Eltrombopag does not affect cardiac repolarization: results from a definitive QTc study in healthy subjects.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Some non-anti-arrhythmic drugs delay cardiac repolarization, which can be measured as an increase in the QT interval. Delays in cardiac repolarization create an electrophysiological environment that favours the development of cardiac arrhythmias, which may lead to torsade de pointes, which can be fatal. As part of the clinical development of eltrombopag, a thorough QT(c) study was conducted to evaluate the effects of eltrombopag on cardiac repolarization at both therapeutic and supratherapeutic doses and to characterize the relationship between plasma eltrombopag concentrations and change in QT(c). WHAT THIS STUDY ADDS: This study found no clinically significant QT prolongation for eltrombopag when administered as 50 mg or 150 mg every day for 5 days. There were no safety or tolerability signals of clinical concern. A small incidence of ventricular premature beats was observed, but this was consistent with previously reported incidences in healthy volunteers without apparent heart disease. AIM: To evaluate the effect of eltrombopag on cardiac repolarization and to characterize the relationship between plasma eltrombopag concentrations and change in QT(c). METHODS: This was a double-blind, placebo- and active-controlled, randomized, balanced four-period, crossover study in healthy men and women. Subjects were randomized to receive eltrombopag 50 mg and 150 mg, moxifloxacin 400 mg (positive control) and placebo in one of four sequences. RESULTS: Eighty-seven subjects entered the study and 48 completed. There was no prolongation of QT(c) (Fridericia) following eltrombopag treatment, as the upper limit of the 90% confidence interval (CI) for the time-matched change from baseline in QT(c)F between drug and placebo (ddQT(c)F) did not exceed 10 ms for eltrombopag at either dose. Maximum observed mean treatment difference was 2.29 ms (90% CI 0.34, 4.24) for eltrombopag 150 mg at 1 h post-dose and 11.64 ms (90% CI 9.64, 13.64) for moxifloxacin 400 mg at 4 h. Eltrombopag C(max) and AUC(0,24 h) increased in a dose proportional manner between 50 mg and 150 mg after 5 days' dosing. Proportions of subjects with adverse events were similar across treatments (52-66% of subjects). Most withdrawals (26/39 subjects) were due to elevated platelets. Three subjects were withdrawn for ventricular premature beats (one following each active treatment) reported as related to the study drug. CONCLUSIONS: No clinically significant QT(c) prolongation was observed for eltrombopag at therapeutic and supratherapeutic doses.

Effects of food and antacids on the pharmacokinetics of eltrombopag in healthy adult subjects: two single-dose, open-label, randomized-sequence, crossover studies.

BACKGROUND: Eltrombopag is the first orally self-administered, small-molecule, nonpeptide thrombopoietin receptor agonist for the treatment of chronic idiopathic thrombocytopenic purpura. OBJECTIVE: The aim of these studies was to assess the effect of food and antacids on the pharmacokinetic and safety profiles of eltrombopag. METHODS: Two independent, single-dose, open-label, randomized-sequence, crossover studies of oral eltrombopag were conducted in healthy adult volunteers. The first study (study A) compared eltrombopag 50 mg (tablets or capsules) administered in the fasted state or tablets with a high-fat, high-calcium breakfast. The second study (study B) investigated eltrombopag tablets (75 mg) administered in the fasted state; immediately after a low-fat, low-calcium meal or a high-fat, low-calcium meal; 1 hour before a high-fat, low-calcium meal; or with an antacid containing aluminum hydroxide and magnesium carbonate. Vital signs were recorded and electrocardiogram and clinical laboratory tests were performed at screening, within 24 hours before and within 48 hours after each dose of study medication. Symptom assessment was performed and adverse events (AEs) were assessed previous to study drug administration through follow-up in terms of severity and relationship to study medication. RESULTS: In study A, 18 male subjects (mean age, 23.0 years; weight, 70.3 kg; white race, 94.4%) who received a high-fat, high-calcium breakfast had reduced bioavailability of eltrombopag in terms of AUC(0-infinity)) by 59% (geometric mean ratio [GMR], 0.41; 90% CI, 0.36-0.46) and C(max) by 65% (GMR, 0.35; 90% CI, 0.30-0.41) compared with subjects in a fasted state. In study B, the bioavailability in 26 subjects (14 male, 12 female; mean age, 35.6 years; weight, 76.0 kg; white race, 65.4%) was not significantly changed when administered with food that was low in calcium, despite the fat content (GMRs ranged from 0.87-1.03 for AUC(0-infinity) and 0.85-1.01 for C(max) across the 3 studied meals). Mean plasma AUC(0-infinity)) and C(max) values decreased by approximately 70% (GMR, 0.30; 90% CI, 0.24-0.36 for AUC(0-infinity)) and 0.24-0.38 for C(max)) when administered with a metal cation-containing antacid. No serious AEs were reported and all AEs were rated as mild to moderate in intensity. The most frequently reported AE was headache (study A, 6.3%; study B, 12.0%-29.2%). CONCLUSIONS: Concomitant administration of eltrombopag with high-calcium food or an antacid containing aluminum and magnesium was associated with significantly reduced systemic exposure, whereas low-calcium meals were not. A single dose of eltrombopag was generally well tolerated in these healthy volunteers.

Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Eltrombopag is an oral, non-peptide, thrombopoietin-receptor agonist that stimulates thrombopoiesis, leading to increased platelet production. This study assessed the efficacy, safety, and tolerability of once daily eltrombopag 50 mg, and explored the efficacy of a dose increase to 75 mg. METHODS: In this phase III, randomised, double-blind, placebo-controlled study, adults from 63 sites in 23 countries with chronic idiopathic thrombocytopenic purpura (ITP), platelet counts less than 30 000 per muL of blood, and one or more previous ITP treatment received standard care plus once-daily eltrombopag 50 mg (n=76) or placebo (n=38) for up to 6 weeks. Patients were randomly assigned in a 2:1 ratio of eltrombopag:placebo by a validated randomisation system. After 3 weeks, patients with platelet counts less than 50 000 per microL could increase study drug to 75 mg. The primary endpoint was the proportion of patients achieving platelet counts 50 000 per microL or more at day 43. All participants who received at least one dose of their allocated treatment were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT00102739. FINDINGS: 73 patients in the eltrombopag group and 37 in the placebo group were included in the efficacy population and were evaluable for day-43 analyses. 43 (59%) eltrombopag patients and six (16%) placebo patients responded (ie, achieved platelet counts >/=50 000 per microL; odds ratio [OR] 9.61 [95% CI 3.31-27.86]; p<0.0001). Response to eltrombopag compared with placebo was not affected by predefined study stratification variables (baseline platelet counts, concomitant ITP drugs, and splenectomy status) or by the number of previous ITP treatments. Of the 34 patients in the efficacy analysis who increased their dose of eltrombopag, ten (29%) responded. Platelet counts generally returned to baseline values within 2 weeks after the end of treatment. Patients receiving eltrombopag had less bleeding at any time during the study than did those receiving placebo (OR 0.49 [95% CI 0.26-0.89]; p=0.021). The frequency of grade 3-4 adverse events during treatment (eltrombopag, two [3%]; placebo, one [3%]) and adverse events leading to study discontinuation (eltrombopag, three [4%]; placebo, two [5%]), were similar in both groups. INTERPRETATION: Eltrombopag is an effective treatment for managment of thrombocytopenia in chronic ITP.

Preclinical activity of eltrombopag (SB-497115), an oral, nonpeptide thrombopoietin receptor agonist.

Eltrombopag is a first-in-class, orally bioavailable, small-molecule, nonpeptide agonist of the thrombopoietin receptor (TpoR), which is being developed as a treatment for thrombocytopenia of various etiologies. In vitro studies have demonstrated that the activity of eltrombopag is dependent on expression of TpoR, which activates the signaling transducers and activators of transcription (STAT) and mitogen-activated protein kinase signal transduction pathways. The objective of this preclinical study is to determine if eltrombopag interacts selectively with the TpoR to facilitate megakaryocyte differentiation in platelets. Functional thrombopoietic activity was demonstrated by the proliferation and differentiation of primary human CD34(+) bone marrow cells into CD41(+) megakaryocytes. Measurements in platelets in several species indicated that eltrombopag specifically activates only the human and chimpanzee STAT pathways. The in vivo activity of eltrombopag was demonstrated by an increase of up to 100% in platelet numbers when administered orally (10 mg/kg per day for 5 days) to chimpanzees. In conclusion, eltrombopag interacts selectively with the TpoR without competing with Tpo, leading to the increased proliferation and differentiation of human bone marrow progenitor cells into megakaryocytes and increased platelet production. These results suggest that eltrombopag and Tpo may be able to act additively to increase platelet production.

Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura.

BACKGROUND: The pathogenesis of chronic idiopathic thrombocytopenic purpura (ITP) involves antibody-mediated platelet destruction and reduced platelet production. Stimulation of platelet production may be an effective treatment for this disorder. METHODS: We conducted a trial in which 118 adults with chronic ITP and platelet counts of less than 30,000 per cubic millimeter who had had relapses or whose platelet count was refractory to at least one standard treatment for ITP were randomly assigned to receive the oral thrombopoietin-receptor agonist eltrombopag (30, 50, or 75 mg daily) or placebo. The primary end point was a platelet count of 50,000 or more per cubic millimeter on day 43. RESULTS: In the eltrombopag groups receiving 30, 50, and 75 mg per day, the primary end point was achieved in 28%, 70%, and 81% of patients, respectively. In the placebo group, the end point was achieved in 11% of patients. The median platelet counts on day 43 for the groups receiving 30, 50, and 75 mg of eltrombopag were 26,000, 128,000, and 183,000 per cubic millimeter, respectively; for the placebo group the count was 16,000 per cubic millimeter. By day 15, more than 80% of patients receiving 50 or 75 mg of eltrombopag daily had an increased platelet count. Bleeding also decreased during treatment in these two groups. The incidence and severity of adverse events were similar in the placebo and eltrombopag groups. CONCLUSIONS: Eltrombopag increased platelet counts in a dose-dependent manner in patients with relapsed or refractory ITP. (ClinicalTrials.gov number, NCT00102739.)

The immune thrombocytopenic purpura (ITP) bleeding score: assessment of bleeding in patients with ITP.

A method for objective quantification of bleeding symptoms in immune thrombocytopenic purpura (ITP) has not been established. The ITP Bleeding Scale (IBLS) is a novel bleeding assessment system comprising 11 site-specific grades. Implementation of the IBLS on 100 patient visits revealed that although platelet count and large platelet count correlated well with bleeding symptoms overall, this relationship disappeared in marked thrombocytopenia. The IBLS is a useful clinical tool for monitoring bleeding and may be used to aid the development of laboratory parameters that correlate with underlying bleeding propensity in thrombocytopenia.

Phase 1 clinical study of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist.

Eltrombopag (SB-497 115) is a first-in-class, oral, small-molecule, nonpeptide agonist of the thrombopoietin receptor (TpoR), being developed as a treatment for thrombocytopenia of various etiologies. In this phase 1 placebo-controlled clinical trial in 73 healthy male subjects, eltrombopag was administered as once-daily oral capsules for 10 days at doses of 5, 10, 25, 30, 50, and 75 mg. The pharmacokinetics of eltrombopag were dose dependent and linear, and eltrombopag increased platelet counts in a dose-dependent manner. There were no apparent differences in the incidence or severity of adverse events in subjects receiving active or placebo study medication. These observations indicate that eltrombopag is a once-daily, oral TpoR agonist with demonstrated thrombopoietic activity in human subjects, encouraging further studies in patients with thrombocytopenia.

The predictive value of the "Hull & Rutherford" classification for tubal damage.

OBJECTIVE: This study explores the predictive value for live birth following tubal reconstructive surgery of the "Hull & Rutherford" (H&R) classification system. DESIGN: Retrospective cohort study. SETTING: Tertiary infertility referral service, University of Bristol. POPULATION: Infertile women younger than 40 years with tubal damage undergoing tubal surgery. METHODS: Women (n= 192) were grouped according to three severity grades of disease based on the H&R classification. Essentially, the main features of grade I tubal damage were filmy adhesions, whereas grades II and III referred to unilateral severe damage and bilateral severe damage, respectively. Standard surgical techniques were employed. Pregnancy and live birth rates were calculated and compared using time-specific univariate Kaplan-Maier curves and multivariate Cox's regression analysis. MAIN OUTCOME MEASURES: Pregnancy, ectopic and live birth within three years of surgery. RESULTS: A significant trend towards higher ectopic pregnancy rates (P < 0.001) with increasing severity of tubal damage was noted, but not miscarriage rates. Univariate analysis revealed significant differences in the live birth rates of 69%, 48% and 9% for grades I, II and III, respectively. Multivariate analysis (controlling for age, duration of and primary infertility) confirmed these differences to be significant with risk ratios of 13.7 (95% CI: 4.49-41.9) and 6.54 (95% CI: 2.48-17.24) for grades I and II disease, respectively, compared with grade III disease, used as the reference. CONCLUSIONS: The H&R classification is a simple classification system that is able to distinguish women into three distinct groups giving a favourable, fair and poor prognosis for live birth following tubal surgery.

The practical implications of a raised serum FSH and age on the risk of IVF treatment cancellation due to a poor ovarian response.

PURPOSE: Chronological age, or biological age as indicated by elevated FSH levels, are related to ovarian reserve. This study addresses the likelihood of cancellation of IVF treatment due to a poor ovarian response utilising both basal serum FSH and woman's age. METHODS: A prospective cohort of 536 infertile but ovulating women were studied in their first cycle of IVF treatment. Standardised methods of pituitary desensitisation and ovarian stimulation prior to IVF treatment were employed. Treatment cycles cancelled due to a poor ovarian response to gonadotrophins were studied. A series of logistic regression models were used to explore the probabilities of cancellation in relation to age and FSH. RESULTS: Both age and basal serum FSH levels were independently associated with the risk of treatment cancellation. A low risk of treatment cancellation was observed in women under the age of 35 irrespective of serum FSH, however in older women the risk of treatment cancellation was most likely in women with a high FSH. CONCLUSIONS: In combination both age and FSH may serve as a valuable indicator of poor ovarian response leading to treatment cancellation. However, among older women FSH has particular importance, while less so in younger women with regular menstrual cycles.

Differences in time to natural conception between women with unexplained infertility and infertile women with minor endometriosis.

BACKGROUND: Opinion remains divided as to whether finding endometriotic lesions in the absence of adhesions has an adverse effect on the likelihood of conception. METHODS: This was a retrospective study of 192 fully investigated infertile couples, followed up for up to 3 years following laparoscopy. Women studied were ovulating, <40 old years and their partners had normal sperm parameters. All 117 women with unexplained infertility and 75 with minimal/mild endometriosis without adhesive disease were managed conservatively. RESULTS: Women with endometriosis were found to have a lower probability of pregnancy compared with women with unexplained infertility (36% versus 55%; P<0.05). Other factors adversely associated with pregnancy were primary infertility, smoking and longer duration (>3 years) of infertility. However, the effects of duration of infertility and primary infertility were not observed to be statistically significant for women with endometriosis. CONCLUSIONS: The findings, although undertaken in a select population undergoing laparoscopy, suggest the likelihood of pregnancy is reduced in infertile women with minimal/mild endometriosis compared with those infertile women with a normal pelvis. Duration of infertility and a previous history of pregnancy are important in predicting the likelihood of pregnancy in women with no obvious cause for their infertility (unexplained), whilst the relationship may be more complex in women with minor endometriosis

Tubal damage in infertile women: prediction using chlamydia serology.

BACKGROUND: The study explores the relationship between serum chlamydia antibody titres (CATs) and detection of tubal damage in infertile women. METHODS: The tubal status and pelvic findings in 1006 women undergoing laparoscopy for infertility were related to CAT, which was measured using the whole-cell inclusion immunofluorescence test. RESULTS: A negative correlation between CAT and age was noted. A linear trend between serum CAT and the likelihood of tubal damage, including severe damage, was observed (P < 0.001). Titres in women with tubal damage (median 1:1024; range <1:64-1:4096) were significantly (P < 0.001) higher than in women with endometriosis alone (median <1:64; range <1:64-1:512) or those with a normal pelvis (median <1:64; range <1:64-1:1024). Women with positive titres were more likely to have pelvic adhesions than tubal occlusion unless titres were very high, when tubal damage was likely to be more severe. CONCLUSIONS: CATs are of predictive value in the detection of tubal damage and are quantitatively related to the severity of damage. For practical clinical purposes, Chlamydia serology is useful mainly as a screening test for the likelihood of tubal damage in infertile women and may facilitate decisions on which women should proceed with further investigations without delay.

Medical student awareness of sexual health is poor.

The aim of the study was to assess sexual health knowledge of medical students. Participants from the student population of an English Medical School (University of Bristol) were asked to fill in a questionnaire on the Internet about sexual health issues. The number of correct responses to each question was analysed according to participants' gender and medical school year. While certain issues relating to sexually transmitted infections, contraception and confidentiality in HIV testing were well understood, there was poor knowledge about the failure rate of condoms, abortion rates and prevalence of chlamydia. Women knew more about the contraceptive pill than men. Although increased years of medical training had some benefit in improving the accuracy of knowledge, this effect was surprisingly small. Most medical students have inaccurate factual knowledge about certain important sexual health issues. We consider this to reflect poorly on sexual health awareness in young people in general. There is need for greater sexual health education for future doctors and for the general public.

Quadruplet pregnancy following transfer of two embryos: Case report.

Following a long period of secondary unexplained infertility, a couple had assisted conception treatment with IVF and transfer of two embryos 2 days later. The woman conceived and was found to have a quadruplet pregnancy. Following spontaneous labour onset at 34 weeks gestation, she was delivered by immediate Caesarean section. All four babies (three boys, one girl) were eventually discharged home with the mother. All the boys were found to be of differing zygosity. The quadruplet pregnancy was attributed to natural conception following intercourse and fertilization of oocytes not collected at the time of IVF. The wisdom of intercourse during a cycle of IVF is discussed.

Pharmacokinetics of GW433908, a prodrug of amprenavir, in healthy male volunteers.

These two Phase I, open-label, single-dose, randomized, crossoverstudies in 40 healthymale subjects investigated the pharmacokinetic and safety profiles of various formulations of the amprenavir prodrug GW433908 in the presence and absence of food compared with amprenavir capsules. GW433908 is a phosphate ester prodrug of the antiretroviral protease inhibitor amprenavir, with improved solubility over the parent molecule and a potential for reduced pill burden on current dosing regimens. The calcium salt of the prodrug, GW433908G, was selected for further investigation, as it appeared to offer the greatest potential for the development of new drug formulations. In the fasting state, (1) GW433908G tablet and suspension were bioequivalent in terms of both AUC and Cmax, and (2) GW433908G tablet and suspension were bioequivalent to amprenavir capsules for AUC; however, Cmax was lower with GW433908G. After a high-fat meal compared with fasting, (1) the bioavailability of GW433908G suspension was decreased by 20% and Cmax by 41%, and (2) for GW433908G tablets, there was no influence on AUC(12% lower Cmax). After a low-fat meal compared with fasting, (1) there was bioequivalence for GW433908G tablets, but (2) bioavailability was decreased by 23% for amprenavir capsules (Cmax was also lower, by 46%). Overall, for GW433908G and amprenavir capsules, food had a negligible influence on plasma concentration at 12 hours postdose (C12). Whether administered as tablets or suspension, GW433908G pharmacokinetics was only slightly affected by food. GW433908G tablets were well tolerated and delivered plasma amprenavir concentrations equivalent to the recommended therapeutic amprenavir dose but with fewer tablets. The possibility of a lower pill burden offered by GW433908 may be of clinical benefit in the treatment of HIV infection.