Population Pharmacokinetics and Pharmacodynamics of Burosumab in Adult and Pediatric Patients With X-linked Hypophosphatemia.

Burosumab is a fully human monoclonal antibody against fibroblast growth factor 23, which has been approved to treat X-linked hypophosphatemia (XLH) in adult and pediatric patients. The present work describes the pharmacokinetics (PK) of burosumab and the pharmacokinetic-pharmacodynamic (PK-PD) relationship between burosumab and serum phosphorus in adult and pediatric patients with XLH. A total of 2844 measurable serum concentrations of burosumab and 6047 measurable serum concentrations of phosphorus in 277 subjects from 9 clinical studies were included in the population PK and PK-PD modeling. The serum concentration of burosumab following a subcutaneous administration was well described by a population PK model comprising a first-order absorption, 1-compartmental distribution, and a linear elimination. The relationship between serum burosumab and serum phosphorus was adequately described by a sigmoid maximal efficacy model. Body weight was the only covariate associated with PK and PK-PD parameters. No other intrinsic factors affected PK or PK-PD relationship in adult and pediatric patients with XLH. Further simulations helped to guide the dosing regimen of burosumab in adult and pediatric patients with XLH including age groups with no clinical data.

Co-administration of CSL112 (apolipoprotein A-I [human]) with atorvastatin and alirocumab is not associated with increased hepatotoxic or toxicokinetic effects in rats.

CSL112 (apolipoprotein A-I, apo AI [human]) is an investigational drug in Phase 3 development for risk reduction of early recurrent cardiovascular events following an acute myocardial infarction (AMI). Although CSL112 is known to be well tolerated with a regimen of four weekly 6 g intravenous infusions after AMI, high doses of reconstituted apo AI preparations can transiently elevate liver enzymes in rats, raising the possibility of additive liver toxicity and toxicokinetic (TK) effects upon co-administration with cholesterol-lowering drugs, i.e., HMG-CoA reductase and proprotein convertase subtilisin/kexin type 9 inhibitors. We performed a toxicity and TK study in CD rats assigned to eleven treatment groups, including two dose levels of intravenous (IV) CSL112 (140 mg/kg, low-dose; 600 mg/kg, high-dose) administered as a single dose, alone or with intravenous alirocumab 50 mg/kg/week and/or oral atorvastatin 10 mg/kg/day. In addition, control groups of atorvastatin and alirocumab alone and in combination were investigated. Results showed some liver enzyme elevations (remaining <2-fold of baseline) related to administration of CSL112 alone. There was limited evidence of an additive effect of CSL112 on liver enzymes when combined, at either dose level, with alirocumab and/or atorvastatin, and histology revealed no evidence of an increased incidence or severity of hepatocyte vacuolation compared to the control treatments. Co-administration of the study drugs had minimal effect on their respective exposure levels, and on levels of total cholesterol and high-density lipoprotein cholesterol. These data support concomitant use of CSL112 with alirocumab and/or atorvastatin with no anticipated negative impact on liver safety and TK.

Effect of emicizumab on global coagulation assays for plasma supplemented with apixaban or argatroban.

Emicizumab is a bi-specific humanized monoclonal antibody mimicking the factor (F) VIII cofactor activity in mediating the activation of FX by FIXa. Recent observations showed that emicizumab when added to pooled normal plasma (PNP), hemophilic plasma or PNP added with unfractionated heparin is able to interfere with coagulation assays. To further explore the mechanisms of assay interference we investigated the effect of emicizumab on global coagulation assays for the PNP added with two direct oral anticoagulants, apixaban or argatroban. Aliquots of PNP were added with purified apixaban or argatroban at a concentration of 500 ng/mL and emicizumab at concentrations ranging from 0 to 100 µg/mL. Plasma samples were then tested for the activated partial thromboplastin time (APTT) and for thrombin generation (the latter for the apixaban plasma only). Emicizumab at a 25-50 µg/mL shortened the APTT of the PNP with or without apixaban or argatroban. The extent of correction was greater for the apixaban or argatroban plasma and amounted to 35% or 42%, respectively. The parameters of thrombin generation (lag-time and time-to-peak) for the PNP supplemented with apixaban were shortened by 30% or 25%, respectively and the endogenous thrombin potential and the peak-thrombin were marginally affected. Emicizumab attenuates in vitro the anticoagulant activity of the PNP induced by apixaban or argatroban as documented by the correction of prolonged APTT and velocity of thrombin generation (i.e., lag-time and time-to-peak). Whether the above effects have any relevance in vivo is unknown.

Emicizumab for hemophilia A without inhibitors.

Introduction: Hemophilia A (HA) is an inherited bleeding disorder that, if not properly treated, is associated with debilitating joint damage due to recurrent hemarthroses as well as life-threatening bleeds including intracranial hemorrhage. For decades, the only method to prevent bleeding events was to infuse factor (F) VIII concentrates intravenously two to three times weekly. Although successful in reducing bleeding frequency, preventing a high proportion of joint disease, and extending life expectancy, standard continuous prophylaxis with FVIII is burdensome and insufficiently effective at preventing long-term joint dysfunction in some patients. In October 2018, the Federal Drug Administration approved a novel agent, emicizumab-kxwh, for the treatment of patients with HA without inhibitors. Areas covered: In this article, the preclinical and clinical development of emicizumab-kxwh will be reviewed. Data from licensure phase 3 clinical trials will be reviewed in detail discussing issues of both safety and efficacy. Expert opinion: As emicizumab-kxwh leads the way of a shift in treatment paradigm for patients with HA without inhibitors, a number of questions remain, including the impact of emicizumab-kxwh on joint and bone health, inhibitor development, and thrombotic risk. Ultimately, time and clinical investigation will be able to elucidate the influence of emicizumab-kxwh in these areas.

Pharmacokinetic Properties of Humanized IgG1 and IgG4 Antibodies in Preclinical Species: Translational Evaluation.

Assessment of the factors that regulate antibody exposure-response relationships in the relevant animal models is critical for the design of successful translational strategies from discovery to the clinic. Depending on the specific clinical indication, preclinical development paradigms may require that the efficacy or dosing-related attributes for the existing antibody be assessed in various species when cross-reactivity of the lead antibody to the intended species is justified. Additionally, with the success of monoclonal antibodies for management of various human conditions, a parallel interest in therapeutic use of these novel modalities in various veterinary species has followed. The protective role of neonatal Fc receptor (FcRn) in regulation of IgG homeostasis and clearance is now well recognized and the "nonspecific clearance" of antibodies through bone marrow-derived phagocytic and vascular endothelial cells (via lysosomal processes) is modulated by interactions with FcRn receptors. In this study, we have attempted to examine the PK properties of human IgG antibodies in dog and monkey. These studies establish a translational framework for evaluation of IgG antibody PK properties across species.

Lanadelumab for the Prophylactic Treatment of Hereditary Angioedema with C1 Inhibitor Deficiency: A Review of Preclinical and Phase I Studies.

Hereditary angioedema (HAE) with C1 esterase inhibitor (C1-INH) deficiency (C1-INH-HAE) is a rare disease characterized by diminished levels or dysfunctional activity of C1-INH, leading to dysregulated plasma kallikrein activity within the kallikrein-kinin pathway. Symptoms manifest as painful, potentially life-threatening swelling of subcutaneous tissues throughout the body and/or submucosal edema in the upper airway or gastrointestinal tract. Attacks recur with unpredictable frequency, intensity, and duration, placing a heavy burden on patients' daily lives. Despite improved availability of medications for on-demand treatment during attacks and prophylaxis of future attacks, unmet needs remain. Lanadelumab, a fully human monoclonal antibody, may help address some of the limitations of existing prophylactic options (e.g., the need for intravenous administration or frequent dosing). Preclinical studies demonstrate that it is highly potent and specifically inhibits plasma kallikrein, and findings from phase Ia and Ib studies suggest this agent is well tolerated and provides sustained inhibition of plasma kallikrein, allowing for less frequent dosing. The phase III HELP Study (NCT02586805) evaluating the efficacy and safety of lanadelumab in preventing HAE attacks has been completed, and its open-label extension (NCT02741596) is ongoing. Lanadelumab is now approved in the USA and Canada for prophylaxis to prevent attacks of HAE in patients aged ≥ 12 years. This review provides an overview of the discovery and clinical development of lanadelumab, from preclinical through phase Ib studies, characterizing its safety/tolerability, efficacy, and pharmacokinetic and pharmacodynamic profiles. It also highlights how this agent may positively impact clinical care of patients with C1-INH-HAE.

Farmacología de sarilumab en la artritis reumatoide / Pharmacology of sarilumab in rheumatoid arthritis

La interleucina (IL) 6 representa una diana de gran interés para el tratamiento de la artritis reumatoide. Un nuevo anticuerpo monoclonal dirigido frente a los receptores IL-6, sarilumab, se ha aprobado recientemente con esta finalidad en combinación con fármacos antirreumáticos modificadores de la enfermedad convencionales o en monoterapia en el caso de intolerancia a metotrexato o cuando su uso no sea apropiado. Este anticuerpo presenta una alta afinidad y actividad intrínseca para bloquear la señalización mediada por IL-6. Su larga vida media (inicial de 8-10 días y efectiva en estado estacionario de 21 días) y sus características de eliminación permiten disminuir la frecuencia de administraciones a cada 2 semanas manteniendo la eficacia. Los ensayos clínicos en fases I y II han aportado datos iniciales sobre la eficacia de las dosis de 150 y 200 mg de sarilumab administradas cada 2 semanas, que resultaron similares a los regímenes de una administración semanal (100 y 150 mg). Los cambios observados en los parámetros de seguridad fueron menos relevantes cuando sarilumab se administró cada 2 semanas. Estos resultados permitieron seleccionar las dosis de 150 y 200 mg cada 2 semanas para los ensayos clínicos en fase III con sarilumab. Sobre la base de los resultados de los estudios de fase I a III, las diferentes agencias recomiendan sarilumab 200 mg cada 2 semanas como la dosis de tratamiento de la artritis reumatoide y, en caso de anormalidades de laboratorio, esta puede administrarse reduciendo la dosis a 150 mg cada 2 semanas. La prolongada estabilidad de este anticuerpo monoclonal a temperatura ambiente (hasta 14 días, máximo 25 °C) también representa una importante ventaja para facilitar la administración del fármaco por parte de los pacientes

Inteleukin-6 (IL-6) represents a promising target for the treatment of rheumatoid arthritis. Sarilumab is a novel antibody targeting the IL-6 receptor that has been recently approved for the treatment of this disease in combination with conventional DMARDs or in monotherapy if there is intolerance to methotrexate. This antibody shows high affinity for the IL-6 receptor and intrinsic activity to block intracellular signalling mediated by IL-6. The long half-life (8 to 10 days initially and an effective half-life of 21 days at steady-state) and pharmacokinetic properties of sarilumab allow the frequency of administration to be reduced to every 2 weeks, while maintaining therapeutic efficacy. Phase I and II trials provided initial information about the efficacy of 150 and 200 mg of sarilumab administered once every two weeks, which was similar to once weekly administration regimens (100 and 150 mg). Changes in safety parameters were less significant when sarilumab was administered once every two weeks. These data allowed the choice of 150 and 200 mg of sarilumab administered every two weeks in the various phase III trials. Taking into account the results of phase I to III studies, the different regulatory agencies recommend a dose of 200 mg of sarilumab every two weeks for the treatment of rheumatoid arthritis, which can be reduced to 150 mg every two weeks if there are laboratory abnormalities. The long-term stability of this monoclonal antibody at room temperature (14 days at 25°C max) represents an additional advantage to facilitate patient management of the product

Review article: nonclinical and clinical pharmacology, pharmacokinetics and pharmacodynamics of etrolizumab, an anti-ß7 integrin therapy for inflammatory bowel disease.

BACKGROUND: Novel treatments with superior benefit-risk profiles are needed to improve the long-term prognosis of patients with inflammatory bowel disease (IBD). Etrolizumab-a monoclonal antibody that specifically targets ß7 integrins-is currently under phase III clinical evaluation in IBD. AIM: This review summarises the available pharmacological and pharmacokinetic/pharmacodynamic data for etrolizumab to provide a comprehensive understanding of its mechanism of action (MOA) and pharmacological effects. METHODS: Published and internal unpublished data from nonclinical and clinical studies with etrolizumab are reviewed. RESULTS: Etrolizumab exerts its effect via a unique dual MOA that inhibits both leucocyte trafficking to the intestinal mucosa and retention within the intestinal epithelial layer. The gut-selectivity of etrolizumab results from its specific targeting of the ß7 subunit of α4ß7 and αEß7 integrins. Etrolizumab does not bind to α4ß1 integrin, which mediates lymphocyte trafficking to tissues including the central nervous system, a characteristic underlying its favourable safety with regard to progressive multifocal leucoencephalopathy. Phase I/II studies in patients with ulcerative colitis (UC) showed linear pharmacokinetics when etrolizumab was administered subcutaneously at 100 mg or higher once every 4 weeks. This dose was sufficient to enable full ß7 receptor occupancy in both blood and intestinal tissues of patients with moderate to severe UC. The phase II study results also suggested that patients with elevated intestinal expression of αE integrin may have an increased likelihood of clinical remission in response to etrolizumab treatment. CONCLUSION: Etrolizumab is a gut-selective, anti-ß7 integrin monoclonal antibody that may have therapeutic potential for the treatment of IBD.

The role of elotuzumab in the treatment of relapsed or refractory multiple myeloma.

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy and safety, cost, and place in therapy of elotuzumab for treatment of relapsed or refractory multiple myeloma (MM) are reviewed. SUMMARY: Elotuzumab is a humanized monoclonal antibody that targets the signaling lymphocytic activation molecule (SLAM) protein SLAMF7 and facilitates an antibody-dependent cellular cytotoxicity interaction between myeloma cells and natural killer cells. Elotuzumab has U.S. marketing approval for use in combination with lenalidomide and dexamethasone in patients with relapsed or refractory MM who have received 1-3 previous therapies; this regimen is among the preferred regimens for relapsed or refractory MM recommended by the National Comprehensive Cancer Network (NCCN). A Phase III trial involving 321 patients demonstrated a median progression-free survival duration of 19.4 months with elotuzumab plus lenalidomide and dexamethasone versus 14.9 months with lenalidomide and dexamethasone alone (hazard ratio for progression or death, 0.70; 95% confidence interval, 0.57-0.85; p < 0.001). Common adverse effects of elotuzumab-lenalidomide-dexamethasone therapy include hematologic toxicities, fatigue, pyrexia, diarrhea, constipation, muscle spasms, and cough. Elotuzumab plus bortezomib and dexamethasone is an NCCN-recommended alternative option for relapsed or refractory MM. CONCLUSION: While elotuzumab plus lenalidomide and dexamethasone is a promising regimen for patients with MM, it is only one of several regimens recommended by NCCN for relapsed or refractory MM. Key factors in patient selection for elotuzumab therapy include adverse effects, prior treatments received, and cost considerations.

Idarucizumab: What Should We Know?

BACKGROUND: Idarucizumab, a humanized monoclonal antibody fragment acting as a specific antidote for dabigatran, is approved for reversing the dabigatran-associated possible bleeding from critical sites or bleeding persisting despite local post-procedure haemostasis. Moreover, it can also be applied to reverse the dabigatran anticoagulant activity in emergency surgery or in other invasive procedure at high risk of bleeding. OBJECTIVE: In this study, we discuss idarucizumab in light of the available literature data by conducting extensive research in the PubMed, EMBASE and Cochrane Library on the topic, using idarucizumab, dabigatran and their combinations as Mesh terms, and focusing on high impact investigations. RESULTS: Several studies have demonstrated the capacity of idarucizumab to reverse laboratory measures of dabigatran-associated coagulopathy, however its efficacy and safety in real world patients are still not very clear because of the scarcity of available data which should be assessed with an extensive post market surveillance. CONCLUSION: The introduction of idarucizumab as dabigatran antidote in clinical practice represents a useful tool for clinicians. The possibility to rapidly restore the anticoagulation activity of dabigatran makes its use simpler and more manageable.

Preclinical and Clinical Development of ABBV-8E12, a Humanized Anti-Tau Antibody, for Treatment of Alzheimer's Disease and Other Tauopathies.

Tau neurofibrillary tangles are found in the brains of patients suffering from Alzheimer's disease and other tauopathies. The progressive spreading of tau pathology from one brain region to the next is believed to be caused by extracellular transsynaptic transmission of misfolded tau between neurons. Preclinical studies have shown that antibodies against tau can prevent this transfer of misfolded tau between cells. Thus, antibodies against tau have the potential to stop or slow the progression of tau pathology observed in human tauopathies. To test this hypothesis, a humanized anti-tau antibody (ABBV-8E12) was developed and a phase 1 clinical trial of this antibody has been completed. The double-blind, placebo-controlled phase 1 study tested single doses of ABBV-8E12 ranging from 2.5 to 50 mg/kg in 30 patients with progressive supranuclear palsy (PSP). ABBV-8E12 was found to have an acceptable safety profile with no clinically concerning trends in the number or severity of adverse events between the placebo and dosed groups. Pharmacokinetic modelling showed that the antibody has a plasma half-life and cerebrospinal fluid:plasma ratio consistent with other humanized antibodies, and there were no signs of immunogenicity against ABBV-8E12. Based on the acceptable safety and tolerability profile of single doses of ABBV-8E12, AbbVie is currently enrolling patients into two phase 2 clinical trials to assess efficacy and safety of multiple doses of ABBV-8E12 in patients with early Alzheimer's disease or PSP.

Non invasive imaging assessment of the biodistribution of GSK2849330, an ADCC and CDC optimized anti HER3 mAb, and its role in tumor macrophage recruitment in human tumor-bearing mice.

The purpose of this work was to use various molecular imaging techniques to non-invasively assess GSK2849330 (anti HER3 ADCC and CDC enhanced 'AccretaMab' monoclonal antibody) pharmacokinetics and pharmacodynamics in human xenograft tumor-bearing mice. Immuno-PET biodistribution imaging of radiolabeled 89Zr-GSK2849330 was assessed in mice with HER3 negative (MIA-PaCa-2) and positive (CHL-1) human xenograft tumors. Dose dependency of GSK2849330 disposition was assessed using varying doses of unlabeled GSK2849330 co-injected with 89Zr-GSK2849330. In-vivo NIRF optical imaging and ex-vivo confocal microscopy were used to assess the biodistribution of GSK2849330 and the HER3 receptor occupancy in HER3 positive xenograft tumors (BxPC3, and CHL-1). Ferumoxytol (USPIO) contrast-enhanced MRI was used to investigate the effects of GSK2849330 on tumor macrophage content in CHL-1 xenograft bearing mice. Immuno-PET imaging was used to monitor the whole body drug biodistribution and CHL-1 xenograft tumor uptake up to 144 hours post injection of 89Zr-GSK2849330. Both hepatic and tumor uptake were dose dependent and saturable. The optical imaging data in the BxPC3 xenograft tumor confirmed the tumor dose response finding in the Immuno-PET study. Confocal microscopy showed a distinguished cytoplasmic punctate staining pattern within individual CHL-1 cells. GSK2849330 inhibited tumor growth and this was associated with a significant decrease in MRI signal to noise ratio after USPIO injection and with a significant increase in tumor macrophages as confirmed by a quantitative immunohistochemistry analysis. By providing both dose response and time course data from both 89Zr and fluorescently labeled GSK2849330, complementary imaging studies were used to characterize GSK2849330 biodistribution and tumor uptake in vivo. Ferumoxytol-enhanced MRI was used to monitor aspects of the immune system response to GSK2849330. Together these approaches potentially provide clinically translatable, non-invasive techniques to support dose optimization, and assess immune activation and anti-tumor responses.

[Monitoring of NOAC]. / Monitoring von NOAK.

BACKGROUND: Monitoring non-vitamin K antagonist oral anticoagulants (NOAC) is usually not necessary; however, in some patients it may prove beneficial. OBJECTIVES: Patient subgroups who may profit from monitoring were identified, and methods of monitoring (including assessment of which coagulation parameters are affected by NOAC) are described. MATERIALS AND METHODS: We searched the PubMed database for each of the search terms, "NOAC", "DOAC", "rivaroxaban", "dabigatran", and "apixaban", in combination with one of the terms, "monitoring", "measurement", "measuring", or "assessment". The results were compiled and reviewed. RESULTS: Monitoring is most advantageous in emergency cases with severe bleeding where drug activity needs to be assessed. It can also help in deciding for or against lysis therapy after acute stroke in patients taking NOAC. Furthermore, it can also identify compliance problems and help in planning periprocedural management. There are quantitative measurement methods which measure plasma concentrations exactly and qualitative methods which only allow for a rough estimate or a general confirmation of drug activity. Recommended quantitative measurement methods are diluted thrombin time for dabigatran, and anti-factor Xa activity (calibrated) for rivaroxaban and apixaban. CONCLUSIONS: Several patient subgroups may profit from monitoring of NOAC plasma concentration. One should, however, take several issues into consideration before measurements, such as the objective of each individual measurement, possible consequences (e. g., dose adjustment), and which measurement method to pick.

[Management of NOAK administration during invasive or surgical interventions : When and how to pause and when to restart?] / Steuerung der NOAK-Gabe bei invasiven oder operativen Interventionen : Wann bzw. wie pausieren und wann wieder starten?

Many patients under oral anticoagulation therapy need percutaneous or surgical interventions/operations. For vitamin K antagonists (VKA), there are recommendations regarding preoperative or postoperative administration. Management of the new oral anticoagulants (NOAC) was supposed to be easier - but some aspects must be considered. Due to the different pharmacokinetic profiles of substances such as dabigatran, rivaroxaban, apixaban, and edoxaban, different recommendations are given.Upon periprocedural management, thromboembolic risk has to be considered in patients treated with NOACs. NOACS have a pharmacokinetic advantage in terms of a rapid onset and rapid elimination via the liver and kidneys. Impaired renal function results in extended half-life of NOACs considerably.Surgical procedures under NOACS can be scheduled at the beginning of next dosing interval or omitted in low/minimal bleeding risk patients, so that only 2-3 NOAC doses are not administered. In patients with moderate and high risk of bleeding, there should be a NOAC break of 24-48 h prior to surgery in order to allow a corresponding decay of the active metabolite. In patients with low/intermediate risk for thromboembolism, no bridging is necessary if the "unprotected" time (NOAC break) is less than 4-5-(7) days. In patients at high risk of thromboembolism, individual consideration must be taken regarding bridging or extended NOAC break. Whether NOACs can be dispensed or bridging is necessary in these patients must be clarified in randomized trials for periprocedural management of NOACs patients.

Phase Ib study of codrituzumab in combination with sorafenib in patients with non-curable advanced hepatocellular carcinoma (HCC).

PURPOSE: Codrituzumab, a humanized antibody against glypican-3, is highly expressed in HCC. A phase I study evaluated the combination with sorafenib in HCC. PATIENTS AND METHODS: In a 3 + 3 design, codrituzumab was given intravenously in various doses with sorafenib 400 mg twice daily to patients with advanced HCC, age ≥18, ECOG 0-1, Child-Pugh A and B7, adequate organ functions, and no prior systemic therapy, with tumor assessment by RECIST 1.0 and safety by CTCAE 3.0. PK and pre, during, and post-therapy 124I radiolabeled codrituzumab PET scan imaging were performed. RESULTS: 41 patients were enrolled: 2.5 mg/kg weekly (qw) (12), 5 mg/kg qw (12), 10 mg/kg qw (3), 1600 mg every 2 weeks (q2w) (6), and 1600 mg qw (7). Two drug limiting toxicities occurred: grade 3 hyponatremia at 5 mg/kg and grade 3 hyponatremia and hyperglycemia at 1600 mg q2w. Adverse events occurred in 80% of patients, including at least one ≥grade 3: ten (25%) increased AST, three (7.5%) increased ALT, and ten (25%) increased lipase. There were no responses and nine (25.7%) had stable disease. PK C max and AUCt of codrituzumab and sorafenib were comparable to single-agent data. Thirteen out of 14 patients showed 124I radiolabeled codrituzumab uptake in tumor. In all three patients who underwent a post-progression PET, glypican-3 remained expressed. CONCLUSION: Codrituzumab plus sorafenib were tolerated at 1600 mg q2w and 400 mg bid, respectively, with no responses. Codrituzumab exerts selective distribution to HCC cells, and GPC3 does not show any down-regulation post-progression (NCT00976170).

Preclinical to Clinical Translation of Antibody-Drug Conjugates Using PK/PD Modeling: a Retrospective Analysis of Inotuzumab Ozogamicin.

A mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model was used for preclinical to clinical translation of inotuzumab ozogamicin, a CD22-targeting antibody-drug conjugate (ADC) for B cell malignancies including non-Hodgkin's lymphoma (NHL) and acute lymphocytic leukemia (ALL). Preclinical data was integrated in a PK/PD model which included (1) a plasma PK model characterizing disposition and clearance of inotuzumab ozogamicin and its released payload N-Ac-γ-calicheamicin DMH, (2) a tumor disposition model describing ADC diffusion into the tumor extracellular environment, (3) a cellular model describing inotuzumab ozogamicin binding to CD22, internalization, intracellular N-Ac-γ-calicheamicin DMH release, binding to DNA, or efflux from the tumor cell, and (4) tumor growth and inhibition in mouse xenograft models. The preclinical model was translated to the clinic by incorporating human PK for inotuzumab ozogamicin and clinically relevant tumor volumes, tumor growth rates, and values for CD22 expression in the relevant patient populations. The resulting stochastic models predicted progression-free survival (PFS) rates for inotuzumab ozogamicin in patients comparable to the observed clinical results. The model suggested that a fractionated dosing regimen is superior to a conventional dosing regimen for ALL but not for NHL. Simulations indicated that tumor growth is a highly sensitive parameter and predictive of successful outcome. Inotuzumab ozogamicin PK and N-Ac-γ-calicheamicin DMH efflux are also sensitive parameters and would be considered more useful predictors of outcome than CD22 receptor expression. In summary, a multiscale, mechanism-based model has been developed for inotuzumab ozogamicin, which can integrate preclinical biomeasures and PK/PD data to predict clinical response.

Reversal of dabigatran by idarucizumab: when and how?

INTRODUCTION: Anticoagulants are highly effective in reducing the risk of embolism in patients with atrial fibrillation and in the treatment of venous thromboembolism. However, interfering with the coagulation system increases the risk of bleeding. Non-vitamin K oral anticoagulants (NOACs) are associated with a reduced risk of major and life-threatening bleeding compared to warfarin, but the absence of a specific reversal agent has caused concern among clinicians. AREAS COVERED: This article describes the indications for and practical use of idarucizumab, a specific reversal agent for the direct thrombin inhibitor dabigatran. Expert commentary: Each year, 3-5% of anticoagulated patients will experience major bleeding and about 10% will require invasive interventions. While most of these situations can be managed without the need for a reversal agent, the ability to promptly switch off anticoagulant activity is likely beneficial in severe bleeding situations and can help to avoid delays and improve safety in the management of patients requiring urgent procedures. Idarucizumab rapidly and completely reverses the anticoagulant effect of dabigatran in vitro, in healthy volunteers, and in patients presenting with severe bleeding or requiring urgent procedures. Further clinical data will help to understand the clinical impact of rapid reversal on the outcome of bleeding patients.

Elotuzumab: First Global Approval.

Elotuzumab (Empliciti™) is a humanised IgG1 monoclonal antibody developed by Bristol-Myers Squibb (BMS) and AbbVie that has been approved as combination therapy with lenalidomide and dexamethasone for relapsed/refractory multiple myeloma in the US. Elotuzumab binds to the cell surface receptor signalling lymphocytic activation molecule F7 (SLAMF7), which is selectively expressed on myeloma cells and natural killer cells, leading to antibody-dependent cellular cytotoxicity and direct natural killer cell activation. In a phase III clinical trial, addition of elotuzumab to lenalidomide and dexamethasone therapy in patients with relapsed/refractory multiple myeloma was associated with a significant improvement in progression-free survival and overall response rate. This article summarizes the milestones in the development of elotuzumab leading to this first approval for relapsed/refractory multiple myeloma.

Bevacizumab: A dose review.

Angiogenesis is a key process in cancer development and has been described has a hallmark of cancer. Two dose-intensities were approved for cancer treatment by the Food and Drug Administration and European Medicines Agency: 2.5mg/kg/week dose equivalent and 5mg/kg/week dose equivalent. While bevacizumab has shown its effectiveness in clinical trials, pharmacodynamics is not fully understood and a dose-effect relationship has not been proven in vivo. Direct trials comparing high or low doses are rare with potential dose-effect toxicity. Discordant data have been reported on the efficacy of doses. This review discusses the dose of bevacizumab via the analysis of studies that led to the approval of bevacizumab in clinical practice. Optimization of doses schemes could reduce potential dose-effect toxicities, potentiate synergetic effects with chemotherapy and permit the prescription to a larger population with a better cost-effectiveness ratio.

Obinutuzumab: a review of its use in patients with chronic lymphocytic leukaemia.

Obinutuzumab (Gazyva(®); Gazyvaro(®)) is an intravenously administered, glycoengineered, humanized, type II, anti-CD20 monoclonal antibody of the IgG1 subclass. It is available in the EU and the USA as combination therapy with oral chlorambucil in adults with previously untreated chronic lymphocytic leukaemia (CLL). In a multinational phase III study in this patient population, obinutuzumab plus chlorambucil significantly prolonged progression-free survival compared with oral chlorambucil alone and intravenous rituximab plus oral chlorambucil. Significant advantages with obinutuzumab plus chlorambucil over chlorambucil alone and rituximab plus chlorambucil were also observed in event-free survival, the time to a new anti-leukaemia treatment and overall response. The overall survival benefit with obinutuzumab plus chlorambucil is as yet unclear, although the most recent analysis suggests a benefit over chlorambucil alone. In the phase III study, obinutuzumab plus chlorambucil had a manageable tolerability profile in accordance with what would be expected for an anti-CD20 antibody. Neutropenia and infusion-related reactions were the most frequently reported grade 3 or higher treatment-emergent adverse events. In the majority of patients, infusion-related reactions were mild to moderate in severity and occurred predominantly during the first infusion and were managed by slowing or temporarily halting the infusion. Thus, current evidence suggests that obinutuzumab plus chlorambucil is a welcome addition to the treatment options currently available for adults with previously untreated CLL and is recommended by the National Comprehensive Cancer Network guidelines as the preferred first option for some, including those with comorbidities.