Kalpana Bakshi

Eltrombopag for children with chronic immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial.

BACKGROUND The thrombopoietin receptor agonist eltrombopag has been shown to be safe, tolerable, and effective for adults with chronic immune thrombocytopenia. We aimed to investigate the safety and efficacy of eltrombopag for children with chronic immune thrombocytopenia. METHODS PETIT2 was a two part, randomised, multicentre, placebo-controlled study done at 38 centres in 12 countries (Argentina, Czech Republic, Germany, Hong Kong, Israel, Italy, Russia, Spain, Taiwan, Thailand, UK, and USA). Paediatric patients aged 1-17 years who had chronic immune thrombocytopenia and platelet counts less than 30 × 10(9) per L were randomly assigned (2:1) to receive eltrombopag or placebo. We stratified patients by age into three cohorts (patients aged 12-17 years, 6-11 years, and 1-5 years) before randomly entering them into a 13 week, double-blind period. Randomisation was done by the GlaxoSmithKline Registration and Medication Ordering System and both patients and study personnel were masked to treatment assignments. Patients who were allocated eltrombopag received tablets (except for those aged 1-5 years who received an oral suspension formulation) once per day for 13 weeks. Starting doses for patients aged 6-17 were based on bodyweight, and ethnic origin and ranged between 50 mg/day and 25 mg/day (starting dose for patients aged 1-5 years was 1·2 mg/kg/day or 0·8 mg/kg/day for east Asian patients). Patients who completed the double-blind period entered a 24 week open-label treatment period in which all patients received eltrombopag at either the starting dose (if they were formerly on placebo) or their established dose. The primary outcome was the proportion of patients achieving platelet counts of at least 50 × 10(9) per L in the absence of rescue therapy for 6 or more weeks from weeks 5 to 12 of the double-blind period. The intention-to-treat population included in the efficacy assessment consisted of all patients who were randomly assigned to one of the treatment groups, and the safety population included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01520909. FINDINGS Beginning in March 15, 2012, 92 patients were enrolled, and the trial was completed on Jan 2, 2014. 63 patients were assigned to receive eltrombopag and 29 were assigned to receive placebo. In the double-blind period, three patients discontinued treatment because of adverse events: two patients in the eltrombopag group withdrew because of increased liver aminotransferases and one in the placebo group withdrew because of abdominal haemorrhage. 25 (40%) patients who received eltrombopag compared with one (3%) patient who received placebo achieved the primary outcome of platelet counts of at least 50 × 10(9) per L for 6 of the last 8 weeks of the double-blind period (odds ratio 18·0, 95% CI, 2·3-140·9; p=0·0004). Responses were similar in all cohorts (eltrombopag vs placebo: 39% vs 10% for patients aged 12-17 years, 42% vs 0% for patients aged 6-11 years, and 36% vs 0% for patients aged 1-5 years). Proportionately fewer patients who received eltrombopag (23 [37%] of 63 patients) had WHO grades 1-4 bleeding at the end of the double-blind period than did those who received placebo (16 [55%] of 29 patients); grades 2-4 bleeding were similar (three [5%] patients who received eltrombopag vs two [7%] patients who received placebo). During the 24-week open-label treatment period, 70 [80%] of 87 patients achieved platelet counts of 50 × 10(9) per L or more at least once. Adverse events that occurred more frequently with eltrombopag than with placebo included nasopharyngitis (11 [17%] patients), rhinitis (10 [16%] patients), upper respiratory tract infection (7 [11%] patients), and cough (7 [11%] patients). Serious adverse events occurred in five (8%) patients who received eltrombopag and four (14%) who received placebo. Safety was consistent between the open-label and double-blind periods. No deaths, malignancies, or thromboses occurred during the trial. INTERPRETATION Eltrombopag, which produced a sustained platelet response in 40% of patients with chronic immune thrombocytopenia, is a suitable therapeutic option for children with chronic symptomatic immune thrombocytopenia. We identified no new safety concerns and few patients discontinued treatment because of adverse events. FUNDING GlaxoSmithKline.

Evaluation of bone marrow reticulin in patients with chronic immune thrombocytopenia treated with eltrombopag: Data from the EXTEND study

Thrombopoietin receptor agonists, which raise platelet counts in patients with chronic immune thrombocytopenia, may be associated with increases in bone marrow (BM) reticulin. Patients with chronic immune thrombocytopenia participating in the Eltrombopag Extended Dosing (EXTEND) study underwent BM biopsies to identify clinically relevant BM fibrosis‐related increases. Specimens were centrally reviewed by 2 hematopathologists. Two hundred thirty‐two biopsy specimens were collected from 117 patients treated for ≤5.5 years. Moderate to marked reticulin fibrosis was found in 2 patients. After withdrawing from the study, the biopsy of 1 patient reverted to normal. There were no other pathologic changes identified among on‐treatment specimens, and no pattern of abnormal reticulin deposition associated with eltrombopag treatment was evident. Am. J. Hematol. 90:598–601, 2015.

A 2-Year, Longitudinal, Prospective Study of the Effects of Eltrombopag on Bone Marrow in Patients with Chronic Immune Thrombocytopenia

Background: The long-term effects of eltrombopag on bone marrow (BM) reticulin and/or collagen deposition in previously treated adults with chronic immune thrombocytopenia (ITP) were assessed. Methods: Three BM biopsies were collected at baseline and after 1 and 2 years of eltrombopag treatment. Specimens were centrally processed, stained for reticulin and collagen, independently reviewed by 2 hematopathologists, and rated according to the European Consensus 0-3 scale of marrow fibrosis (MF). Results: Of 162 patients enrolled, 93 completed all 3 protocol-specified BM biopsies. All patients with a baseline assessment were negative for collagen. Of 159 patients assessed at baseline, 150 (94%) had normal reticulin (MF-0) and 9 (6%) had minimally increased reticulin (MF-1). After 2 years, 83/93 patients (89%) with BM biopsies had MF-0, 10 (11%) had MF-1, and none had MF-2 or MF-3. Five out of 127 patients (4%) at 1 year and 1 out of 93 (1%) at 2 years had collagen deposition. None of the patients had clinical symptoms typical of BM dysfunction or abnormalities of clinical concern based on white blood cell count or peripheral blood smear. Conclusion: For most patients with chronic ITP, eltrombopag is not associated with clinically relevant increases in BM reticulin or collagen formation.

Hemostatic challenges in patients with chronic immune thrombocytopenia treated with eltrombopag

Chronic immune thrombocytopenia (ITP) is an autoimmune disease that results in chronically low platelet counts. Treatment guidelines recommend a platelet count of at least 50 000/µl before minor surgery and at least 80 000/µl before major surgery. This retrospective analysis explored invasive non-dental procedures associated with the risk of bleeding (hemostatic challenges) among patients with chronic ITP in five phase 2/phase 3 studies of the thrombopoietin-receptor agonist, eltrombopag. Data collection for patients who underwent hemostatic challenges included demographics, study medication, timing of the procedure, platelet counts at last assessment before and first assessment after the procedure, supplemental ITP treatment, and bleeding events. Among 494 patients who participated in the studies, 87 hemostatic challenges were recorded. Median platelet counts before 44 major procedures in 32 patients were 100 000/µl and 18 500/µl among patients who received eltrombopag and placebo, respectively; before 43 minor procedures in 38 patients, median platelet counts were 82 000/µl and 20 000/µl among patients who received eltrombopag and placebo, respectively. A minority of patients required supplemental ITP treatment. Only 2 of 87 hemostatic challenges were associated with bleeding events; both patients received eltrombopag and pre-procedural platelet counts were 83 000/µl and 2000/µl. Although the number of patients who did not undergo procedures due to thrombocytopenia was not captured, these data suggest a majority of patients with chronic ITP who receive eltrombopag and experience increases in platelet counts meet current pre-procedural platelet count recommendations. The potential role of eltrombopag in supporting preparation of chronic ITP patients for surgical procedures still needs to be clinically established.

Thrombophilia in patients with chronic immune thrombocytopenia.

Abstract An increased risk of thromboembolic events among patients with chronic immune thrombocytopenia has been reported but is still not fully understood. A thrombophilia panel (factors suspected/known to denote a thrombophilic state or indicate activation of the clotting cascade) was measured in previously treated patients with chronic immune thrombocytopenia enrolled in an eltrombopag trial to assess potential thrombophilia risk markers. Of 167 patients, 136 (81%) had abnormal levels of at least 1 known or suspected thrombosis risk marker or coagulation cascade activation marker. Six patients reported thromboembolic events, and all of these patients had at least two abnormal analytes in the thrombophilia panel. The presence of multiple baseline thrombophilia risk markers support the theory that chronic immune thrombocytopenia is a pro-thrombotic disease.

Pharmacokinetics of Cabotegravir in Subjects with Severe Renal Impairment

Abstract Background Cabotegravir (CAB) is an integrase inhibitor in phase 3 clinical trials for the treatment and prevention of HIV. CAB undergoes glucuronidation via UGT1A1 with <1% renal elimination of unchanged CAB. Renal impairment may affect PK of drugs that are primarily metabolized or secreted in bile; thus impact of renal impairment on CAB pharmacokinetics was evaluated. Methods This was a multi-center, single-dose study of oral CAB 30mg administered to subjects with severe renal impairment (creatinine clearance [CLcr] <30 mL/minute; not on renal replacement therapy) and to healthy controls (CLcr ≥90 mL/minute) matched for gender, age (±10 years), and body mass index (BMI) (±25%) (8 per group). Serial PK for plasma CAB concentrations were collected through 168 hours post dose and unbound CAB concentrations determined at 2 and 24 hours post dose. Non-compartmental PK analysis was performed; geometric least squares (GLS) mean ratios and 90% confidence intervals (CI) were generated. Results Sixteen subjects completed study; 12 (75%) male, mean age 54 years (range:35–69), mean BMI 28 kg/m2 (range: 24–35), and mean CLcr 22 mL/minute (range: 17–29) and 121 mL/minute (range: 95–162) for renal impaired and healthy subjects, respectively. CAB PK parameters were similar between severe renal impairment and healthy subjects. Based on preliminary PK, GLS mean ratios (90% CI) for AUC(0-¥), Cmax, C24, CL/F, and t1/2 were 0.97 (0.835, 1.14), 1.01 (0.865, 1.17), 1.02 (0.868, 1.20), 1.03 (0.881, 1.20) and 0.93 (0.831, 1.04), respectively. Although highly protein bound, the unbound fraction was higher in subjects with severe renal impairment with GLS mean ratio (90%CI) of 1.31 (0.843, 2.03) at 2 hours and 1.51 (1.19, 1.92) at 24 hours post dose. One renal impairment subject developed grade 3 lipase elevation considered drug-related by investigator, otherwise all reported adverse events (AE) were Grade 1 in severity with no serious AEs reported. Conclusion Plasma CAB exposures in subjects with severe renal impairment were similar to healthy subjects; therefore, no dose adjustment of CAB is required in renal impairment. Although no data are available, CAB PK is not expected to be affected in subjects undergoing dialysis given CAB’s non-renal clearance and high plasma protein binding (~99%). Disclosures R. Parasrampuria, GlaxoSmithKline: Employee and Shareholder, Salary; S. Ford, PAREXEL International: Employee, Salary; Y. Lou, PAREXEL International: Employee, Salary; C. Fu, PAREXEL International: Employee, Salary; K. Bakshi, GlaxoSmithKline: Employee and Shareholder, Salary; A. Tenorio, ViiV Healthcare: Employee and Shareholder, Salary; C. Trezza, ViiV Healthcare: Employee and Shareholder, Salary; W. Spreen, ViiV Healthcare: Employee and Shareholder, Salary; P. Patel, ViiV Healthcare: Employee and Shareholder, Salary

Effect of a High-Fat Meal on the Pharmacokinetics of the HIV Integrase Inhibitor Cabotegravir

Cabotegravir is an integrase inhibitor in clinical development for the treatment and prevention of HIV infection using oral tablets for short‐term, lead‐in use before subsequent administration of a long‐acting injectable formulation. This phase 1, single‐center, randomized, 2 × 2 crossover study evaluated the effect of a high‐fat meal on the pharmacokinetics (PK) of oral cabotegravir. Healthy adults received oral cabotegravir 30 mg as a single dose on 2 separate occasions, either after fasting or following a high‐fat meal (∼53% fat, ∼870 kcal). Safety evaluations and serial PK samples were collected, and a mixed‐effects model was used to determine within‐participant treatment comparison of noncompartmental PK parameters. Twenty‐four patients were enrolled and had a mean body mass index of 25.6 kg/m2; 67% were male. Compared with the fasting state, coadministration of cabotegravir with a high‐fat meal increased plasma cabotegravir area under the concentration‐time curve and maximal drug concentration, each by 14%. The slight 14% to 17% increase in exposure associated with a high‐fat, high‐calorie meal was not considered clinically significant. No grade 3/4 adverse events (AEs), drug‐related AEs, or AEs leading to discontinuation were reported.