A Dosing/Cross-Development Study of the Multikinase Inhibitor Sorafenib in Patients With Pulmonary Arterial Hypertension

Gomberg‐Maitland, Mardi; Maitland, Michael L.; Barst, Robyn J.; Sugeng, Lissa; Coslet, Sandra; Perrino, T J; Bond, Linda M; Lacouture, Mario E.; Archer, Stephen L.; Ratain, Mark J.

doi:10.1038/clpt.2009.217

Cited by 88 publications

(50 citation statements)

References 44 publications

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“…have observed a decrease in sorafenib exposure over a prolonged time; (ii) Hornecker et al 23. have recommended fractionated dosing to overcome saturable absorption; and (iii) Gomberg‐Maitland et al 38. recommended a dose of 200 mg b.i.d.…”

Section: Discussionmentioning

confidence: 99%

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

Liu

Ivaturi

Sabato

et al. 2018

Clinical Translational Sci

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Sorafenib administered at the approved dose continuously is not tolerated long‐term in patients with acute myeloid leukemia (AML). The purpose of this study was to optimize the dosing regimen by characterizing the sorafenib exposure‐response relationship in patients with AML. A one‐compartment model with a transit absorption compartment and enterohepatic recirculation described the exposure. The relationship between sorafenib exposure and target modulation of kinase targets (FMS‐like tyrosine kinase 3 (FLT3)‐ITD and extracellular signal‐regulated kinase (ERK)) were described by an inhibitory maximum effect (Emax) model. Sorafenib could inhibit FLT3‐ITD activity by 100% with an IC50 of 69.3 ng/mL and ERK activity by 84% with an IC50 of 85.7 ng/mL (both adjusted for metabolite potency). Different dosing regimens utilizing 200 or 400 mg at varying frequencies were simulated based on the exposure‐response relationship. Simulations demonstrate that a 200 mg twice daily (b.i.d.) dosing regimen showed similar FLT3‐ITD and ERK inhibitory activity compared with 400 mg b.i.d. and is recommended in further clinical trials in patients with AML.

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Section: Discussionmentioning

confidence: 99%

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

Liu

Ivaturi

Sabato

et al. 2018

Clinical Translational Sci

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“…These are crucial aspects for further research, particularly because broadspectrum tyrosine kinase inhibition may have pleiotropic effects on the cardiopulmonary system. Sorafenib, for instance, had detrimental effects on cardiac output in patients with PAH, 36 and dasatinib has been identified as a potential cause of PAH. 37 In conclusion, this study provides evidence that imatinib, as the first representative of a new class of drugs for the treatment of PAH, improves exercise capacity and hemodynamics in patients with advanced PAH who remain symptomatic on at least 2 drugs of the currently available 3 drug classes.…”

Section: Discussionmentioning

confidence: 99%

Imatinib Mesylate as Add-on Therapy for Pulmonary Arterial Hypertension

et al. 2013

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P ulmonary arterial hypertension (PAH) is characterized by progressive obliteration of the pulmonary vascular bed, eventually leading to right heart failure and death if not treated effectively.1,2 Although some forms of PAH are heritable or associated with other conditions such as scleroderma, many cases are idiopathic in origin. Editorial see p 1098 Clinical Perspective on p 1138The median survival of patients with idiopathic or heritable PAH was >3 years before the availability of targeted PAH drugs.4 Current treatment options consist of prostacyclin and Background-By its inhibitory effect on platelet-derived growth factor signaling, imatinib could be efficacious in treating patients with pulmonary arterial hypertension (PAH). Methods and Results-Imatinib in Pulmonary Arterial Hypertension, a Randomized, Efficacy Study (IMPRES), a randomized, double-blind, placebo-controlled 24-week trial, evaluated imatinib in patients with pulmonary vascular resistance ≥800 dyne·s·cm −5 symptomatic on ≥2 PAH therapies. The primary outcome was change in 6-minute walk distance. Secondary outcomes included changes in hemodynamics, functional class, serum levels of N-terminal brain natriuretic peptide, and time to clinical worsening. After completion of the core study, patients could enter an openlabel long-term extension study. Of 202 patients enrolled, 41% patients received 3 PAH therapies, with the remainder on 2 therapies. After 24 weeks, the mean placebo-corrected treatment effect on 6-minute walk distance was 32 m (95% confidence interval, 12-52; P=0.002), an effect maintained in the extension study in patients remaining on imatinib. Pulmonary vascular resistance decreased by 379 dyne·s·cm −5 (95% confidence interval, −502 to − 255; P<0.001, betweengroup difference). Functional class, time to clinical worsening, and mortality did not differ between treatments. Serious adverse events and discontinuations were more frequent with imatinib than placebo (44% versus 30% and 33% versus 18%, respectively). Subdural hematoma occurred in 8 patients (2 in the core study, 6 in the extension) receiving imatinib and anticoagulation. Conclusions-Imatinib improved exercise capacity and hemodynamics in patients with advanced PAH, but serious adverse events and study drug discontinuations were common.

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“…Studies in animal models of PAH showed that treatment with sorafenib resulted in improvements in haemodynamic parameters and attenuation of pulmonary hypertension [91], and prevention of pulmonary remodelling and improvement in cardiac and pulmonary function [60]. In a preliminary dosing study, 12 patients with advanced but stable PAH on parenteral prostanoids (with or without oral sildenafil) were initiated on 200 mg sorafenib daily (the lowest active dosage administered to cancer patients) with dose escalations to a final dosage of 400 mg twice daily [92]. Sorafenib was well tolerated at 200 mg twice daily, and is currently under investigation in a phase I safety and tolerability study in patients with PAH already on existing therapy with a prostacyclin with or without sildenafil [93].…”

Section: Terguridementioning

confidence: 99%

Looking to the future: a new decade of pulmonary arterial hypertension therapy

McLaughlin¹

2011

European Respiratory Review

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Pulmonary arterial hypertension (PAH) is a severe and debilitating disease characterised by vascular proliferation and remodelling of the small pulmonary arteries, leading to a progressive increase in pulmonary vascular resistance, increased afterload on the right ventricle and, ultimately, right heart failure. Although there is no "cure" for PAH, the availability of targeted therapies over the past decade has led to major advances in the management of PAH, reflected in improvements in survival in the modern treatment era. However, despite this, disease progression is inevitable in the majority of patients with PAH and overall the long-term prognosis, although improved, remains poor. There is a clear and urgent need for new therapeutic options, either through the development of improved drugs that act on targets established by existing PAH-specific therapies, or of agents targeting novel pathogenic pathways not addressed by currently available therapies. A number of such new agents that have shown promise in experimental models and preliminary human studies are discussed in this article.

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A Dosing/Cross-Development Study of the Multikinase Inhibitor Sorafenib in Patients With Pulmonary Arterial Hypertension

Cited by 88 publications

References 44 publications

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

Imatinib Mesylate as Add-on Therapy for Pulmonary Arterial Hypertension

Looking to the future: a new decade of pulmonary arterial hypertension therapy

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