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Clinical Trial
. 2016 Jan;77(1):77-88.
doi: 10.1007/s00280-015-2922-5. Epub 2015 Dec 8.

Population pharmacokinetic and exposure-response analysis for trastuzumab administered using a subcutaneous "manual syringe" injection or intravenously in women with HER2-positive early breast cancer

Angelica L Quartino  1 , Carina Hillenbach  2 , Jing Li  1 , Hanbin Li  3 , Russell D Wada  3 , Jennifer Visich  1 , Chunze Li  1 , Dominik Heinzmann  2 , Jin Y Jin  1 , Bert L Lum  4
Affiliations
Clinical Trial

Population pharmacokinetic and exposure-response analysis for trastuzumab administered using a subcutaneous "manual syringe" injection or intravenously in women with HER2-positive early breast cancer

Angelica L Quartino et al. Cancer Chemother Pharmacol. 2016 Jan.

Abstract

Purpose: To characterize the population pharmacokinetics (PKs) of subcutaneous (SC) and intravenous (IV) trastuzumab in early breast cancer (EBC), assess the impact of covariates on trastuzumab PK, and evaluate fixed (nonweight-based) dosing for the SC regimen administrated via handheld syringe.

Methods: Serum trastuzumab concentrations from 595 patients with HER2-positive EBC in the HannaH study (fixed 600 mg SC trastuzumab or weight-based IV trastuzumab) were analyzed using nonlinear mixed-effects modeling. Multiple logistic regression was used to assess the exposure-response relationships between PK, efficacy [pathologic complete response (pCR)], and safety [grade ≥3 adverse events (AEs)].

Results: Trastuzumab PK was described by a two-compartment model with parallel linear and nonlinear elimination and first-order SC absorption, with a bioavailability of 77 %. Estimated total clearance (CL) values were 0.18-0.22 L/day for steady-state trough/peak concentrations of 75-148 µg/mL; the estimate for central volume of distribution was 2.9 L. Body weight and alanine transaminase, while showing significant effects on PK, only explained 8% of the variability in CL. Exposure-response analyses showed no relationship between PK, pCR, and grade ≥3 AEs for either regimen.

Conclusion: A fixed 600 mg SC dose of trastuzumab provides the desired exposure, with steady-state trough concentrations (35-123 μg/mL for the 5th-95th percentiles) above the historical target concentration of 20 μg/mL for efficacy. Fixed dosing is further supported by lack of an exposure-response relationship between PK, pCR, and grade ≥3 AEs. No dose adjustment per patient factors is required within the ranges studied.

Keywords: Early breast cancer; Fixed dose; HER2; NONMEM; Population pharmacokinetics modeling; Trastuzumab.

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Figures

Fig. 1
Fig. 1
Simulated and observed concentrations with the SC (top) and IV (bottom) regimens. IV, intravenous; SC, subcutaneous. Circles are observed trastuzumab serum concentrations; solid lines represent the median observed values; dashed lines represent 5 and 95 % prediction intervals of the observed values; shaded areas represent the median predicted values or the spread (5 and 95 %) of the predicted concentrations; the width of the shaded areas indicate 95 % CIs; left panel shows the entire time course while the right panel shows cycle 7 only
Fig. 2
Fig. 2
Impact of body weight on C min,ss for the fixed-dose SC regimen (left) and the weight-based IV regimen (right). C min,ss, steady-state trough concentration; IV, intravenous; q3w, every 3 weeks; SC, subcutaneous. C min,ss following administration of a fixed 600 mg dose SC q3w regimen (left) and a weight-based 8 mg/kg loading dose, 6 mg/kg maintenance dose IV q3w regimen (right). Circles are the individual model-predicted C min,ss values for patients in the HannaH study. The solid line shows the impact of body weight on C min,ss in patients with typical pharmacokinetics. The dashed area represents the spread (5 and 95 %) based on stochastic simulations (n = 300 for each body weight value), including between-subject variability. The dotted horizontal line is the 20 μg/mL target C min,ss based on preclinical xenograft efficacy models
Fig. 3
Fig. 3
Model-predicted concentration–time profiles for the approved SC and IV regimens. ALT, alanine transaminase; IV, intravenous; q3w, every 3 weeks; SC, subcutaneous. Concentration–time profiles are simulated for a 600 mg fixed-dose q3w SC regimen, an 8/6 mg/kg q3w IV regimen and a 4/2 mg/kg qw IV regimen, using estimated population pharmacokinetic parameters for a typical patient (with body weight 68 kg and ALT 19 IU/L, as provided in Table 1. Inter-individual variability and model residual error were not included in the simulation). Simulation was performed for seven cycles. Left panel shows the profile from cycles 1 to 7; right panel shows cycle 7 only
Fig. 4
Fig. 4
Odds ratios for a pCR subgroups of body weight and predicted C min,ss quartiles (per-protocol population) and b rates of grade ≥3 AEs of subgroups by body weight and predicted AUCss quartiles (safety population). AE, adverse event; AUCss, steady-state area under the curve; C min,ss, steady-state trough concentration; IV, intravenous; pCR, pathologic complete response; SC, subcutaneous
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