Caplacizumab Dosing Rational in aTTP Patients Supported by Mechanism Based PKPD Modelling
Martin Bergstrand (1), Emma Hansson (1), Laura Sargentini-Maier (2)
(1) Pharmetheus, Sweden (2) Ablynx, Belgium
Objectives: To describe the interplay between caplacizumab concentrations and its target, von Willebrand factor antigen (vWF:Ag) following treatment in different adult populations. The developed model should be utilized for simulations of what-if scenarios to support the dosing regimen.
Methods: The analysis was based on data from ten phase I to III studies [1-10] of caplacizumab in healthy volunteers (n=100), patients undergoing percutaneous coronary intervention (PCI) (n=225) and patients with acquired thrombotic thrombocytopenic purpura (aTTP, an orphan disease) (n=216), with a total of 3629 PK and 6295 PD observations. The majority of the aTTP patients received plasma exchange (PE) and immunosuppressant treatment as standard of care. A wide range of dose levels, treatment and PE schedules was represented in data. Data following both i.v and s.c administration was included.
The Population PKPD analysis was conducted by nonlinear mixed-effects modelling using NONMEM, version 7.3.0. The model was developed stepwise. Initially, a subset of the data set including data in healthy volunteers and PCI patients was used for the model development. Subsequently, the model was updated to describe the specific characteristics related to the aTTP disease status and standard of care, PE, in the subset of the data set with aTTP patients. The effects of age, sex, race, blood group, body weight, creatinine clearance, and concomitant treatment were evaluated based on graphical evaluation by means of stratified prediction corrected visual predictive checks and univariate evaluation in NONMEM.
Simulations were performed using the final model for aTTP patients to evaluate the effect of change in doses, patient bodyweight, need for dose adjustment in paediatric patients etc.
Result: The interaction between caplacizumab and vWF:Ag was adequately described by a full target-mediated drug disposition model. The model included a two-compartment drug disposition model with a parallel slow and fast first-order absorption processes and first-order linear elimination of the free drug. The model described the formation of drug-vWF complexes with the ability to form both dimers and trimers. The production and maturation of vWF were described by transit compartments and storage of vWF in a pool compartment, mimicking the storage in the Weibel-Palade bodies in the endothelium and subsequent rapid release and elimination of free vWF. The half-life of free vWF was fixed to the literature value 16 hours [11-14]. A dual feedback mechanism was included, stimulating the production rate and release of vWF from the pool when vWF decreased below the subject’s baseline level.
For aTTP patients, disease progression was captured as a transient increase in vWF:Ag over time and the effect of PE was described as parallel removal of free vWF, free drug and drug-vWF complex. The population typical total elimination rate under PE was estimated to be 3.7-fold higher for free drug, 3.5-fold higher for free vWF and 1.7-fold higher for the drug-vWF complex.
Body weight was allometrically included in the model (fixed exponents) and creatinine clearance was identified as a statistically significant covariate with a minor reduction in CL for patients with CRCL below the median CRCL (100 ml/min) in aTTP patients.
The model was successfully applied to simulate what-if scenarios to support the dosing regimen, dosing in special populations and how to handle missed doses. Simulations were also performed to inform the dosing regimen in paediatric patients and to predict the PKPD behaviour in Japanese aTTP patients based on differences in body size. Simulations were also conducted to learn more about the impact of baseline vWF:Ag concentrations as well as the effect of the PE schedules in terms of timing, intensity, and duration.
Conclusions: A semi-mechanistic population PKPD model was developed to describe the interaction between caplacizumab and vWF (based on observations of vWF:Ag). The model adequately described the drug-vWF complex interaction over time, including disease progression in aTTP patients and the effects governed by PE treatment. The model has successfully been applied to increase the understanding of the PKPD interplay between caplacizumab and vWF in the target population and by the use of simulations supported the dosing rational in both adult and paediatric patients and allowed bridging to Japanese aTTP patients.
References:
[1-10] Caplacizumab studies: study ALX-0081/0681-1.2/08a, study ALX-0081/0681-1.2/08b, study ALX-0081/0681-1.2/08c OLE, study ALX-0081/0681-1.1/08 First part, study ALX-0081/0681-1.1/08 Second part, study ALX-0081/0681-2.1/09, study ALX-0681-2.1/10, study ALX-0681-C102, ALX-0681-C301.
[11] Lenting P, Christophe O and Denis C, 2015, von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends. Blood vol. 26: 2019–2028.
[12] Favaloro E, Lloyd J, Rowell J, Baker R, Rickard K, Kershaw G, Street A, Scarff K, Barrese G, Maher D and McLachlan A, 2007, Comparison of the pharmacokinetics of two von Willebrand factor concentrates. Biostate and AHF (High Purity) in people with von Willebrand disorder. A randomised cross-over, multi-centre study. Thromb Haemost vol. 97: 922–930.
[13] Dobrkovska A, Krzensk U and Chediak J, 1998, Pharmacokinetics, efficacy and safety of Humate-P in von Willebrand disease. Haemophilia vol. 4: 33–39.
[14] Goudemand J, Scharrer I, Berntorp E, Lee C, Borel-Derlon A, Stieltjes N, Caron C, Scherrmann J,Bridey F, Tellier Z, Federici, AB and Mannucci P, 2005, Pharmacokinetic studies on Wilfactin, a von Willebrand factor concentrate with a low factor VIII content treated with three virus-inactivation/removal methods. J Thromb Haemost vol. 3: 2219–2227.