Trastuzumab pharmacokinetics

In these phase I studies, trastuzumab displayed dose-dependent pharmacokinetics, with a serum half-life ranging from 1 day at the 10-mg dose level to 14 days at the 500-mg dose level. Importantly, when administered at the higher dose levels, consistent serum trough concentrations of trastuzumab above 10 pg/ml were achieved, which was the target concentration based on the in vitro antiproliferative activity. Soluble HER ECD was detected in 24 of 28 patients and was correlated with altered trastuzumab pharmacokinetics. Also, in contrast to 4D5 therapy, no human antihuman antibodies (HAHA) were observed following trastuzumab administration. 

Pharmacodynamics and Pharmacokinetics of mAbs Muromonab CD-3 Pharmacokinetics Basiliximab Pharmacokinetics Trastuzumab Pharmacokinetics Infliximab Pharmacokinetics Rituximab Pharmacokinetics Palivizumab Pharmacokinetics Recommendations for Future Study References... 

Herceptin with cisplatin, doxorubicin or epirubicin plus cyclophosphamide, or paclitaxel. A comparison of serum levels of trastuzumab given in combination with various chemotherapeutic agents did not suggest the possibility of any pharmacokinetic interactions except in combination with paclitaxel. Although not statistically signihcant, mean serum trough concentrations of trastuzumab were consistently elevated, about 1.5-fold, when Herceptin was administered in combination with paclitaxel. However, trastuzumab and paclitaxel were used concurrently in clinical trials with positive outcome results. The concurrent administration of anthracyclines, cyclophosphamide, and trastuzumab increased the incidence and severity of cardiac dysfunction during clinical trials. 

An assumption concerning the number of compartments is, by nature, not required. For reliable results and precise parameter estimates, however, a relatively large number of data points per individual are required. Phase 1 studies of mAbs usually provide sufficient data for a noncompartmental analysis, but the assumption of linear pharmacokinetics is not valid for most mAbs. This prerequisite, however, was frequently neglected during the early years of therapeutic mAh development, and an overall estimate for CL, for example, was frequently reported in the literature. In dose-escalating studies, however, the concentration-time plots of the raw data clearly indicate that the slope of the terminal phase is not parallel for the different doses, but increases with increasing dose (Fig. 3.10). As a result, the listing of different clearance values for different doses can be found. For example, the clearance of trastuzumab was reported to be 88.3 mL/h for a 10-mg dose, 34.3 mL/h for a 50-mg dose, 25.0 mL/h for a 100-mg dose, 19.0 mL/h for a 250-mg dose, and 16.7 mL/h for a 300-mg dose. 

Various methods are available to estimate population parameters, but today the nonlinear mixed effects modeling approach is the most common one employed. Population analyses have been performed for mAbs such as basiliximab, daclizu-mab and trastuzumab, as well as several others in development, including clenolixi-mab and sibrotuzumab. Population pharmacokinetic models comprise three submodels the structural the statistical and covariate submodels (Fig. 3.13). Their development and impact for mAbs will be discussed in the following section. 

G. Lieberman, L. Banken, and P. Klein. 2005. Population pharmacokinetics of trastuzumab in patients with HER2+ metastatic breast cancer. Cancer Chemother. Pharmacol. 56 361-369. 

P. Ghahramani. 2003. Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel./. Clin. Oncol. 21 3965-3971. 

Following construction, characterization, and scale-up of trastuzumab, phase I testing of the humanized mAh was carried out in patients with HER2-overexpressing metastatic breast cancer. The initial phase I study evaluated the safety and pharmacokinetics of a single, escalating (10-500 mg) intravenous dose of trastuzumab. A subsequent phase I study evaluated the safety and pharmacokinetics of multiple-dose administration, with weekly intravenous doses and similar dose escalation by cohort (10-500 mg). Both studies of 32 patients overall demonstrated that trastuzumab monotherapy was very well tolerated, with no serious adverse events attributable to mAh treatment. A third phase I study included trastuzumab, again via weekly intravenous administration of 10-500 mg, in combination with cisplatin chemotherapy at 50 or 100 mg/m2 per 4-week cycle. Toxicities in this trial were those commonly seen with cisplatin. 

Trastuzumab has dose-dependent pharmacokinetics with a mean t of 5.8 days at the 2-mg/kg maintenance dose. Steady-state levels were achieved between the 16th and the 32nd weeks. The infusion effects of trastuzumab are typical of other monoclonal antibodies and include fever, chills, nausea, dyspnea, and rashes. Allergic reactions also may be observed. Cardiac dysfunction is an unexpected and potentially serious side effect that was observed in the pivotal trial of trastuzumab chemotherapy. Left ventricular dysfunction was seen most commonly in those patients who received doxorubicin and cyclophosphamide. 

Baselga J, Carbonell X, Castaneda-Soto N J, et al. (2005). Phasell study of efficacy, safety, and pharmacokinetics of trastuzumab monotherapy administered on a 3-weekly schedule./. Clin. Oncol. 23 2162-2171. 

Palm S, Enmon RM Jr, Matei C, Kolbert KS, Xu S, Zanzonico PB, Finn RL, Koutcher JA, Larson SM, Sgouros G. Pharmacokinetics and Biodistribution of (86)Y-Trastuzumab for (90)Y dosimetry in an ovarian carcinoma model correlative MicroPET and MRI. J Nucl Med 2003 44 1148-1155. 

Storniolo AM, Pegram DM, Overmoyer B, Silverman P, Peacock NW, Jones SF, Loftiss J, Arya N, Koch KM, Paul E, Pandite L, Fleming RA, Lebowitz PF, Ho PTC, Burris HA. Phase I dose escalation and pharmacokinetic study of lapatinib in combination with trastuzumab in patients with advanced ErbB2-positive breast cancer. J Clin Oncol 2008 26(20) 3317-23. 

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