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Michael Z Liao, 1 Marloes Berkhout, 2 Hans Prenen, 3 Sandeep Dutta, 4 Vijay V Upreti 1 1Clinical Pharmacology, Modeling & Simulation, Amgen Inc., South San Francisco, CA, USA; 2Medical Development, Amgen B.V, Breda, the Netherlands; 3Department of Medical Oncology, University Hospital Antwerp, Edegem, Belgium; 4Clinical Pharmacology, Modeling & Simulation, Amgen Inc., Thousand Oaks, CA, USACorrespondence: Vijay V UpretiClinical Pharmacology, Modeling & Simulation, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USAFax +1 650-837-9421Email vupreti@amgen.comIntroduction: Body weight can affect exposure, safety and efficacy of antibody-based therapies; sometimes these effects may not be clinically relevant. Panitumumab is approved for wild-type RAS metastatic colorectal cancer, using a body weight–based dosing regimen. Recently, a report cited fixed-dose usage of panitumumab, rather than approved body weight–based dosing. The current work evaluates optimal dosing regimen scientifically based on clinical data, modeling and simulation. Herein, we assessed the effect of fixed and body weight–based dosing on panitumumab pharmacokinetics to determine which approach resulted in the least interpatient pharmacokinetic variability.Patients and Methods: From the Vectibix program, 352 patients enrolled in three studies were evaluated; they had received panitumumab (body weight–based dose: 6 mg/kg every 2 weeks) and had pharmacokinetic (maximum serum [Cmax] and trough [Cmin] concentrations) and body weight data available. Additionally, concentration-time profiles at fixed (480 mg) and body weight–based doses (6 mg/kg) were simulated using a population pharmacokinetics model developed from 1200 patients.Results: After administration of panitumumab 6 mg/kg, Cmax and Cmin increased with increasing body weight; the mean Cmax and Cmin for patients weighing < 65 kg (lower quartile) were

Michael Z Liao,1 Johannes Kast,1 Marloes Berkhout,2 Hans Prenen,3 Sandeep Dutta,4 Vijay V Upreti1 1Clinical Pharmacology, Modeling & Simulation, Amgen Inc., South San Francisco, CA, USA; 2Amgen B.V., Breda, the Netherlands; 3Antwerp University Hospital, Edegem, Belgium; 4Clinical Pharmacology, Modeling & Simulation, Amgen Inc., Thousand Oaks, CA, USACorrespondence: Vijay V UpretiClinical Pharmacology, Modeling & Simulation, Amgen, 1120 Veterans Boulevard, South San Francisco, CA 94080, USAEmail vupreti@amgen.com Thank you for the opportunity to respond to the letter by Dr. Hendrikx and colleagues. We wish to thank Dr. Hendrikx and colleagues for their interest in our recent publication by Liao et al1 and their comments about the optimal dosing regimen for panitumumab. The body weight-based dosing, 6 mg/kg once every two-week (Q2W) regimen, for panitumumab as an optimal dosing regimen is fully supported by clinical study data and pharmacokinetic modeling and simulations.2   View the original paper by Liao and colleagues   This is in response to the Letter to the Editor

Michael Z Liao, 1 Marloes Berkhout, 2 Hans Prenen, 3 Sandeep Dutta, 4 Vijay V Upreti 1 1Clinical Pharmacology, Modeling & Simulation, Amgen Inc., South San Francisco, CA, USA; 2Medical Development, Amgen B.V, Breda, the Netherlands; 3Department of Medical Oncology, University Hospital Antwerp, Edegem, Belgium; 4Clinical Pharmacology, Modeling & Simulation, Amgen Inc., Thousand Oaks, CA, USACorrespondence: Vijay V UpretiClinical Pharmacology, Modeling & Simulation, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USAFax +1 650-837-9421Email vupreti@amgen.comIntroduction: Body weight can affect exposure, safety and efficacy of antibody-based therapies; sometimes these effects may not be clinically relevant. Panitumumab is approved for wild-type RAS metastatic colorectal cancer, using a body weight–based dosing regimen. Recently, a report cited fixed-dose usage of panitumumab, rather than approved body weight–based dosing. The current work evaluates optimal dosing regimen scientifically based on clinical data, modeling and simulation. Herein, we assessed the effect of fixed and body weight–based dosing on panitumumab pharmacokinetics to determine which approach resulted in the least interpatient pharmacokinetic variability.Patients and Methods: From the Vectibix program, 352 patients enrolled in three studies were evaluated; they had received panitumumab (body weight–based dose: 6 mg/kg every 2 weeks) and had pharmacokinetic (maximum serum [Cmax] and trough [Cmin] concentrations) and body weight data available. Additionally, concentration-time profiles at fixed (480 mg) and body weight–based doses (6 mg/kg) were simulated using a population pharmacokinetics model developed from 1200 patients.Results: After administration of panitumumab 6 mg/kg, Cmax and Cmin increased with increasing body weight; the mean Cmax and Cmin for patients weighing < 65 kg (lower quartile) were

Michael Z Liao,1 Johannes Kast,1 Marloes Berkhout,2 Hans Prenen,3 Sandeep Dutta,4 Vijay V Upreti1 1Clinical Pharmacology, Modeling & Simulation, Amgen Inc., South San Francisco, CA, USA; 2Amgen B.V., Breda, the Netherlands; 3Antwerp University Hospital, Edegem, Belgium; 4Clinical Pharmacology, Modeling & Simulation, Amgen Inc., Thousand Oaks, CA, USACorrespondence: Vijay V UpretiClinical Pharmacology, Modeling & Simulation, Amgen, 1120 Veterans Boulevard, South San Francisco, CA 94080, USAEmail vupreti@amgen.com Thank you for the opportunity to respond to the letter by Dr. Hendrikx and colleagues. We wish to thank Dr. Hendrikx and colleagues for their interest in our recent publication by Liao et al1 and their comments about the optimal dosing regimen for panitumumab. The body weight-based dosing, 6 mg/kg once every two-week (Q2W) regimen, for panitumumab as an optimal dosing regimen is fully supported by clinical study data and pharmacokinetic modeling and simulations.2   View the original paper by Liao and colleagues   This is in response to the Letter to the Editor

Vijay V Upreti,1 Yan Song,1 Jessie Wang,2 Wonkyung Byon,3 Rebecca A Boyd,3 Janice M Pursley,4 Frank LaCreta,1 Charles E Frost1 1Clinical Pharmacology and Pharmacometrics, Discovery Medicine and Clinical Pharmacology, 2Exploratory Development Global Biometric Sciences, Bristol-Myers Squibb, Princeton, NJ, 3Primary Care Clinical Pharmacology, Pfizer, Groton, CT, 4Analytical and Bioanalytical Department, Bristol-Myers Squibb, Princeton, NJ, USA Background: Apixaban is an oral, selective, direct factor Xa inhibitor approved for thromboprophylaxis after orthopedic surgery and stroke prevention in patients with atrial fibrillation, and under development for treatment of venous thromboembolism. This study investigated the effect of a gastric acid suppressant, famotidine (a histamine H2-receptor antagonist), on the pharmacokinetics of apixaban in healthy subjects. Methods: This two-period, two-treatment crossover study randomized 18 healthy subjects to receive a single oral dose of apixaban 10 mg with and without a single oral dose of famotidine 40 mg administered 3 hours before dosing with apixaban. Plasma apixaban concentrations were measured up to 60 hours post-dose and pharmacokinetic parameters were calculated. Results: Famotidine did not affect maximum apixaban plasma concentration (Cmax) or area under the plasma concentration-time curve from zero to infinite time (AUC∞). Point estimates for ratios of geometric means with and without famotidine were close to unity for Cmax (0.978) and AUC∞ (1.007), and 90% confidence intervals were entirely contained within the 80%–125% no-effect interval. Administration of apixaban alone and with famotidine was well tolerated. Conclusion: Famotidine does not affect the pharmacokinetics of apixaban, consistent with the physicochemical properties of apixaban (lack of an ionizable group and pH-independent solubility). Apixaban pharmacokinetics would not be affected by an increase in gastrointestinal pH due

Vijay V Upreti,1 Yan Song,1 Jessie Wang,2 Wonkyung Byon,3 Rebecca A Boyd,3 Janice M Pursley,4 Frank LaCreta,1 Charles E Frost1 1Clinical Pharmacology and Pharmacometrics, Discovery Medicine and Clinical Pharmacology, 2Exploratory Development Global Biometric Sciences, Bristol-Myers Squibb, Princeton, NJ, 3Primary Care Clinical Pharmacology, Pfizer, Groton, CT, 4Analytical and Bioanalytical Department, Bristol-Myers Squibb, Princeton, NJ, USA Background: Apixaban is an oral, selective, direct factor Xa inhibitor approved for thromboprophylaxis after orthopedic surgery and stroke prevention in patients with atrial fibrillation, and under development for treatment of venous thromboembolism. This study investigated the effect of a gastric acid suppressant, famotidine (a histamine H2-receptor antagonist), on the pharmacokinetics of apixaban in healthy subjects. Methods: This two-period, two-treatment crossover study randomized 18 healthy subjects to receive a single oral dose of apixaban 10 mg with and without a single oral dose of famotidine 40 mg administered 3 hours before dosing with apixaban. Plasma apixaban concentrations were measured up to 60 hours post-dose and pharmacokinetic parameters were calculated. Results: Famotidine did not affect maximum apixaban plasma concentration (Cmax) or area under the plasma concentration-time curve from zero to infinite time (AUC∞). Point estimates for ratios of geometric means with and without famotidine were close to unity for Cmax (0.978) and AUC∞ (1.007), and 90% confidence intervals were entirely contained within the 80%–125% no-effect interval. Administration of apixaban alone and with famotidine was well tolerated. Conclusion: Famotidine does not affect the pharmacokinetics of apixaban, consistent with the physicochemical properties of apixaban (lack of an ionizable group and pH-independent solubility). Apixaban pharmacokinetics would not be affected by an increase in gastrointestinal pH due