Population pharmacokinetic and exploratory exposure–response analysis of the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer in the FeDeriCa study

Abstract

Purpose To characterize pertuzumab pharmacokinetics (PK) in FeDeriCa (NCT03493854: fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection [PH FDC SC] versus intravenous pertuzumab plus trastuzumab); derive individual pertuzumab exposures in the PH FDC SC arm for subsequent pertuzumab exposure–response (ER) analyses; compare observed trastuzumab PK with predicted exposures from a previous SC trastuzumab model; assess whether pertuzumab affects trastuzumab PK; evaluate pertuzumab exposure–efficacy and –safety relationships and support the approved SC dosing regimen. Methods Population pharmacokinetic modeling and simulations were used to describe the data. Standard goodness-of-fit diagnostics and prediction-corrected visual predictive checks were used for model performance assessment. Covariates were included from previously reported models. ER analysis was conducted using logistic regression. Results SC pertuzumab PK was described adequately by a two-compartment model with first-order absorption; significant covariates included in the final model were albumin, lean body weight, and Asian region; however, these appeared not to be clinically relevant. Trastuzumab concentrations were described adequately by the previous model; there was no evidence of a pertuzumab effect on trastuzumab PK as part of PH FDC SC and higher model-predicted pertuzumab exposure was not associated with differences in pathologic complete response rate or an increased probability of selected grade ≥ 3 adverse events of interest. Conclusion The approved PH FDC SC dose [loading: 1200/600 mg pertuzumab/trastuzumab (15 mL); maintenance: 600 mg pertuzumab/trastuzumab (10 mL) and 2000 U/mL recombinant human hyaluronidase every 3 weeks] provides a positive benefit–risk profile with comparable efficacy and safety to intravenous pertuzumab plus trastuzumab.

C-Terminal Lysine Processing of IgG in Human Suction Blister Fluid: Implications for Subcutaneous Administration

“…Fortunately, a wide range of k a values were simulated as part of this study and should cover k a values of most antibody therapeutics with rhuPH20. It is also worth noting that the respective population PK model parameters for atezolizumab , and pertuzumab used in this study were derived from clinical trials where each molecule was co-formulated or co-administered with rhuPH20. The second case involves molecules exhibiting significant target-mediated drug disposition, which means that target engagement leads to more rapid clearance, usually manifesting as non-linear PK.…”

“…In this model, subcutaneously administered IgG + 1CTK molecules either directly absorb into the central compartment or get processed by carboxypeptidase into IgG + 0CTK; a 6 h delay in the carboxypeptidase activity was also included to account for equilibration of the SC depot with the surrounding SC interstitial fluid (Figure S1). PK simulations were performed using the respective model-estimated clearance (CL), central compartment volume of distribution ( V c ), peripheral compartment volume of distribution ( V p ), intercompartmental clearance ( Q ), SC bioavailability ( F ), and absorption rate constant ( k a ) from either atezolizumab , or pertuzumab population PK models (Table ). Additional parameters of the model used for simulation included the absorption rate constant ( k a,CTK ) and bioavailability of the IgG + 1CTK molecule ( F CTK ), which were assumed to be the absorption rate constant and 50% of the bioavailability of the parental IgG + 0CTK molecule, respectively (the rationale for these two assumptions are discussed in the Results section).…”

Application of population physiologically based pharmacokinetic modelling to optimize target expression and clearance mechanisms of therapeutic monoclonal antibodies

“…After optimizing HER2 parameterisation in tumour and normal tissues with PTZ PBPK modelling, it was validated by running different simulations after single IV infusions of TTZ at 1, 2, 4 and 8 mg/kg dose levels. Additionally, simulations of multiple IV infusions of PTZ were compared with observed data in Phase I, II and III clinical trials 24,25 and after subcutaneous single-dose administration to cancer patients 25 as well.…”

Pharmacokinetic characterization, benefits and barriers of subcutaneous administration of monoclonal antibodies in oncology

“…The exceptions were rituximab, which has a time-dependent component due to B-cell depletion, 52,53 and pertuzumab, whose model did not enclose the non-linear component. 54 In the denosumab model, a quasi-steady-state approximation was used to characterize non-linear clearance. 55 Body weight or body surface area was the main covariate influencing the PK of rituximab.…”

“…Population pharmacokinetic (PK) parameters of monoclonal antibodies (mAbs) available as subcutaneous (SC) formulations[52][53][54][55][56][57][58] …”