Model-informed precision dosing for alemtuzumab in pediatric and young adult patients undergoing allogeneic hematopoietic cell transplantation

Aim: Alemtuzumab is a lymphodepleting monoclonal antibody utilized in conditioning regimens for allogeneic hematopoietic cell transplantation (HCT). A therapeutic range of 0.15-0.6 µg/mL on the day of transplantation is associated with better HCT outcomes. The purpose of this study was to characterize alemtuzumab population pharmacokinetic/pharmacodynamic (PK/PD) and to propose individualized subcutaneous dosing schemes to achieve this optimal level for pediatric patients. Methods: Alemtuzumab concentration and absolute lymphocyte count (ALC) profiles were obtained from 29 patients with non-malignant disorders undergoing HCT. PK/ PD analyses were performed using non-linear mixed effects modeling. Monte Carlo simulation was conducted to evaluate different improved dosing approaches. Results: A one-compartment model with sequential zero- and first-order absorption adequately described subcutaneously administered alemtuzumab PK. Model fit was significantly improved by including allometrically scaled body weight on clearance (0.080 L/h/70kg) and volume of distribution (17.4 L/70kg). ALC reduction following subcutaneous alemtuzumab was swift. An inhibitory Emax model best characterized the relationship between alemtuzumab concentration and ALC. Emax and EC50 were estimated as 1.18*103/µL and 0.045µg/mL, respectively. The currently used per kg dosing was found to cause uneven alemtuzumab exposure across different age and weight cohorts. Simulations indicated target achieving dose as allometry-based of 18 mg*(weight/70)0.75 or body surface area (BSA)-based of 10 mg/m2, divided over 3 days, with a potential individualized top-up dose; both of which yielded similar results. Conclusion: An allometry- or BSA-based starting dosing regimen in combination with individualized Bayesian PK estimation using concentration feedback is proposed for alemtuzumab precision dosing in children undergoing allogeneic HCT.

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Population Pharmacokinetic Modeling of Thymoglobulin in Children Receiving Allogeneic-Hematopoietic Cell Transplantation (HCT): Towards Individualized Dosing to Improve Survival

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2013.12.129 ◽

2014 ◽

Vol 20 (2) ◽

pp. S96-S98 ◽

Cited By ~ 3

Author(s):

R. Admiraal ◽

Charlotte van Kesteren ◽

Cornelia M. Jol-van der Zijde ◽

Maarten van Tol ◽

Imke Bartelink ◽

...

Keyword(s):

Cell Transplantation ◽

Hematopoietic Cell Transplantation ◽

Pharmacokinetic Modeling ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Population Pharmacokinetic ◽

Population Pharmacokinetic Modeling ◽

Individualized Dosing

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Fludarabine exposure in the conditioning prior to allogeneic hematopoietic cell transplantation predicts outcomes

Blood Advances ◽

10.1182/bloodadvances.2018029421 ◽

2019 ◽

Vol 3 (14) ◽

pp. 2179-2187 ◽

Cited By ~ 8

Author(s):

J. B. Langenhorst ◽

C. van Kesteren ◽

E. M. van Maarseveen ◽

T. P. C. Dorlo ◽

S. Nierkens ◽

...

Keyword(s):

Cell Transplantation ◽

Graft Failure ◽

Hematopoietic Cell Transplantation ◽

Strong Predictor ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Time Curve ◽

Conditioning Regimens

Abstract Fludarabine is the most frequently used agent in conditioning regimens for allogeneic hematopoietic cell transplantation (HCT). Body surface area–based dosing leads to highly variable fludarabine exposure. We studied the relation between fludarabine exposure and clinical outcomes. A retrospective, pharmacokinetic-pharmacodynamic analysis was conducted with data from patients undergoing HCT with fludarabine (160 mg/m2) as part of a myeloablative conditioning (busulfan targeted to an area under the plasma-concentration-time curve [AUC] of 90 mg*h/L) and rabbit antithymocyte globulin (6-10 mg/kg; from day −9/−12) between 2010 and 2016. Fludarabine exposure as AUC was calculated for each patient using a previously published population pharmacokinetic model and related to 2-year event-free survival (EFS) by means of (parametric) time-to-event models. Relapse, nonrelapse mortality (NRM), and graft failure were considered events. One hundred ninety-two patients were included (68 benign and 124 malignant disorders). The optimal fludarabine exposure was determined as an AUC of 20 mg*h/L. In the overexposed group, EFS was lower (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.1-3.5; P = .02), due to higher NRM (HR, 3.4; 95% CI, 1.6-6.9; P < .001) associated with impaired immune reconstitution (HR, 0.43; 95% CI, 0.26-0.70; P < .001). The risks of NRM and graft failure were increased in the underexposed group (HR, 3.3; 95% CI, 1.2-9.4; P = .02; HR, 4.8; 95% CI, 1.2-19; P = .02, respectively). No relationship with relapse was found. Fludarabine exposure is a strong predictor of survival after HCT, stressing the importance of optimum fludarabine dosing. Individualized dosing, based on weight and “renal function” or “therapeutic drug monitoring,” to achieve optimal fludarabine exposure might improve survival.

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