Population pharmacokinetics of recombinant human C1 inhibitor in patients with hereditary angioedema

Abstract

AIMSTo characterize the pharmacokinetics (PK) of recombinant human C1 inhibitor (rhC1INH) in healthy volunteers and hereditary angioedema (HAE) patients. METHODSPlasma levels of C1INH following 294 administrations of rhC1INH in 133 subjects were fitted using nonlinear mixed-effects modelling. The model was used to simulate maximal C1INH levels for the proposed dosing scheme. RESULTSA one-compartment model with Michaelis-Menten elimination kinetics described the data. Baseline C1INH levels were 0.901 [95% confidence interval (CI): 0.839-0.968] and 0.176 U ml -1 (95% CI: 0.154-0.200) in healthy volunteers and HAE patients, respectively. The volume of distribution of rhC1INH was 2.86 l (95% CI: 2.68-3.03). The maximal rate of elimination and the concentration corresponding to half this maximal rate were 1.63 U ml -1 h -1 (95% CI: 1.41-1.88) and 1.60 U ml -1 (95% CI: 1.14-2.24), respectively, for healthy volunteers and symptomatic HAE patients. The maximal elimination rate was 36% lower in asymptomatic HAE patients. Peak C1INH levels did not change upon repeated administration of rhC1INH. Bodyweight was found to be an important predictor of the volume of distribution. Simulations of the proposed dosing scheme predicted peak C1INH concentrations above the lower level of the normal range (0.7 U ml -1) for at least 94% of all patients. CONCLUSIONSThe population PK model for C1INH supports a dosing scheme on a 50 U kg -1 basis up to 84 kg, with a fixed dose of 4200 U above 84 kg. The PK of rhC1INH following repeat administration are consistent with the PK following the first administration.

Recombinant human C1-esterase inhibitor relieves symptoms of hereditary angioedema attacks: phase 3, randomized, placebo-controlled trial

“…14 Population pharmacokinetic analyses have demonstrated that rhC1INH dosing at 50 IU/kg (up to maximum of 4,200 IU/treatment) achieves C1INH activity of 0.7 in more than 90% of patients. 11 In an indirect comparison of reported response rates within 4 hours (corrected for response in the corresponding placebo group) with different doses of pdC1INH (10 to 25 IU/kg) or rhC1INH (50 IU/kg) in the acute treatment of attacks of HAE, the higher rhC1INH dosing regimen appeared to provide improved efficacy. 15 The present randomized controlled study was conducted to extend previous studies and evaluate the efficacy and safety of rhC1INH (50 IU/kg up to a maximum of 4,200 IU/treatment) compared with placebo for the treatment of acute angioedema attacks in a larger cohort of patients with HAE.…”

Recombinant Human-C1 Inhibitor Is Effective and Safe for Repeat Hereditary Angioedema Attacks

“…10 Population pharmacokinetic modeling supports a dosing scheme of 50 IU/kg, which achieves C1INH levels above the lower level of the normal range (0.7 U/ mL) in at least 94% of the patients. 11 These plasma levels are required to achieve complete inhibition of inflammatory cascades as demonstrated by continued C4 cleavage and higher C4 b/c concentrations at lower doses. 12 Previous randomized controlled trials (RCTs) indicate that rhC1INH at 50 and 100 IU/kg is a highly effective and welltolerated treatment for acute HAE attacks.…”

Recombinant Replacement Therapy for Hereditary Angioedema Due to C1 Inhibitor Deficiency

“…The PPK simulations support capping the weightbased dosing of Ruconest at 4200 U (two vials) maintaining the concentration of functional C1-INH within an acceptable range for patients in any weight category. The PPK model did not indicate any significant differences in peak C1-INH activity levels after initial administration versus repeated administrations for subsequent attacks [61].…”

“…C1-INH inhibits several target proteases of complement and regulatory points of the contact and coagulation systems [60,61]. The formation of covalent complexes between the target protease and C1-INH leads to their inactivation.…”

“…A population PK (PPK) analysis was conducted on PK data from a total of 120 subjects who received a combined total of 214 administrations of Ruconest across six clinical studies [61]. A one compartment Adapted from Feussner et al [58].…”