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      Dose Selection Based on Modeling and Simulation for Rivipansel in Pediatric Patients Aged 6 to 11 Years With Sickle Cell Disease

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      1 , 2 ,
      CPT: Pharmacometrics & Systems Pharmacology
      John Wiley and Sons Inc.

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          Abstract

          This modeling and simulation exercise aimed to provide dosing recommendations for rivipansel phase III studies in children aged 6–11 years with sickle cell disease (SCD). Pharmacokinetic data from 109 patients aged 12–51 years who received rivipansel (2–40 mg/kg) in previous studies (three phase I and one phase II) were integrated to build a three‐compartmental simulation model. Renal clearance simulations across the age range accounted for renal function development and postulated hyperfiltration in SCD. Simulated demographic distributions for the pediatric SCD population were used to predict concentration‐time profiles from three dosing regimens, which were then compared against efficacious average steady‐state concentrations observed in phase II. A dosing regimen comprising a 40‐mg/kg loading dose followed by a 20‐mg/kg maintenance dose every 12 hours was selected, as it will likely provide an efficacious concentration range. Its validity will be confirmed in the ongoing phase III study.

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          Most cited references20

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          Prediction of creatinine clearance from serum creatinine.

          A formula has been developed to predict creatinine clearance (Ccr) from serum creatinine (Scr) in adult males: (see article)(15% less in females). Derivation included the relationship found between age and 24-hour creatinine excretion/kg in 249 patients aged 18-92. Values for Ccr were predicted by this formula and four other methods and the results compared with the means of two 24-hour Ccr's measured in 236 patients. The above formula gave a correlation coefficient between predicted and mean measured Ccr's of 0.83; on average, the difference predicted and mean measured values was no greater than that between paired clearances. Factors for age and body weight must be included for reasonable prediction.
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            Vasculopathy in sickle cell disease: Biology, pathophysiology, genetics, translational medicine, and new research directions.

            Sickle cell disease has been very well characterized as a single amino acid molecular disorder of hemoglobin leading to its pathological polymerization, with resulting red cell rigidity that causes poor microvascular blood flow, with consequent tissue ischemia and infarction. More recently, an independent spectrum of pathophysiology of blood vessel function has been demonstrated, involving abnormal vascular tone and activated, adhesive endothelium. These vasculopathic abnormalities are attributable to pathways involving hemolysis-associated defects in nitric oxide bioavailability, oxidative stress, ischemia-reperfusion injury, hemostatic activation, leukocytes and platelets. Vasculopathy of sickle cell disease has been implicated in the development of pulmonary hypertension, stroke, leg ulceration and priapism, particularly associated with hemolytic severity, and reported also in other severe hemolytic disorders. This vasculopathy might also play a role in other chronic organ dysfunction in patients with sickle cell disease. These pathways present novel targets for pharmacologic intervention, and several clinical trials are already under way. The authors present their perspectives of a workshop held at the National Institutes of Health in August 2008 on vasculopathy in sickle cell disease, along with meritorious future scientific questions on the topic of vascular complications of sickle cell disease.
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              The endothelial biology of sickle cell disease: inflammation and a chronic vasculopathy.

              A single amino acid substitution in hemoglobin comprises the molecular basis for sickle cell anemia, but evolution of the corresponding clinical disease is extraordinarily complicated and likely involves multiple pathogenic factors. Sickle disease is fundamentally an inflammatory state, with activation of the endothelium, probably through proximate effects of reperfusion injury physiology and chronic molestation by adherent red cells and white cells. The disease also involves enhanced angiogenic propensity, activation of coagulation, disordered vasoregulation, and a component of chronic vasculopathy. Sickle cell anemia is truly an endothelial disease, and it is likely that genetic differences in endothelial function help govern its astonishing phenotypic diversity.
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                Author and article information

                Contributors
                Lutz.O.Harnisch@pfizer.com
                Journal
                CPT Pharmacometrics Syst Pharmacol
                CPT Pharmacometrics Syst Pharmacol
                10.1002/(ISSN)2163-8306
                PSP4
                CPT: Pharmacometrics & Systems Pharmacology
                John Wiley and Sons Inc. (Hoboken )
                2163-8306
                06 December 2017
                December 2017
                : 6
                : 12 ( doiID: 10.1002/psp4.v6.12 )
                : 845-854
                Affiliations
                [ 1 ] Pfizer, Collegeville Pennsylvania USA
                [ 2 ] Pfizer, Sandwich UK
                Author notes
                [*] [* ]Correspondence: L O Harnisch ( Lutz.O.Harnisch@ 123456pfizer.com )
                Article
                PSP412263
                10.1002/psp4.12263
                5744176
                29115052
                cdc84020-f54e-4cab-a682-29b3338596ed
                © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 06 July 2017
                : October 2017
                : 23 October 2017
                Page count
                Figures: 6, Tables: 1, Pages: 10, Words: 6654
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                psp412263
                December 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.2.8 mode:remove_FC converted:27.12.2017

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