Li Zhang (1), Yue Gao (1), Meng Li (1), John D. Davis (2), Vanaja Kanamaluru (1), Qiang Lu (1)
(1) Sanofi, Bridgewater, NJ, USA, (2) Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA
Objectives: Dupilumab, a fully human interleukin (IL)-4 receptor α mAb, inhibits signaling of IL-4 and IL-13, key drivers of type 2 inflammation[1]. Dupilumab is approved for treatment of adults with inadequately controlled moderate-to-severe atopic dermatitis (AD). Dupilumab has also demonstrated positive efficacy for the treatment of asthma in patients 12 years or older. This analysis aimed to (1) develop a population pharmacokinetic (Pop PK) model for dupilumab and assess the influences of intrinsic and extrinsic factors on dupilumab PK in patients with moderate-to-severe asthma; and (2) use the model to determine dupilumab exposure in severe oral corticosteroid (OCS)-dependent asthma patients who were not included in model development.
Methods: The Pop PK model was developed using concentrations of functional dupilumab in serum pooled across six phase 1, two phase 2, and one phase 3 studies in adult and adolescent patients with moderate-to-severe asthma after subcutaneous (SC) administration as well as healthy subjects after intravenous or SC administration. The base model structure from a previously developed Pop PK model in AD patients[2] was used: 2-compartment with parallel linear and nonlinear saturable Michaelis-Menten [M-M] elimination, with body weight included as a covariate on central volume (Vc). Forward selection and backward elimination were used to evaluate the following covariates: demographics, lab parameters of renal and liver function, anti-drug antibodies (ADAs), baseline biomarkers/disease characteristics (blood eosinophils, fractional exhaled nitric oxide [FeNO], % of predicted normal forced expiratory volume in one second [FEV1%]), and population (healthy subjects vs asthma patients). The final model was validated by visual predictive checks and bootstrap. Additionally, dupilumab PK from severe OCS-dependent asthma patients were evaluated with a maximum a posteriori (MAP) Bayesian analysis using the established asthma Pop PK model.
Results: The final Pop PK model development dataset included 1,912 asthma patients (including 68 adolescent patients) and 202 healthy adults, with 14,584 concentrations of dupilumab. The PK of dupilumab in asthma patients were adequately described by a 2-compartment with parallel linear and nonlinear saturable M-M elimination model plus first-order absorption. The population estimates of the key PK parameters in asthma patients were similar to AD patients[2] and were: volume of distribution at steady-state 4.37 L, linear elimination rate 0.042 day-1, and bioavailability 60.9%. As in AD patients, body weight was the primary source of variability in PK, with lower body weight associated with higher PK exposure. Compared with a typical 78 kg (median) patient, steady state area under the concentration time curve was 48.0% and 40.7% lower in a 116 kg (95th percentile) patient and 43.8% and 36.1% higher in a 60 kg (typical weight of adolescents) patient, at phase 3 study doses of dupilumab 200 and 300 mg q2w (every other week), respectively. Other statistically significant covariates (ADA, albumin, and creatinine clearance) had no clinically meaningful effect, with less than 20% change in exposure estimates at 5th or 95th percentile of the covariate range relative to the median. All other covariates, including age (12–83 years), gender, race, laboratory parameters of liver function, biomarkers/disease characteristics (eosinophils, FeNO, and FEV1%), and population had no statistically significant effect on dupilumab PK in asthma patients. Moreover, the concomitant use of common asthma medications has no effect on dupilumab PK, based on post-hoc analysis. Dupilumab PK in severe OCS-dependent asthma patients and non-OCS dependent asthma patients was highly comparable; the established asthma Pop PK model was able to accurately predict dupilumab exposure in OCS-dependent asthma patients.
Conclusion: The Pop PK model adequately described dupilumab PK in adult and adolescent patients with asthma and enabled robust prediction of individual patient exposure. PK properties of dupilumab in asthma patients are comparable to those of AD patients. Only body weight exerted a noticeable effect explaining between-subject variability in the PK of dupilumab, but dose adjustment for weight is not warranted based on results from pivotal clinical studies. There is no PK difference between adolescent and adult patients after correction for body weight.
References:
[1] Gandhi NA, Bennett BL, Graham NMH, Pirozzi G, Stahl N, Yancopoulos GD. Targeting key proximal drivers of type 2 inflammation in disease. Nat Rev Drug Discov (2016) 15(1): 35-50.
[2] Kovalenko P, Davis JD, Li M, DiCioccio AT. Population Pharmacokinetic Analysis of Dupilumab Using Early Phase and Phase 3 Data. J Pharmacokinet Pharmacodyn (2017) 44: S69.
Reference: PAGE 27 (2018) Abstr 8652 [www.page-meeting.org/?abstract=8652]
Poster: Drug/Disease Modelling - Other Topics