MODELING AND SIMULATION (M&S) SUPPORT ELTROMBOPAG (EPAG) DOSAGE ESCALATION BASED ON PLATELET COUNT FOR PEDIATRIC PATIENTS WITH PERSISTENT OR CHRONIC IMMUNE THROMBOCYTOPENIA (CITP)
(Abstract release date: 05/19/16)
EHA Library. Grainger J. 06/09/16; 132969; E1420
Disclosure(s): JDG has received research funding from Baxter and has received honoraria from Amgen, Baxter, and GlaxoSmithKline (GSK); NS has no conflict of interest to disclose; MBW was an employee of GSK at the time of the study conduct and is currently an employee of Chimerix; VA is an employee of Novartis Pharma AG; WS is an employee of Novartis Pharmaceuticals Corporation; JZ is an employee of PAREXEL; JBB has been a consultant for Portola; received research funding from Amgen, Cangene, Eisai, Genzyme, GSK, IgG of America, Immunomedics, Ligand, Shionogi, and Sysmex; participated in advisory boards for Amgen, Eisai, GSK, Ligand, Shionogi, and Symphogen; and has received honoraria from Amgen, BMS, Cangene, GSK, Novartis, and Rigel.
Dr. J Grainger
Contributions
Contributions
Abstract
Abstract: E1420
Type: Eposter Presentation
Background
EPAG is approved for use in patients with persistent or cITP, chronic hepatitis C, and severe aplastic anemia. M&S supported EPAG dosing in adult populations (Gibiansky E et al. J Clin Pharmacol 2011; Hayes S et al. J Clin Pharmacol 2011; Wu K et al. J Clin Ther 2015; Zhang J et al. Pharm Res 2015).
Aims
To support initial EPAG doses and dose titration based on platelet count response in pediatric patients with cITP.
Methods
Plasma EPAG concentration and platelet count (PLTC) data collected in pediatric cITP patients in the PETIT & PETIT2 studies (Bussel JB et al. Lancet Haematol 2015; Grainger JD et al. Lancet 2015) were analyzed by nonlinear mixed-effects modeling. Patients received EPAG for ≥24 weeks. Doses were increased at 2-week intervals for PLTC <50 Gi/L, decreased for >200 Gi/L, and interrupted for >400 Gi/L. Serial pharmacokinetic (PK) samples were collected at Week 6 in PETIT. A single PK sample and PLTC were collected at all visits in both studies. A population PK (PPK) model was developed with PETIT data. Following successful external validation with data from PETIT2, data from both studies were combined to obtain final model parameter estimates. PLTC data were fitted alone using individual post-hoc PK parameter estimates. Simulations of PLTC for various starting doses and dose titration schedules were completed.
Results
The analyses included 168 patients (mean age 9.5 [1–17] years; weight 42.1 [11–135] kg; baseline PLTC 14 [1–38] Gi/L; 51% female; 20% East Asian; 6% splenectomized); 98% received prior ITP medication. Concurrent ITP medications were used at 17% of the PLTC assessments. PK was described by a 2-compartment model. Inter-individual variation (IIV) was included on apparent clearance (CL/F), intercompartmental exchange/clearance rate (Q/F), distribution volume of central compartment (Vc/F), and inter-occasion variability (IOV) on CL/F. Typical values were CL/F=0.612 L/h, Vc/F=2.74 L, Q/F=0.716 L, distribution volume of peripheral compartment (Vp/F)=21.5 L, and Ka=0.189/h. The final PPK/pharmacodynamics (PD) model was a 7-compartment life-span model, including 3 PK and 4 PD compartments. Zero-order production rate of platelet precursors (KIN) was fixed to the value from adult healthy volunteers (KIN=1.43 Gi/L/h). The increase in KIN due to EPAG was linearly related to plasma EPAG concentrations by the parameter SLOP (ie, linear coefficient of drug effect on KIN). SLOP, first-order maturation rate of platelet precursors (KOUT), and proportion of patients identified as responders (P1) were estimated; IIV was included on SLOP and KOUT. Typical PD parameter values were P1=0.96, SLOP=0.651 mL/µg in responders, and KOUT=0.0126/h, and increased with age. The average platelet half-life was 7 h. A majority of patients, as also seen in PETIT/PETIT2, required dose escalation to achieve target platelet response.
Conclusion
M&S supports eltrombopag starting doses and dose adjustments based on platelet counts in children with cITP. A majority of children require dose escalation from eltrombopag starting doses to achieve platelet thresholds ≥50 Gi/L. Higher starting doses may need to be considered when clinically indicated such as in cases of severe bleeding or pending surgery. Studies NCT00908037/NCT01520909 were sponsored by GlaxoSmithKline; EPAG became an asset of Novartis AG as of March 2, 2015.
Session topic: E-poster
Keyword(s): Immune thrombocytopenia (ITP), Pediatric, Pharmacokinetic
Type: Eposter Presentation
Background
EPAG is approved for use in patients with persistent or cITP, chronic hepatitis C, and severe aplastic anemia. M&S supported EPAG dosing in adult populations (Gibiansky E et al. J Clin Pharmacol 2011; Hayes S et al. J Clin Pharmacol 2011; Wu K et al. J Clin Ther 2015; Zhang J et al. Pharm Res 2015).
Aims
To support initial EPAG doses and dose titration based on platelet count response in pediatric patients with cITP.
Methods
Plasma EPAG concentration and platelet count (PLTC) data collected in pediatric cITP patients in the PETIT & PETIT2 studies (Bussel JB et al. Lancet Haematol 2015; Grainger JD et al. Lancet 2015) were analyzed by nonlinear mixed-effects modeling. Patients received EPAG for ≥24 weeks. Doses were increased at 2-week intervals for PLTC <50 Gi/L, decreased for >200 Gi/L, and interrupted for >400 Gi/L. Serial pharmacokinetic (PK) samples were collected at Week 6 in PETIT. A single PK sample and PLTC were collected at all visits in both studies. A population PK (PPK) model was developed with PETIT data. Following successful external validation with data from PETIT2, data from both studies were combined to obtain final model parameter estimates. PLTC data were fitted alone using individual post-hoc PK parameter estimates. Simulations of PLTC for various starting doses and dose titration schedules were completed.
Results
The analyses included 168 patients (mean age 9.5 [1–17] years; weight 42.1 [11–135] kg; baseline PLTC 14 [1–38] Gi/L; 51% female; 20% East Asian; 6% splenectomized); 98% received prior ITP medication. Concurrent ITP medications were used at 17% of the PLTC assessments. PK was described by a 2-compartment model. Inter-individual variation (IIV) was included on apparent clearance (CL/F), intercompartmental exchange/clearance rate (Q/F), distribution volume of central compartment (Vc/F), and inter-occasion variability (IOV) on CL/F. Typical values were CL/F=0.612 L/h, Vc/F=2.74 L, Q/F=0.716 L, distribution volume of peripheral compartment (Vp/F)=21.5 L, and Ka=0.189/h. The final PPK/pharmacodynamics (PD) model was a 7-compartment life-span model, including 3 PK and 4 PD compartments. Zero-order production rate of platelet precursors (KIN) was fixed to the value from adult healthy volunteers (KIN=1.43 Gi/L/h). The increase in KIN due to EPAG was linearly related to plasma EPAG concentrations by the parameter SLOP (ie, linear coefficient of drug effect on KIN). SLOP, first-order maturation rate of platelet precursors (KOUT), and proportion of patients identified as responders (P1) were estimated; IIV was included on SLOP and KOUT. Typical PD parameter values were P1=0.96, SLOP=0.651 mL/µg in responders, and KOUT=0.0126/h, and increased with age. The average platelet half-life was 7 h. A majority of patients, as also seen in PETIT/PETIT2, required dose escalation to achieve target platelet response.
Conclusion
M&S supports eltrombopag starting doses and dose adjustments based on platelet counts in children with cITP. A majority of children require dose escalation from eltrombopag starting doses to achieve platelet thresholds ≥50 Gi/L. Higher starting doses may need to be considered when clinically indicated such as in cases of severe bleeding or pending surgery. Studies NCT00908037/NCT01520909 were sponsored by GlaxoSmithKline; EPAG became an asset of Novartis AG as of March 2, 2015.
Session topic: E-poster
Keyword(s): Immune thrombocytopenia (ITP), Pediatric, Pharmacokinetic
Abstract: E1420
Type: Eposter Presentation
Background
EPAG is approved for use in patients with persistent or cITP, chronic hepatitis C, and severe aplastic anemia. M&S supported EPAG dosing in adult populations (Gibiansky E et al. J Clin Pharmacol 2011; Hayes S et al. J Clin Pharmacol 2011; Wu K et al. J Clin Ther 2015; Zhang J et al. Pharm Res 2015).
Aims
To support initial EPAG doses and dose titration based on platelet count response in pediatric patients with cITP.
Methods
Plasma EPAG concentration and platelet count (PLTC) data collected in pediatric cITP patients in the PETIT & PETIT2 studies (Bussel JB et al. Lancet Haematol 2015; Grainger JD et al. Lancet 2015) were analyzed by nonlinear mixed-effects modeling. Patients received EPAG for ≥24 weeks. Doses were increased at 2-week intervals for PLTC <50 Gi/L, decreased for >200 Gi/L, and interrupted for >400 Gi/L. Serial pharmacokinetic (PK) samples were collected at Week 6 in PETIT. A single PK sample and PLTC were collected at all visits in both studies. A population PK (PPK) model was developed with PETIT data. Following successful external validation with data from PETIT2, data from both studies were combined to obtain final model parameter estimates. PLTC data were fitted alone using individual post-hoc PK parameter estimates. Simulations of PLTC for various starting doses and dose titration schedules were completed.
Results
The analyses included 168 patients (mean age 9.5 [1–17] years; weight 42.1 [11–135] kg; baseline PLTC 14 [1–38] Gi/L; 51% female; 20% East Asian; 6% splenectomized); 98% received prior ITP medication. Concurrent ITP medications were used at 17% of the PLTC assessments. PK was described by a 2-compartment model. Inter-individual variation (IIV) was included on apparent clearance (CL/F), intercompartmental exchange/clearance rate (Q/F), distribution volume of central compartment (Vc/F), and inter-occasion variability (IOV) on CL/F. Typical values were CL/F=0.612 L/h, Vc/F=2.74 L, Q/F=0.716 L, distribution volume of peripheral compartment (Vp/F)=21.5 L, and Ka=0.189/h. The final PPK/pharmacodynamics (PD) model was a 7-compartment life-span model, including 3 PK and 4 PD compartments. Zero-order production rate of platelet precursors (KIN) was fixed to the value from adult healthy volunteers (KIN=1.43 Gi/L/h). The increase in KIN due to EPAG was linearly related to plasma EPAG concentrations by the parameter SLOP (ie, linear coefficient of drug effect on KIN). SLOP, first-order maturation rate of platelet precursors (KOUT), and proportion of patients identified as responders (P1) were estimated; IIV was included on SLOP and KOUT. Typical PD parameter values were P1=0.96, SLOP=0.651 mL/µg in responders, and KOUT=0.0126/h, and increased with age. The average platelet half-life was 7 h. A majority of patients, as also seen in PETIT/PETIT2, required dose escalation to achieve target platelet response.
Conclusion
M&S supports eltrombopag starting doses and dose adjustments based on platelet counts in children with cITP. A majority of children require dose escalation from eltrombopag starting doses to achieve platelet thresholds ≥50 Gi/L. Higher starting doses may need to be considered when clinically indicated such as in cases of severe bleeding or pending surgery. Studies NCT00908037/NCT01520909 were sponsored by GlaxoSmithKline; EPAG became an asset of Novartis AG as of March 2, 2015.
Session topic: E-poster
Keyword(s): Immune thrombocytopenia (ITP), Pediatric, Pharmacokinetic
Type: Eposter Presentation
Background
EPAG is approved for use in patients with persistent or cITP, chronic hepatitis C, and severe aplastic anemia. M&S supported EPAG dosing in adult populations (Gibiansky E et al. J Clin Pharmacol 2011; Hayes S et al. J Clin Pharmacol 2011; Wu K et al. J Clin Ther 2015; Zhang J et al. Pharm Res 2015).
Aims
To support initial EPAG doses and dose titration based on platelet count response in pediatric patients with cITP.
Methods
Plasma EPAG concentration and platelet count (PLTC) data collected in pediatric cITP patients in the PETIT & PETIT2 studies (Bussel JB et al. Lancet Haematol 2015; Grainger JD et al. Lancet 2015) were analyzed by nonlinear mixed-effects modeling. Patients received EPAG for ≥24 weeks. Doses were increased at 2-week intervals for PLTC <50 Gi/L, decreased for >200 Gi/L, and interrupted for >400 Gi/L. Serial pharmacokinetic (PK) samples were collected at Week 6 in PETIT. A single PK sample and PLTC were collected at all visits in both studies. A population PK (PPK) model was developed with PETIT data. Following successful external validation with data from PETIT2, data from both studies were combined to obtain final model parameter estimates. PLTC data were fitted alone using individual post-hoc PK parameter estimates. Simulations of PLTC for various starting doses and dose titration schedules were completed.
Results
The analyses included 168 patients (mean age 9.5 [1–17] years; weight 42.1 [11–135] kg; baseline PLTC 14 [1–38] Gi/L; 51% female; 20% East Asian; 6% splenectomized); 98% received prior ITP medication. Concurrent ITP medications were used at 17% of the PLTC assessments. PK was described by a 2-compartment model. Inter-individual variation (IIV) was included on apparent clearance (CL/F), intercompartmental exchange/clearance rate (Q/F), distribution volume of central compartment (Vc/F), and inter-occasion variability (IOV) on CL/F. Typical values were CL/F=0.612 L/h, Vc/F=2.74 L, Q/F=0.716 L, distribution volume of peripheral compartment (Vp/F)=21.5 L, and Ka=0.189/h. The final PPK/pharmacodynamics (PD) model was a 7-compartment life-span model, including 3 PK and 4 PD compartments. Zero-order production rate of platelet precursors (KIN) was fixed to the value from adult healthy volunteers (KIN=1.43 Gi/L/h). The increase in KIN due to EPAG was linearly related to plasma EPAG concentrations by the parameter SLOP (ie, linear coefficient of drug effect on KIN). SLOP, first-order maturation rate of platelet precursors (KOUT), and proportion of patients identified as responders (P1) were estimated; IIV was included on SLOP and KOUT. Typical PD parameter values were P1=0.96, SLOP=0.651 mL/µg in responders, and KOUT=0.0126/h, and increased with age. The average platelet half-life was 7 h. A majority of patients, as also seen in PETIT/PETIT2, required dose escalation to achieve target platelet response.
Conclusion
M&S supports eltrombopag starting doses and dose adjustments based on platelet counts in children with cITP. A majority of children require dose escalation from eltrombopag starting doses to achieve platelet thresholds ≥50 Gi/L. Higher starting doses may need to be considered when clinically indicated such as in cases of severe bleeding or pending surgery. Studies NCT00908037/NCT01520909 were sponsored by GlaxoSmithKline; EPAG became an asset of Novartis AG as of March 2, 2015.
Session topic: E-poster
Keyword(s): Immune thrombocytopenia (ITP), Pediatric, Pharmacokinetic
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