T-DM1 PHARMACOKINETICS
Clin Pharmacokinet. 2013 Apr 4. [Epub ahead of print]An Integrated Multiple-Analyte Pharmacokinetic Model to Characterize Trastuzumab Emtansine (T-DM1) Clearance Pathways and to Evaluate Reduced Pharmacokinetic Sampling in Patients with HER2-Positive Metastatic Breast Cancer.
Lu D, Joshi A, Wang B, Olsen S, Yi JH, Krop IE, Burris HA, Girish S.
Source
Abstract
BACKGROUND AND OBJECTIVE:
METHODS:
RESULTS:
CONCLUSIONS:
Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA, lu.dan@gene.com.
Trastuzumab
emtansine (T-DM1) is an antibody-drug conjugate recently approved by
the US Food and Drug Administration for the treatment of human epidermal
growth factor receptor 2 (HER2)-positive metastatic breast cancer
previously treated with trastuzumab and taxane chemotherapy. It
comprises the microtubule inhibitory cytotoxic agent DM1 conjugated to
the HER2-targeted humanized monoclonal antibody trastuzumab via a stable
linker. To characterize the pharmacokinetics of T-DM1 in patients with
metastatic breast cancer, concentrations of multiple analytes were
quantified, including serum concentrations of T-DM1 conjugate and total
trastuzumab (the sum of conjugated and unconjugated trastuzumab), as
well as plasma concentrations of DM1. The clearance of T-DM1 conjugate
is approximately 2 to 3 times faster than its parent antibody,
trastuzumab. However, the clearance pathways accounting for this faster
clearance rate are unclear. An integrated population pharmacokinetic
model that simultaneously fits the pharmacokinetics of T-DM1 conjugate
and total trastuzumab can help to elucidate the clearance pathways of
T-DM1. The model can also be used to predict total trastuzumab
pharmacokinetic profiles based on T-DM1 conjugate pharmacokinetic data
and sparse total trastuzumab pharmacokinetic data, thereby reducing the
frequency of pharmacokinetic sampling.
T-DM1 conjugate and total trastuzumab serum concentration data, including baseline trastuzumab concentrations prior to T-DM1 treatment, from phase I and II studies were used to develop this integrated population pharmacokinetic model. Based on a hypothetical T-DM1 catabolism scheme, two-compartment models for T-DM1 conjugate and trastuzumab were integrated by assuming a one-step deconjugation clearance from T-DM1 conjugate to trastuzumab. The ability of the model to predict the total trastuzumab pharmacokinetic profile based on T-DM1 conjugate pharmacokinetics and various sampling schemes of total trastuzumab pharmacokinetics was assessed to evaluate total trastuzumab sampling schemes.
The final model reflects a simplified catabolism scheme of T-DM1, suggesting that T-DM1 clearance pathways include both deconjugation and proteolytic degradation. The model fits T-DM1 conjugate and total trastuzumab pharmacokinetic data simultaneously. The deconjugation clearance of T-DM1 was estimated to be ~0.4 L/day. Proteolytic degradation clearances for T-DM1 and trastuzumab were similar (~0.3 L/day). This model accurately predicts total trastuzumab pharmacokinetic profiles based on T-DM1 conjugate pharmacokinetic data and sparse total trastuzumab pharmacokinetic data sampled at preinfusion and end of infusion in cycle 1, and in one additional steady state cycle.
This semi-mechanistic integrated model links T-DM1 conjugate and total trastuzumab pharmacokinetic data, and supports the inclusion of both proteolytic degradation and deconjugation as clearance pathways in the hypothetical T-DM1 catabolism scheme. The model attributes a faster T-DM1 conjugate clearance versus that of trastuzumab to the presence of a deconjugation process and suggests a similar proteolytic clearance of T-DM1 and trastuzumab. Based on the model and T-DM1 conjugate pharmacokinetic data, a sparse pharmacokinetic sampling scheme for total trastuzumab provides an entire pharmacokinetic profile with similar predictive accuracy to that of a dense pharmacokinetic sampling scheme.
T-DM1 conjugate and total trastuzumab serum concentration data, including baseline trastuzumab concentrations prior to T-DM1 treatment, from phase I and II studies were used to develop this integrated population pharmacokinetic model. Based on a hypothetical T-DM1 catabolism scheme, two-compartment models for T-DM1 conjugate and trastuzumab were integrated by assuming a one-step deconjugation clearance from T-DM1 conjugate to trastuzumab. The ability of the model to predict the total trastuzumab pharmacokinetic profile based on T-DM1 conjugate pharmacokinetics and various sampling schemes of total trastuzumab pharmacokinetics was assessed to evaluate total trastuzumab sampling schemes.
The final model reflects a simplified catabolism scheme of T-DM1, suggesting that T-DM1 clearance pathways include both deconjugation and proteolytic degradation. The model fits T-DM1 conjugate and total trastuzumab pharmacokinetic data simultaneously. The deconjugation clearance of T-DM1 was estimated to be ~0.4 L/day. Proteolytic degradation clearances for T-DM1 and trastuzumab were similar (~0.3 L/day). This model accurately predicts total trastuzumab pharmacokinetic profiles based on T-DM1 conjugate pharmacokinetic data and sparse total trastuzumab pharmacokinetic data sampled at preinfusion and end of infusion in cycle 1, and in one additional steady state cycle.
This semi-mechanistic integrated model links T-DM1 conjugate and total trastuzumab pharmacokinetic data, and supports the inclusion of both proteolytic degradation and deconjugation as clearance pathways in the hypothetical T-DM1 catabolism scheme. The model attributes a faster T-DM1 conjugate clearance versus that of trastuzumab to the presence of a deconjugation process and suggests a similar proteolytic clearance of T-DM1 and trastuzumab. Based on the model and T-DM1 conjugate pharmacokinetic data, a sparse pharmacokinetic sampling scheme for total trastuzumab provides an entire pharmacokinetic profile with similar predictive accuracy to that of a dense pharmacokinetic sampling scheme.
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