in the 25-mg group (fasted vs fed, 1156 [482] vs 686 [411] ng/mL, respectively; P < 0.05) and the 50-mg group (2365 [1034] vs 1154 [592 ng/mL; P < 0.05) and delayed T(max) in the 25-mg group (0.49 [0.16] vs 1.02 [0.55] hours; P < 0.05) and 50-mg group (0.51 [0.19] vs 1.28 [0.71] hours; P < 0.05). Two mild AEs (nasal congestion and light-headedness) were reported in 2 participants who received 25 mg under fed conditions and 50 mg under fasted conditions, respectively. CONCLUSIONS: Food intake did not appear to affect the extent of absorption (ie, total exposure) of oral DPSGC at doses of 25 and 50 mg in these healthy adult volunteers. Both single doses appeared to be well tolerated.

Single-dose pharmacokinetic study of rapidly dispersing diclofenac potassium formulations in healthy volunteers.

OBJECTIVE: The clinical utility of diclofenac potassium, a commonly prescribed analgesic that provides mild to moderate pain relief, may be hindered by its delayed, depressed, and/or inconsistent absorption characteristics. A diclofenac potassium formulation using proprietary dispersion technology (ProSorb) was developed to overcome these limitations. The authors evaluated and compared the pharmacokinetics (PK) of 2 investigational diclofenac potassium liquid filled soft gelatin capsule (DPSGC) preparations and one investigational diclofenac liquid formulation, each incorporating the proprietary dispersion technology, to establish bioequivalence and identify a formulation for further clinical study. RESEARCH DESIGN AND METHODS: In an open-label, single-dose, three-way crossover, relative bioavailability study, 24 healthy volunteers were randomized to receive each of the 25-mg DPSGC formulations (development processes A and B) and the 1-mL (25-mg) liquid diclofenac formulation (similar to the fill liquid used in the DPSGC products) during three inpatient visits. Each dose was separated by 3 days. Plasma samples were collected at preselected time points through 6 hours post dose. Diclofenac concentrations were determined using a validated HPLC method. Bioequivalence was established within the 80% to 125% acceptance range. Safety and tolerability were monitored throughout. RESULTS: Area under the plasma concentration-time curves (AUC(0-)(t)) for the three formulations were between 577 and 585 ng-hr/mL and peak plasma concentrations (C(max)) were between 958 and 1087 ng/mL, with the DPSGC process B group having the highest C(max). The times to C(max) (t(max)) were all below 30 minutes, with the liquid formulation producing the shortest t(max) (15 minutes). Plasma concentration-time course profiles were similar for all three rapidly dispersing diclofenac potassium formulations. One mild adverse event was observed (lingual paresthesia) and one participant discontinued due to an unrelated event (acute tonsillitis). CONCLUSIONS: These data show that diclofenac potassium formulations using proprietary dispersion technology are rapidly and consistently absorbed. These characteristics may be beneficial in settings where rapid and consistent drug absorption is desirable. These results may differ in other patient populations such as those experiencing pain or illness.