Time Course Of Platelet Counts Research Articles

Population Pharmacokinetic and Exposure-Response Modeling for the EZH1/2 Dual Inhibitor DS-3201b in Patients with Non-Hodgkin Lymphomas

▪Introduction: Epigenetic regulators are an emerging new target class for cancer therapy. Enhancer of zeste homolog 1 (EZH1) and EZH2 are alternative subunits of polycomb repressive complex 2 (PRC2), and catalyze tri-methylation of the 27th lysine residue of histone H3 (H3K27). The tri-methylation of H3K27 (H3K27me3) plays an important role in the repression of genes associated with tumor suppression and cell differentiation. DS-3201b is a dual inhibitor of EZH1/2 with activity against hematological cancer cell lines that include acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), and adult T-cell leukemia-lymphoma (ATL). The first-in-human (FIH) study (NCT02732275) is on-going to assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and potential anti-tumor activity in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), including ATL. This preliminary analysis was aimed to develop a population PK model, to explore the exposure-response (E-R) relationships for key safety and PD endpoints, and to find the optimal dose and schedule for DS-3201b.Methods: As of August 2, 2017, clinical data that include plasma levels of DS-3201a (a free form of DS-3201b) and platelet counts were collected from 15 patients with NHL who were participated in the FIH study. They received DS-3201b oral once-daily dosing ranging from 150 mg to 300 mg in 28-day cycles. Population PK analysis for DS-3201a in plasma was carried out and the potential influence of patient characteristics on the PK of DS-3201a was investigated in a covariate analysis. The PK/PD model for platelet counts was developed using a semi-mechanistic model which consists of compartments that imitate platelet proliferation, maturation, circulation, and a feedback on proliferation. Preliminary E-R analyses were also performed for PD biomarker.Results: A 2-compartment PK model with first order elimination and absorption lag-time best characterized the plasma concentration-time profile of DS-3201a. Serum albumin was a significant covariate for total clearance. In the FIH study, platelet counts decreased to a nadir during the first treatment cycle and it returned to baseline without drug interruption in most patients who received 150 mg or 200 mg doses, whereas all patients who received 300 mg required dose interruption. The PK/PD model with drug effect on platelet proliferation and feedback compartments aptly described the time-course of platelet counts. Model-based simulations showed that up-titration schedule based on each patient's platelet count after cycle 1 treatment could allow administration of higher DS-3201b doses to a subset of patients with low risk of grade ≥3 thrombocytopenia. The results of E-R relationship for the inhibition of H3K27me3 in surrogate tissues will also be presented.Conclusion: We developed preliminary population PK and E-R models for DS-3201b in patients with relapsed or refractory NHL. Model-based simulations suggested that up-titration approach can be effective for DS-3201b to ensure continuity of treatment benefit while minimizing dose-dependent thrombocytopenia. DisclosuresAtsumi:Daiichi Sankyo Co., Ltd.: Employment. Yoshiba:DaiichiSankyo Co., Ltd: Employment. Maruyama:Dai-ichi Sankyo, Chugai, Kyowa Hakko Kirin, Ono, Celgene, Janssen, GSK, Eisai, Mundipharma, Takeda, AbbVie, MSD, Sanofi, Pfizer, Otsuka, Novartis, Solasia, Zenyaku: Research Funding; Chugai, Kyowa Hakko Kirin, Ono, Celgene, Janssen, Eisai, Mundipharma, Takeda: Honoraria. Tobinai:HUYA Bioscience: Honoraria; Janssen: Honoraria, Research Funding; AbbVie: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; Chugai: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Servier: Research Funding; Daiichi Sankyo Co., Ltd: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding. Ishida:Kyowa Hakko Kirin Co., Ltd. Celgene K.K. Bayer Pharma AG: Honoraria, Research Funding. Ishitsuka:Celgene Kyowa Hakko Kirin Bristol-Myers Squibb Chugai Pharmaceutical Takeda Pharmaceutical mundiharma Taiho Daiichi Sankyo Janssen Novartis Pfizer Astellas sanofi Genzyme Alexion Sumitomo Dainippon Eisai Mochida Shire Otsuka Ono Teijin: Honoraria, Research Funding. Tsukasaki:Kyowa-Kirin: Honoraria; Chugai/Roche: Honoraria; DaiichiSankyo: Consultancy; Celgene: Honoraria, Research Funding; Mundypharma: Research Funding; Takeda: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; HUYA: Honoraria. Adachi:Daiichi Sankyo Co., Ltd.: Employment. Fujitani:DaiichiSankyo: Employment. Tachibana:Daiichi Sankyo Co., Ltd: Employment. Yoshihara:Daiichi Sankyo Co., Ltd: Employment. Ishizuka:Daiichi Sankyo Co., Ltd: Employment.

Time course of platelet counts in relation to the neurologic outcome in patients undergoing targeted temperature management after cardiac arrest

BackgroundThrombocytopenia is common and associated with mortality in critically ill patients. However, the time course of platelet counts and its association with the neurologic outcome after out-of-hospital cardiac arrest (OHCA) are not well known. The purpose of this study is to describe the time course of platelet counts in relation to the neurologic outcome in patients undergoing targeted temperature management (TTM) after CA. MethodsReview of consecutive patients receiving TTM after out-of-hospital CA between 2009 and 2016. The blood sample was collected daily until 7 days. The primary outcome was poor neurologic outcome at 6 months after CA defined as Cerebral Performance Category of 3–5 and secondary outcome was mortality at 6 months. ResultsA total of 261 consecutive patients treated with TTM after OHCA between 2009 and 2016. One hundred seventy-five patients (67.0%) had poor neurologic outcomes 6 months after CA. The changes in the platelet counts over time between the good and poor outcome groups were statistically significant (p < 0.001). The platelet counts declined during TTM in both groups. The platelet counts recovered to the normal range at the end of the first week in the good neurologic outcome group. However, the platelet counts remained low in the poor outcome group. Low platelet counts on the 7th day were associated with poor neurologic outcomes (aOR 0.975, 95% CI, 0.961–0.989) and mortality at 6 months (aOR 0.986, 95% CI, 0.975–0.997) after adjusting for covariates. ConclusionThe changes in platelet counts in OHCA patients have a biphasic pattern that is significantly different in patients with good neurologic outcomes and those with poor neurologic outcomes at 6 months. A low platelet count 7 days after CA was associated with a poor neurologic outcome and mortality at 6 months.

Heparin-induced thrombocytopaenia diagnostic testing after adult cardiac surgery: a single-centre experience and development.

To assess the incidence and outcome of heparin-induced thrombocytopaenia (HIT) in patients after cardiac surgery on cardiopulmonary bypass (CPB) and to review the time course of platelet counts and the use of different immunological diagnostic tests. All patients ≥18 years of age who underwent CPB from 2006 to 2015 and who were postoperatively admitted to our cardiac intensive care unit (ICU) were included in this retrospective study. Screening for heparin/platelet factor-4 antibodies was performed using an antibody test, which was later replaced with a screening test specific for IgG antibodies without IgA/IgM cross-reactivity. The enzyme immunoassay (EIA) for the detection of antibodies of all immunoglobulin classes against heparin/PF4 complexes was replaced with an IgG-specific EIA. HIT was confirmed by a heparin-induced platelet aggregation test until 2014. Among 4978 patients admitted between 2006 and 2015, 539 (11%) patients were evaluated for HIT. Patients were excluded because of age <18 years (n = 9), non-cardiac surgery without CPB (n = 10) or incomplete data (n = 3). Of the remaining 517 patients, 43 (8.3%) patients were HIT-positive. HIT incidence was 0.86%. The proportion of HIT-positive patients was similar in men and women (8.4% and 8.2%, respectively). Men and women with suspected HIT also had similar in-hospital mortality (odds ratio ≈ 1; P = 0.926). The incidence of HIT was lower in our study than previously reported. Novel immunological tests have improved to specifically detect IgG antibodies. Furthermore, they are able to detect anti-protamine antibodies, which may be present in patients with high clinical probability of testing negative for HIT. Incidence and clinical relevance of heparin/protamine antibodies will be subjects of future investigation.

Romiplostim dose–response in patients with myelodysplastic syndromes

To characterize the romiplostim dose-response in subjects with low or intermediate-1 risk myelodysplastic syndromes (MDS) receiving subcutaneous romiplostim. Data from 44 MDS subjects receiving subcutaneous romiplostim (dose range 300-1500 μg week(-1) ) were used to develop a pharmacodynamic model consisting of a romiplostim-sensitive progenitor cell compartment linked to the peripheral blood compartment through four transit compartments representing the maturation in the bone marrow from megakaryocytes to platelets. A kinetics of drug effect model was used to quantify the stimulatory effect of romiplostim on the proliferation of sensitive progenitor cells and pharmacodynamics-mediated disposition was modelled by assuming the kinetics of drug effect constant (kDE ) to be proportional to the change in platelet count relative to baseline. The estimated values (between subject variability) for baseline platelet count, mean transit time, and kDE were 24 × 10(9) l(-1) (47%), 9.6 days (44%) and 0.28 days(-1) , respectively. MDS subjects had a shorter platelet lifespan (42 h) than healthy subjects (257 h). Romiplostim effect was described for responders (78%) and non-responders (22%). The average weekly stimulatory effect of romiplostim on the production rate of sensitive progenitor cells at baseline was 269% per 100 μg week(-1) for responders. Body weight, age, gender and race were not statistically related to romiplostim pharmacodynamic parameters. Visual predictive checks confirmed the model adequacy. The time course of platelet counts in MDS subjects receiving subcutaneous administration of escalating doses of romiplostim was characterized and showed a linear dose-response for romiplostim responders to increase the platelet counts.

Population PK/PD modeling of eltrombopag in subjects with advanced solid tumors with chemotherapy-induced thrombocytopenia

Eltrombopag, a thrombopoietin receptor agonist, is being evaluated for the treatment of chemotherapy-induced thrombocytopenia. Due to the delay in platelet response after the administration of eltrombopag or chemotherapy, a modeling and simulation approach was used to optimize the eltrombopag dosing regimen. Pharmacokinetic (PK) data from 2 studies in healthy subjects and PK and platelet data from a Phase II study in subjects with cancer receiving carboplatin/paclitaxel (where eltrombopag was given 10 days after chemotherapy) were used to develop a nonlinear mixed-effects PK/PD model. Alternative eltrombopag dosing regimens were then simulated. The PK model was a linear two-compartment model with first-order absorption. Being Asian, female, and >50 years of age were associated with higher eltrombopag exposure. The time course of platelet counts was described by a four-compartment transit model. Carboplatin inhibited platelet precursor production linearly with dose, with increased effect with each cycle of chemotherapy. Eltrombopag stimulated platelet precursor production, proportional to plasma eltrombopag concentration, and stimulation (slope of the concentration effect) was attenuated with each cycle of chemotherapy. Simulations indicated that eltrombopag administered 5 days before and 5 days after chemotherapy minimizes the decrease and fluctuations in platelet counts relative to other evaluated dosing regimens.

Platelets at a crossroad of pathogenic pathways in sepsis

Platelets at a crossroad of pathogenic pathways in sepsis

Time course of platelet counts in critically ill patients.

Although thrombocytopenia in the intensive care unit (ICU) is associated with a poorer outcome, the precise relationship between the time course of platelet counts and the mortality rate has not been well defined. To describe the time course of the platelet count in relation to the mortality rate in critically ill patients. Substudy of a prospective, multicenter, observational cohort analysis. Forty ICUs in 16 countries from Europe, America, and Australia. Data were collected from all ICU admissions in a 1-month period, excluding patients younger than 12 yrs old and those who stayed in the ICU for <48 hrs after uncomplicated surgery. A total of 1,449 critically ill patients were enrolled, including 257 who stayed in the ICU for >2 wks. None. Platelet counts were collected daily throughout the ICU stay, together with other measures of organ dysfunction. Thrombocytopenia was defined as a platelet count of <150 x 103/mm3. A relative increase in platelet count was defined as a 25% increase above the admission value, together with an absolute platelet count of > or =150 x 103/mm3. For the entire population, the platelet count was lower in the 313 nonsurvivors than in the 1,131 survivors throughout the ICU course. Of the 257 patients who stayed in the ICU for >2 wks, 187 (64%) survived. The platelet count decreased significantly in the first days after admission to reach a nadir on day 4 in both survivors and nonsurvivors. In the survivors, the platelet count returned to the admission value by the end of the first week and continued to rise to become significantly greater than the admission value by day 9. In the nonsurvivors, the platelet count also returned to the admission value after 1 wk, but there was no subsequent increase in platelet count. A total of 138 (54%) patients had thrombocytopenia on day 4, and these patients had a greater mortality rate than the other patients (33% vs. 16%; p <.05). On day 14, 51 (20%) patients had thrombocytopenia, and these patients had a greater mortality rate than the other patients (66% vs. 16%; p <.05). Thrombocytopenia was less common on day 14 than on day 4 (20% vs. 54%; p <.05), but the mortality rate was greater in the thrombocytopenic patients on day 14 than those who were thrombocytopenic on day 4 (66% vs. 33%; p <.05). The ICU mortality rate of nonthrombocytopenic patients on day 14 was also significantly lower in patients with, than without, a relative increase in platelet count on day 14 (11% vs. 30%; p <.05). Platelet count changes in the critically ill have a biphasic pattern that is different in survivors and nonsurvivors. Late thrombocytopenia is more predictive of death than early thrombocytopenia. A relative increase in platelet count after thrombocytopenia was present in survivors but not in nonsurvivors. Although a single measured platelet count is of little value for predicting outcome, changes in platelet count over time are related to patient outcome.

Effects of autologous platelet concentrate reinfusion after open heart surgery in patients with congenital heart disease

Background. Plsma pheresis and reinfusion of platelet-rich plasma has not been shown to reduce blood loss in cardiac patients. Recently, freshly prepared autologous platelet concentrates (PC) can be made from patient’s blood and has a higher concentration than conventional platelet rich plasma. In this study, the effects of autologous PC reinfusion were examined after open heart surgery in patients with congenital heart disease.Methods. Eight patients with noncyanotic congenital heart disease, who underwent open heart surgery and reinfusion of autologous PC, were classified as the PC group. Eight other patients with noncyanotic congenital heart disease, who underwent only open heart surgery, were defined as the control group. Ages ranged from 2 to 24 years and were not significantly different between the two groups (9.3 ± 5.1 years in the PC group and 12.6 ± 7.9 years in the control group, p = 0.33). In the PC group, blood was collected from the femoral vein through a 6F catheter introducer; 9 to 20 U (13.0 ± 5.4 U, 0.42 ± 0.22 U/kg) of autologous PC were prepared and were reinfused after protamine administration. The time course of platelet counts was examined until postoperative day 7. Aggregation responses to adenosine diphosphate; (4 μmol/L and 8 μmol/L), collagen (1 μmol/L and 5 μmol/L), and epinephrine (5 μmol/L and 10 μmol/L) were evaluated after induction of anesthesia (individual references), after protamine administration, at the end of the operation; these responses were shown as recovery ratios.Results. Blood loss during surgery in the PC group was significantly less than in the control group (4.8 ± 3.0 mL/kg versus 7.8 ± 1.7 mL/kg, p = 0.044). Similarly blood loss on postoperative day 1 in the PC group was significantly less than in the control group (3.6 ± 1.2 mL/kg versus 7.2 ± 3.1 mL/kg, p = 0.013). The platelet counts in the PC group were larger than those in the control group until postoperative day 5, after reinfusion of prepared autologous PC. The recovery ratios of the aggregation responses to adenosine diphosphate, collagen, and epinephrine after protamine administration were not significantly different between the two groups. However, recovery in the PC group after reinfusion of the prepared autologous PC was greater than in the control group.Conclusions. Reinfusion of the freshly prepared autologous PC was followed by good aggregation responses and low blood loss in patients with noncyanotic congenital heart disease after open heart surgery. This procedure may be useful in pediatric open heart surgery without blood transfusion or with little administration of homologous blood products.

Immune-mediated Thrombocytopenia is More Severe in Human FcγRIIa Transgenic Mice than in Wild-type Mice • 782

Human FcγRIIa is the platelet receptor for IgG. FcγRIIa is also expressed in man along with the FcγRI/γ and FcγRIIa/γ complexes on spleen macrophages. Mice lack an equivalent of FcγRIIa although it is likely to be a key receptor in immune-mediated thrombocytopenias. We established transgenic mouse lines that express human platelet FcγRIIa at levels equivalent to human platelets in order to determine if immune-mediated thrombocytopenia would be more severe in these transgenic mice which more fully recapitulate the human Fc receptor endowment. We showed that the human receptor is functional on mouse platelets using platelet aggregation stimulated by antibody in vitro. To determine whether this receptor was functional in vivo, we injected mice from this transgenic line with 70 μg of 4A5 antibody, a previously characterized rat anti-mouse platelet antibody found to cause moderate thrombocytopenia in wild type mice. We compared the transgenic mice to wild type mice. We followed the time course of platelet counts in mice injected with saline or isotype control (n=6 each) versus wild type mice (n=6) and FcγRIIa transgenic mice (n=9) receiving a single intraperitoneal dose of antibody on day 0. Intravenous injection gave comparable nadir platelet counts, with more rapid kinetics as expected. The average platelet count in wild type mice decreased to a nadir of 0.60 × 106 / μL on day 6 from a pre-treatment count of 1.13 × 106/ μL following injection of the antibody, in keeping with literature results on this antibody. In FcγRIIa transgenic mice there was a greater response to 4A5. The average count reached a nadir on day 6 after injection of 0.12 × 106 / μL (n = 9; statistically significantly different from wild-type, p < 0.05), while the pre-treatment and recovery counts of the transgenic mice were similar to the controls, with platelet counts of 0.96 × 106 / μL. In FcR γ-chain knockout mice which express no FcγRI or RIII, no 4A5-induced thrombocytopenia was seen (n = 6). Human FcγRIIa transgenic mice have more severe antibody-mediated thrombocytopenia in vivo, suggesting that the human FcγRIIa receptor is functional in vivo in these transgenic mice and contributes to the increased clearance of platelets. Our human FcγRIIa transgenic mice will be a valuable model of the pathophysiology and therapy of human immune-mediated thrombocytopenia disorders, including neonatal alloimmune thrombocytopenia.

Anticoagulant-induced Pseudothrombocytopenia and Pseudoleucocytosis

Pseudothrombocytopenia (PTP) is the phenomenon of falsely low platelet counts due to in vitro platelet clumping in the presence of platelet autoantibodies and anticoagulants. We assessed anticoagulant-dependence, time course of platelet counts and impact of different counter devices on the phenomenon. Blood of 10 persons with previously recognized pronounced EDTA-dependent PTP was collected into 7 different anticoagulants and counted after different intervals in parallel in a Coulter T540 and a Coulter STKS counter and by phase contrast microscopy. With the Coulter T540 model PTP was most pronounced in blood samples anticoagulated with EDTA, Na-oxalate or Na-citrate. In the STKS counter EDTA, heparin and oxalate presented as the worst anticoagulants. The time course of platelet counts was significantly different between the two counters. Our results demonstrate that PTP is not restricted to EDTA, but is also present with other anticoagulants. In contrast, pseudoleucocytosis was observed only in EDTA-anticoagulated blood in the Coulter T540 device. We investigated the expression of platelet integrins and activation antigens on platelets of persons with anticoagulant-dependent PTP and in healthy controls without PTP. In the presence of EDTA the expression of GpIIb/IIIa was significantly reduced in the PTP subjects compared to control. Activation antigens CD62, CD63 and thrombospondin-antigen were upregulated in the presence of EDTA. These alterations in the expression of platelet antigens could also be induced on platelets of normal donors by incubation with sera of PTP subjects and EDTA.(ABSTRACT TRUNCATED AT 250 WORDS)