Alternative Treatment Regimens With the PCSK9 Inhibitors Alirocumab and Evolocumab: A Pharmacokinetic and Pharmacodynamic Modeling Approach

Abstract

Alirocumab and evolocumab are 2 human monoclonal antibodies that inhibit the proprotein convertase subtilisin/kexin type 9 (PCSK9). These antibodies can potently lower low-density lipoprotein cholesterol (LDLc) serum concentrations. The aims of this analysis were to develop a pharmacokinetic (PK) and pharmacodynamic (PD) model for both antibodies, to simulate and investigate different dosage and application regimens, and finally, to note the effects on LDLc levels. Alirocumab was clinically studied and approved with 2 doses, 75 and 150 mg every 2 weeks (Q2W), whereas evolocumab was tested and approved with 2 dosing intervals, 140 mg Q2W and 420 mg Q4W. Data were digitized from published studies describing alirocumab and evolocumab PK, as well as LDLc levels in humans for various single and multiple doses. Alirocumab dosages ranged between 75 and 300 mg and evolocumab from 7 to 420 mg. The analysis was performed using a nonlinear mixed-effects modeling technique. A 2-compartment model with first-order absorption and saturable elimination described the PK of both antibodies best. LDLc levels were described by a turnover model with zero-order synthesis rate decreased by the antibodies and a first-order degradation rate that was increased by the antibodies. Simulations show a comparable effectiveness for alirocumab 75 mg Q2W and 150 mg Q3W as well as evolucmab 140 mg Q2W and 420 mg Q5W, respectively. This is the first PK/PD model describing the link between alirocumab and evolocumab PK and LDLc concentrations. The model may serve as an important tool to simulate different dosage regimens in order to optimize therapy.

2017 Update of ESC/EAS Task Force on practical clinical guidance for proprotein convertase subtilisin/kexin type 9 inhibition in patients with atherosclerotic cardiovascular disease or in familial hypercholesterolaemia

“…34,35 This response is similar for either regimens of alirocumab or evolocumab. 36 Information documenting the interindividual variability in the LDL-C lowering response to PCSK9 inhibition is, however, limited. This is a pertinent issue, in the light of evidence from the SPIRE programme (see Box 1).…”

Influence of Antigen Mass on the Pharmacokinetics of Therapeutic Antibodies in Humans

“…[38,53,76,156] An evolocumab study using a TMDD model showed that PCSK9 levels were higher in patients treated with statins. [38] This increase in PCSK9 levels may lead to higher target-mediated clearance of anti-PCSK9 mAbs.…”

“…However, the Michaelis-Menten term has been used in simplified forms. In five studies on clenoliximab [73] (anti CD4), alemtuzumab [74] (anti CD52), cetuximab [27] (anti-EGFR) otelixizumab [75] (anti-CD3) and anti-PCSK9 mAbs (alirocumab and evolocumab) [76] , no linear (endogenous) elimination term was integrated in the model. The absence of first-order elimination term lead to apparent VM and KM values that may be superior than "actual" values.…”

Physiologically Based Precision Dosing Approach for Drug‐Drug‐Gene Interactions: A Simvastatin Network Analysis

“…Furthermore, it should be noted that dose optimization was only performed for matching exposure and not linked with a pharmacodynamic (PD) model connecting SL and SA exposure with drug efficacy like change in LDL levels or drug toxicity. 43,45,46 Such a PBPK/ PD MIPD decision support system could enable clinicians to individually balance therapy risks and chances. 47,48 However, as recent investigations have shown, those models should also regard the exposure of SL, which had not been recognized for a long time.…”