Proposal for individualized dosing of eculizumab in atypical haemolytic uraemic syndrome: patient friendly and cost-effective.
Nephrol Dial Transplant
; 38(2): 362-371, 2023 02 13.
Article
in En
| MEDLINE
| ID: mdl-35238929
ABSTRACT
BACKGROUND:
Eculizumab is a lifesaving yet expensive drug for atypical haemolytic uraemic syndrome (aHUS). Current guidelines advise a fixed-dosing schedule, which can be suboptimal and inflexible in the individual patient.METHODS:
We evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) [classical pathway (CP) activity levels] of eculizumab in 48 patients, consisting of 849 time-concentration data and 569 CP activity levels. PK-PD modelling was performed with non-linear mixed-effects modelling. The final model was used to develop improved dosing strategies.RESULTS:
A PK model with parallel linear and non-linear elimination rates best described the data with the parameter estimates clearance 0.163 L/day, volume of distribution 6.42 L, maximal rate 29.6 mg/day and concentration for 50% of maximum rate 37.9 mg/L. The PK-PD relation between eculizumab concentration and CP activity was described using an inhibitory Emax model with the parameter estimates baseline 101%, maximal inhibitory effect 95.9%, concentration for 50% inhibition 22.0 mg/L and Hill coefficient 5.42. A weight-based loading dose, followed by PK-guided dosing was found to improve treatment. On day 7, we predict 99.95% of the patients to reach the efficacy target (CP activity <10%), compared with 94.75% with standard dosing. Comparable efficacy was predicted during the maintenance phase, while the dosing interval could be prolonged in â¼33% of the population by means of individualized dosing. With a fixed-dose 4-week dosing interval to allow for holidays, treatment costs will increase by 7.1% and we predict 91% of the patients will reach the efficacy target.CONCLUSIONS:
A patient-friendly individualized dosing strategy of eculizumab has the potential to improve treatment response at reduced costs.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Atypical Hemolytic Uremic Syndrome
Type of study:
Guideline
/
Health_economic_evaluation
/
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Nephrol Dial Transplant
Journal subject:
NEFROLOGIA
/
TRANSPLANTE
Year:
2023
Type:
Article
Affiliation country:
Netherlands