ANTICANCER RESEARCH 25: 2327-2344 (2005)
`
`Review
`
`Pharmacokinetics of Therapeutic Monoclonal
`Antibodies Used in Oncology
`
`DOMINIQUE LEVÊQUE1,2, SANDRA WISNIEWSKI1 and FRANÇOIS JEHL2
`
`1Hôpital de Hautepierre, pharmacie, Avenue Molière, 67000 Strasbourg;
`2Institut de Bactériologie, Laboratoire d’antibiologie, 3 rue Koeberle, 67000 Strasbourg, France
`
`Abstract. This review presents the clinical pharmacokinetics
`of the marketed therapeutic monoclonal antibodies used in
`oncology. Aspects regarding absorption, tissue distribution,
`elimination as well as factors influencing pharmacokinetics,
`pharmacodynamics and kinetic interactions are also discussed.
`
`instance, the elimination process, is emphasized by the
`empiricism sometimes observed in the modalities of
`treatment. The purpose of this paper is to review the kinetic
`characteristics of the monoclonal antibodies approved for
`the treatment of cancer.
`
`Monoclonal antibodies constitute a source of therapeutic
`agents used in the management of various diseases (1-6). In
`clinical oncology, the rationale for using monoclonal
`antibodies is to preferentially eradicate cancer cells by
`specific targeting and, in corollary, to gain in tolerance when
`compared with conventional agents or polyclonal antibodies
`(serotherapy). The therapeutic potential of monoclonal
`antibodies was rapidly recognized after the original report
`large scale
`of Köhler and Milstein in 1975 (7) (i.e.
`production of antibodies with a defined specificity) and the
`first paper dealing with the treatment of a cancer patient
`with a monoclonal antibody was published in 1980 (8).
`Nevertheless, the first monoclonal antibody for the
`treatment of cancer (edrecolomab) was only approved in
`1994, in Germany, and was followed by rituximab in
`November 1997 in the United States (9). To date,
`worldwide nine monoclonal antibodies used
`in the
`treatment of cancer are commercially available (Table I).
`Most of the pharmacological studies have focussed on the
`mechanisms of action (remaining often unresolved) and the
`cytotoxic properties of the monoclonal antibodies. Few
`works have described in full the clinical pharmacokinetics
`of therapeutic monoclonal antibodies. The lack of kinetic
`data, as well as the absence of knowledge concerning, for
`
`Correspondence to: D Levêque, Hôpital de Hautepierre, Pharmacie,
`Avenue Molière, 67000 Strasbourg, France. Tel: 33(0)388128213,
`Fax: 33(0)388127804, e-mail: dominique.leveque@chru-strasbourg.fr
`
`Key Words: Monoclonal antibodies, pharmacokinetics, oncology,
`review.
`
`General pharmacokinetics
`
`Structure of the monoclonal antibodies. Therapeutic mono-
`clonal antibodies are homogeneous immunoglobulins G
`(IgG) of murine or murine/human origin (chimeric,
`humanised). These proteins are bifunctional and are
`composed of two domains: the Fab domain that binds the
`antigen site and the Fc domain that interacts with effector
`cytotoxic cells and that is also involved in the transport
`across epithelial cells and in the regulation of serum
`concentrations. Chimeric and humanised antibodies display a
`human Fc domain. The molecular weight of monoclonal
`antibodies is high, around 150,000D, when compared with
`those of commonly used drugs (less that 1,000D).
`Chemotherapeutic monoclonal antibodies are either naked
`or conjugated to anticancer drugs (gemtuzumab ozogamicin)
`or radioisotopes (ibritumomab tiuxetan, tositumomab). The
`goal of conjugation is to increase the antitumoral activity of
`the antibody preferentially on targeted tissues by adding that
`of combined cytotoxic entities.
`
`Absorption. With respect to the official labelling, all
`monoclonal antibodies are administered by the intravenous
`route. Some papers have described
`the activity of
`alemtuzumab given subcutaneously in patients with B-cell
`chronic lymphocytic leukemia (B-CLL) (10-16). The kinetics
`of subcutaneous alemtuzumab (30 mg 3 times weekly for up
`to 18 weeks) have been investigated in 20 untreated patients
`with B-CLL (16). When compared with values obtained in 30
`other patients treated by the intravenous route, alemtuzumab
`plasma concentrations were
`judged similar, but the
`cumulative dose to reach the potentially
`lympholytic
`
`0250-7005/2005 $2.00+.40
`
`2327
`
`1
`
`EX2116
`Eli Lilly & Co. v. Teva Pharms. Int'l GMBH
`IPR2018-01426
`
`

`

`ANTICANCER RESEARCH 25: 2327-2344 (2005)
`
`concentration (1 mg/l) was higher (mean 551 mg versus 90
`mg). The highest concentrations ranged between 0.6 and
`24.8 mg/l (mean: 5.4) and between 2.8 and 26.4 mg/l (mean:
`10.7) after subcutaneous and
`intravenous
`injections,
`respectively (16). The concentrations appeared to increase
`during the 12 weeks of subcutaneous treatment when
`considering an example of a patient profile (i.e. no steady
`state was attained) (16). The elimination parameters could
`not be determined (lack of terminal points) and it is not
`known if the subcutaneous route has an impact on the
`terminal half-life. Regarding a patient with myeloma,
`Gasparetto et al. (17) observed 2 absorption peaks (2 and 6
`h) after subcutaneous administration of alemtuzumab.
`Overall, the bioavailability of subcutaneous alemtuzumab
`remains unknown.
`Subcutaneous injection could lead to improved ease of
`administration
`(self administration) and,
`recently,
`formulations of concentrated crystalline rituximab and
`trastuzumab enabling a low volume of injection have been
`developed (18). In the case of alemtuzumab, subcutaneous
`administration was associated with diminished acute
`systemic toxicity when compared with intravenous infusion.
`However, site skin reactions were observed during the first
`2 weeks (13).
`
`Distribution. The penetration of monoclonal antibodies in
`tumor tissues is determinant for their activity. The antibodies
`target proteins expressed on the membrane of tumors cells,
`except bevacizumab that binds the circulating cytokine
`VEGF (Vascular Endothelial Growth Factor). Once the
`antibodies have been administered systemically, they must
`leave the tumoral vessels to diffuse in the interstitial matrix
`and hence reach the tumoral cells. Given that monoclonal
`antibodies were used for diagnostic purposes and tumor
`imaging, an extensive literature has been devoted to the
`distribution process. In general, the diffusion of monoclonal
`antibodies is limited and appears heterogeneous. This
`feature is underscored by their low volume of distribution (3-
`5l) approaching that of the plasma. This limitation had
`already been observed in the mid eighties after the first
`clinical trials (19). Animal studies have shown that most
`monoclonal antibodies were concentrated in the region
`adjacent to vessels (i.e. within 40 Ìm or 2 cell diameters)
`(20). Experimental works using intravital microscopy (a
`methodology enabling the continuous monitoring of cellular
`processes in living systems) have revealed the spatial and
`temporal heterogeneous aspects of tumoral blood circulation
`(21). The heterogeneity of tumoral distribution (inter- and
`intra-individual) of an anti-angiogenic antibody was
`originally observed, in vivo, in 20 patients using positron
`emitting tomography (22).
`The distribution depends on the tumoral physiology and
`the characteristics of the antibody (affinity, molecular
`
`2328
`
`vascularization
`to
`relative
`Parameters
`weight).
`(permeability, blood supply ), the difference of pressure
`between the tumoral capillary and the interstitial fluid, the
`extracellular matrix (particularly the content and the
`organisation of the collagen), the type and the localization
`of the tumor appear to determine the penetration of an
`antibody (23-28). Tumors display
`increased vascular
`permeability when compared with normal
`tissues.
`Unfortunately, this permeability is coupled with elevated
`interstitial pressure, thus hindering the extravasation of
`drugs (29, 30). Furthermore, as stated before, the blood
`supply is heterogeneous and can be impaired due to the
`compression of the tumoral vessels by cancer cells limiting
`the efficient and homogeneous delivery of drugs (31). In this
`regard, Jain et al. have shown that elevated interstitial
`pressure observed in tumors limits their penetration (26). In
`addition, they observed in xenografted mice that the
`interstitial diffusion of a non-specific IgG was prevented in
`tumors with high collagen levels (27).
`Concerning the monoclonal antibody, one of the factors
`that may limit the diffusion in tumor tissues is the affinity
`of the macromolecule for the tumoral antigen and the
`intensity of the antigenic expression (32-35). This constitutes
`the concept of the “binding site barrier” proposed by
`Weinstein et al. at the end of the eighties. According to their
`experiments performed in guinea pigs bearing allografts of
`primitive (34) and metastatic tumors (35), the binding of
`antibodies to antigens at the periphery of the tumor limits
`and delays the diffusion. The lack of affinity for the tumoral
`antigens (IgG control of the same molecular weight) results
`in a more homogeneous distribution
`in the tumor.
`Increasing the dose of the monoclonal antibody partially
`enhances the tumoral penetration (34, 35). The decrease in
`affinity (by 100) for the tumoral antigen can lead to a better
`diffusion (36). Clinically,
`the problem of
`tumoral
`accessibility has been advanced by some investigators
`reporting the poor response of bulky lymph nodes to
`alemtuzumab in patients with B-CLL (37, 38). Given their
`limited diffusion, the therapeutic potential of monoclonal
`antibodies is enhanced when they are combined with a
`conventional chemotherapy (39, 40), in the adjuvant setting
`(subclinical tumor) (41) or when they are linked to cytotoxic
`agents (calicheamicin derivative) (42) or radioisotopes
`(iodine 131, yttrium 90) (43).
`Plasma IgG are considered to be excluded from the
`central nervous system (CNS) given their size. Experimental
`studies have shown that IgG were transported across the
`blood brain barrier, from brain to blood, but not the reverse
`(i.e. from blood to brain) (44, 45). As will be discussed
`below, the efflux appears to be mediated by the transporter
`FcRn expressed in brain capillary endothelial cells (45).
`Diffusion in the CNS has been examined for trastuzumab
`and rituximab by determining
`their
`levels
`in
`the
`
`2
`
`

`

`Levêque et al: Pharmacokinetics of Monoclonal Antibodies Used in Cancer Therapy
`
`Table I. Presentation of the therapeutic monoclonal antibodies used in oncology.
`
`Monoclonal antibody
`
`Type
`
`Conjugated
`
`Status
`
`Target
`
`Approved indications
`
`Rituximab
`Ibritumomab Tiuxetan
`Tositumomab
`Alemtuzumab
`Gemtuzumab
`Ozogamicin
`Trastuzumab
`Cetuximab
`Edrecolomab
`Bevacizumab
`
`IgG1, chimeric
`IgG1, murine
`IgG2a, murine
`IgG1, humanised
`IgG4, humanised
`
`IgG1, humanised
`IgG1, chimeric
`IgG2a, murine
`IgG1, humanised
`
`No
`Yttrium 90
`Iodine 131
`No
`Derivative of
`calicheamycin
`No
`No
`No
`No
`
`Approved
`Approved
`Approved USA
`Approved
`Approved USA
`
`CD20
`CD20
`CD20
`CD52
`CD33
`
`Follicular NHL, Large cell NHL
`Relapsed low-grade/follicular NHL
`Relapsed follicular NHL
`Refractory B cell CLL
`Relapsed AML
`
`Approved
`Approved
`Approved Germany
`Approved USA
`
`HER2
`EGFR
`Ag17-1a
`VEGF
`
`Metastatic breast cancer
`Relapsed metastatic colorectal cancer
`Adjuvant treatment of colorectal cancer
`Metastatic colorectal cancer
`
`cerebrospinal fluid (CSF) as a surrogate. Trastuzumab
`concentrations have been measured in the CSF and the
`serum of a patient with meningeal carcinomatosis, following
`intravenous infusion (46). The concentration in the CSF was
`very low (0.21 mg/l versus 70.32 mg/l in the serum).
`According to another case report, the CSF concentration of
`rituximab administered intravenously (800 mg) to a patient
`with CNS involvement of a lymphoma was around 1% of
`the blood concentration (47). However, the treatment that
`associated 12 rituximab
`infusions and 5
`intrathecal
`chemotherapies was active for the authors. The CSF
`concentration of rituximab (375 mg/m2) was 0.35 mg/l in a
`patient with CNS lymphoma 7 days after intravenous
`infusion (48). The simultaneous serum concentration was
`not measured. In a general way, systemic treatment of
`cerebral tumors with monoclonal antibodies is likely to be
`ineffective because of poor diffusion across the blood brain
`barrier. An approach to increase the cerebral concentrations
`of rituximab has been to deliver the antibody by the
`intraventricular route via an Ommaya reservoir. One day
`after an intraventricular injection of 25 mg in a patient with
`CNS lymphoma, the concentration in the CSF of rituximab
`was 10 mg/l (48). After 4 intraventricular administrations
`(total dose 80 mg), the lymphoma cells were cleared from
`the CSF, indicating that the concentration was sufficient.
`Unfortunately, no
`response was observed
`in
`the
`parenchymal tumor mass (48). Extended kinetic data of
`intrathecal rituximab are available in the cynomolgus
`monkey. After inventricular injections of 2 to 5 mg, the CSF
`concentrations appeared to decrease biphasically with a
`terminal half-life of 5 h (49).
`
`Elimination. Very few data are available on the elimination
`pathways of therapeutic monoclonal antibodies. By analogy to
`endogenous IgG, monoclonal antibodies could be metabolized
`in the vascular compartment by endothelial cells. IgG levels
`in rodents and probably in humans are regulated by the FcRn
`receptor (50). The FcRn receptor is known to possess two
`main functions: the transport of IgG (particularly the transfer
`
`of IgG across the maternofetal barrier) known as transcytosis
`and the control of IgG catabolism (50, 51). Expression of
`FcRn has been reported in endothelial cells, monocytes and
`epithelial cells of various human tissues (52) According to the
`hypothesis of Brambell et al. (53) and the model of Junghans
`and Anderson (54), the circulating IgG is internalized in low
`pH endosomes, wheras binding of the Fc domain with FcRn is
`promoted. The IgG is then recycled to the cell surface and
`released. The IgG in excess (not bound to the saturable FcRn)
`undergoes degradation in lysosomes (50, 55). This theory
`could explain the long half-life of IgG (3 weeks, except for 7
`days for the subclass IgG3 in humans) relative to other plasma
`proteins (56) and the dose-dependent catabolism linked to the
`saturable protection. Mice knocked out for a deletion of the
`light chain of FcRn exhibit a shorter catabolic half-life for IgG
`than wild-type animals (0.47 versus 4.9 days) (54). In addition,
`the impact of FcRn in the disposition of a monoclonal
`antibody has been shown in the mouse (57). Nevertheless,
`comparative kinetics of chemotherapeutic monoclonal
`antibodies in FcRn-deleted and wild-type mice have not be
`reported. The behavior of monoclonal antibodies bound to
`target cells is unknown. Kennedy et al. (58) suggested that
`circulating B lymphoma cells bound to rituximab via the CD20
`antigen could be sequestered by phagocytic cells where the
`complex antigen/antibody is removed, releasing into the
`circulation the CD20-depleted cancer cell. This could explain
`the acute loss of the membrane target (CD20) from the
`circulating lymphocytes after rituximab treatment in patients
`with CLL and supports the possible degradation of rituximab
`in phagocytic cells.
`The renal excretion of chemotherapeutic monoclonal
`antibodies is poorly documented. The expression of FcRn
`in proximal renal cells (59) could suggest the transfer of IgG
`in urine by transcytosis. The bidirectional transport of IgG
`in human renal cells has been shown, in vitro (59). Renal
`insufficiency does not seem to have an impact on
`trastuzumab elimination (60) and successful administration
`of rituximab (i.e. at full dose) has been reported in 3
`patients with renal failure (2 being on hemodialysis) (61,
`
`2329
`
`3
`
`

`

`ANTICANCER RESEARCH 25: 2327-2344 (2005)
`
`Table II. Pharmacokinetic data for rituximab. Results as mean (SD).
`
`No. of
`patients
`
`Dose
`(mg/m2)
`
`Duration of
`study (days)
`
`Assay
`
`Cmax
`(mg/l)
`
`Vd
`
`Cl (ml/min)
`
`t1/2 (hours)
`
`Reference
`
`9
`3
`
`14
`
`4
`8
`37
`
`26
`
`375
`375
`375 (4th dose)
`375 (1st dose
`375 (4th dose)
`250
`375
`375 (1st dose)
`375 (8th dose)
`375(9th dose)
`
`4
`NR
`
`7
`90
`90
`90
`7
`180
`365
`
`Elisa
`Elisa
`
`Elisa
`
`Elisa
`Elisa
`Elisa
`
`Elisa
`
`500(135)
`254(148)
`433(273)
`205(59)
`464(119)
`64(21)
`92(34)
`581
`1177
`463 (109)
`
`ND
`ND
`ND
`ND
`ND
`Vss:10.7(2.7)
`Vss:11.1(3.2)
`ND
`
`ND
`1.9(2.4)
`0.7(1)
`0.64(0,3)
`0.15(0,05)
`2.8(5.1)
`0.7(1)
`ND
`
`225(102)
`33(21)
`76(43)
`76.6(31)
`205(95)
`560(607)
`387(189)
`ND
`
`ND
`
`ND
`
`ND
`
`81
`80
`
`79
`
`82
`
`83
`
`84
`
`Cmax, Concentration peak ; Vd, volume of distribution ; Cl, Clearance ; t1/2, terminal half-life ; NR, not reported ; ND, not determined; Vss,
`volume of distribution at steady state.
`
`62). In addition, rituximab is not removed by hemodialysis
`(63). Urinary excretion of some radiolabelled antibodies
`(64), and particularly ibritumomab tiuxetan (65), has been
`quantified using a radioactive assay. This methodology is
`generally hampered by lack of specificity since it can not
`discriminate the intact antibody from the unconjugated
`radioisotope. Urinary recovery of ibritumomab tiuxetan
`labelled with yttrium 90 (Y-90) accounted for 5.9% of the
`dose over 7 days, when determined with a radioactive assay
`(65). Preclinical data suggest a good retention of Y-90 in the
`chelator tiuxetan with no demonstrable loss over 4 days
`(66). This suggests that the urinary radioactivity reflects the
`catabolic
`fate and not
`the dissociation of
`the
`radionucleotide from the conjugate in the plasma. On the
`other hand, it can not exclude the presence of the labelled
`antibody. Clinically, the administration of ibritumomab
`tiuxetan labelled with Y-90 has been judged feasible at
`therapeutic dosage in a patient with chronic renal failure
`(67). Similarly, the urine excretion of trastuzumab labelled
`with indium 111 (In-111) has been estimated in 11 patients
`after a single injection (68). It represented 25% of the
`injected dose over 7 days.
`
`Pharmacokinetic parameters
`
`Some kinetic studies suffer from a lack of information
`regarding the assay, the sampling process and the
`calculation of the parameters. Furthermore, the data are
`often incomplete and not cleary presented. Concentrations
`of monoclonal antibodies in biological fluids are generally
`determined by enzyme-linked
`immunosorbent assay
`(ELISA). Radioimmunoassay (RIA) and flow cytometry
`have also been used. Concerning antibodies conjugated to
`radionuclides, pharmacokinetic characteristics are derived
`from the blood or organ radioactivity content. The sampling
`
`duration or the number of time-points often appear
`insufficient to correctly estimate the elimination parameters,
`given their potential long half-life (3 weeks, by analogy to
`endogenous IgG). Hence, some data must be interpreted
`with caution. In general, monoclonal antibodies exhibit a
`low volume of distribution (3-5l), approaching the
`serum/plasma volume, a low systemic clearance (around 0.5-
`4 ml/min) and a terminal half-life varying between 2 days
`and 28 days. The half-life of murine antibodies is generaly
`shorter than that of antibodies containing a human Fc
`domain (i.e. chimeric, humanised) (69). This could be due
`to a lesser affinity of the murine Fc domain for the human
`FcRn (70). Indeed, preclinical data have indicated that
`increasing the affinity of the antibody for FcRn could lead
`to a longer half-life (71, 72).
`
`Rituximab
`
`Rituximab is a chimeric anti-CD20 monoclonal antibody
`actually approved in the treatment of indolent and agressive
`forms of B-cell non-Hodgkin lymphoma (NHL). It has also
`been
`investigated
`in other CD20-positive B-cell
`malignancies such B-CLL (73, 74) and in autoimmune
`diseases (75). The CD20 antigen is expressed on the surface
`of normal and malignant mature B lymphocytes. Data from
`in vitro and in vivo studies suggest various mechanisms of
`action for rituximab such as antibody-dependent cellular
`cytotoxicity (ADCC), complement-mediated cytotoxicity
`(CMC), as well as induction of apoptosis (76, 77).
`Rituximab is administered by intravenous infusion at the
`dosage of 375 mg/m2 weekly for 4 to 8 courses when given
`alone, or every 3 weeks when combined with chemotherapy.
`Three assays based on ELISA and flow cytometry for the
`determination of rituximab in human plasma have been
`published in full (78).
`
`2330
`
`4
`
`

`

`Levêque et al: Pharmacokinetics of Monoclonal Antibodies Used in Cancer Therapy
`
`Table III. Pharmacokinetic data for alemtuzumab. Results as mean (SD).
`
`No. of
`patients
`
`Dose
`(mg)
`
`Duration of
`study (days)
`
`Assay
`
`Cmax
`(mg/l)
`
`Vss (l)
`calculated
`for 70 kg
`
`Cl
`(ml/min)
`
`t1/2
`(days)
`
`Reference
`
`30
`20
`11
`5
`10
`
`30 thrice weekly
`30 SC thrice weekly
`10/day ( 5 days)
`10/day (10 days)
`20/day (5 days)
`
`84
`126
`30
`30
`30
`
`Immunofluorescence flow cytometry
`Immunofluorescence flow cytometry
`Immunofluorescence flow cytometry
`Immunofluorescence flow cytometry
`Immunofluorescence flow cytometry
`
`10.7(range 2.8-26.4)
`5.4 (range 0.6-24.8)
`2.5 (0.9)
`6.1(2.3)
`13.7(range 7.5-16.6)
`
`12.95
`ND
`ND
`ND
`ND
`
`ND
`ND
`ND
`ND
`ND
`
`6.1
`ND
`21
`15
`8 (range 4-32)
`
`16
`16
`97
`97
`98
`
`Cmax, Concentration peak ; Vss, volume of distribution at steady state; Cl, Clearance ; t1/2, terminal half-life ; ND, not determined; SC,
`subcutaneous.
`
`The most complete kinetic data are derived from a phase
`III study that included 166 patients with low-grade NHL
`who were receiving rituximab at 375 mg/m2 as single therapy
`(79) (Table II, (79-84)). The pharmacokinetic parameters
`were determined in 14 patients after the first and the fourth
`infusion over sampling periods of 7 and 90 days, respectively
`(Table II). The mean value of peak serum concentration
`(Cmax) increased from 205.6 mg/l (standard deviation or SD:
`59.9) after the first cycle to 464.7 mg/l (SD: 119) after the
`fourth cycle. The mean systemic clearances were 0.64 ml/min
`(SD: 0.3) and 0.15 ml/min (SD: 0.05) after the first and
`fourth courses, respectively (79). The terminal half-lives were
`estimated after the two administrations and were 76.6 h (SD:
`31.1) and 205 h (SD: 95). In addition, serum rituximab
`concentrations were measured in 147 patients over 6 months.
`At 3 months post-treatment, rituximab was still detectable
`with a median value of 20 mg/l.
`
`Ibritumomab tiuxetan
`
`Ibritumomab tiuxetan is a radioimmunotherapeutic agent
`composed of a murine anti-CD20 antibody (ibritumomab)
`covalently linked to a chelator (tiuxetan) radiolabelled with
`Y-90 for therapy or In-111 for imaging (85). The concept of
`radioimmunotherapy is to target ionizing radiation to
`radiosensible tumors (lymphoma cells herein) by means of
`monoclonal antibodies. Radiolabelling can partially
`circumvent the problems of tumoral diffusion observed with
`naked antibodies and appears interesting for the treatment
`of bulky, poorly vascularized tumors (86, 87). The
`cytotoxicity of ibritumomab tiuxetan is attributable to the
`dose of radiation and to the intrinsic activity of the murine
`antibody carrier (87). Y-90 delivers beta emission capable
`of reaching cells 5 mm away
`from
`the antibody
`(corresponding approximately to 100-200 cell diameters)
`(86). Ibritumomab tiuxetan is approved for the treatment of
`patients with follicular NHL refractory to rituximab and of
`patients with relapsed or refractory low-grade, follicular or
`transformed B-cell NHL. The treatment consists of a single
`
`course (dose: 0.4 or 0.3 mCi/kg depending on the platelet
`count, maximum 32 mCi) preceded by rituximab infused at
`250 mg/m2, to deplete circulating blood B cells and improve
`the distribution of the conjugate. Prior to treatment (1
`week), imaging is performed to evaluate the radiation
`absorbed dose to healthy organs and bone marrow (i.e. to
`ensure that the exposure is within acceptable limits) with
`In-111 ibritumomab tiuxetan. The gamma emitter In-111 is
`more suitable for imaging purposes than Y-90 (beta
`emitter) and has no therapeutic emission.
`Pharmacokinetics of Y-90 ibritumomab tiuxetan have
`been estimated from In-111 measurements in blood samples
`of 72 patients, obtained over a period of 7 days (65). The
`median biological half-life of the antibody was 47 h (range:
`22-140). It is shorter than that of the chimeric form
`(rituximab), probably attributable to a lesser affinity of the
`murine Fc domain for the human FcRn receptor. The
`elimination process has also to account for the exponential
`decrease of Y-90 beta-emitting radiation (half-life of 64 h).
`As suggested, a rapid clearance of the conjugate (both in
`terms of antibody and activity) is desirable to avoid
`excessive exposure. Urinary excretion of Y-90 ibritumomab
`tiuxetan was determined in 10 patients over 7 days. As
`stated before, it represented 5.9% (range: 3.2-8.5) of the
`injected dose when determined by Y-90 radioactivity (65).
`
`Tositumomab
`
`Tositumomab is a murine anti-CD20 antibody radiolabelled
`with iodine-131 (I-131) that has been approved for the
`treatment of NHL, with or without transformation,
`refractory to rituximab and that has relapsed following
`chemotherapy (87). When compared with the metal Y-90,
`I-131 links directly in the antibody and does not require a
`chelate like tiuxetan. Furthermore, I-131 produces beta
`and gamma emissions with a half-life of 193 h (8 days)
`(87). High energy gamma emissions necessitate restrictive
`radiation procedures to protect the patient’s family
`members and healthcare workers. In addition, the range
`
`2331
`
`5
`
`

`

`ANTICANCER RESEARCH 25: 2327-2344 (2005)
`
`Table IV. Pharmacokinetic data for gemtuzumab ozogamicin. Results as mean (SD).
`
`No. of
`patients
`
`59
`49
`14(children)
`14(children)
`2(children)
`1(child)
`14(children)
`9(children)
`
`Dose
`(mg/m2)
`
`Duration of
`study (days)
`
`Assay
`
`9
`9 (2nd dose)
`6
`6 (2nd dose)
`7.5
`7.5 (2nd dose)
`9
`9 (2nd dose)
`
`10
`28
`10
`10
`10
`10
`10
`10
`
`Elisa
`Elisa
`Elisa
`Elisa
`Elisa
`Elisa
`Elisa
`Elisa
`
`Cmax
`(mg/l)
`
`2.9(1.3)
`3.7(1.3)
`1.7(1.1)
`1.9(1.1)
`3.1
`3
`3.4(1)
`4.6(2.1)
`
`Vss (l)
`
`Cl (ml/min)
`
`t1/2 (hours)
`
`Reference
`
`20.9(21.5)
`9.9(8.8)
`13.7(14)
`12.5(13.1)
`6.3
`14.5
`6.5(5.5)
`3.9(2.1)
`
`4.4(3.8)
`2.2(2.5)
`10.1(22.3)
`5.3(8.1)
`2
`1.5
`2.6(3.8)
`3.5(7.5)
`
`72.4(42)
`93.7(67.4)
`43.1(22.7)
`49.4(25.6)
`40
`33.4
`63.7(44.3)
`57.8(33.4)
`
`104
`104
`105
`105
`105
`105
`105
`105
`
`Cmax, Concentration peak ; Vss, volume of distribution at steady state ; Cl, Clearance ; t1/2, terminal half-life.
`
`of beta emission from I-131 is shorter than that of Y-90
`(0.4 mm versus 5 mm). The mechanism of cytotoxic action
`involves the intrinsic activity of the murine antibody
`vector (ADCC, induction of apoptosis) and the dose of
`radiation
`(88, 89). Contrasting with
`rituximab,
`tositumomab shows very weak CMC activity (77). The
`treatment consists of a single course (patient-specific mCi
`dose adjusted to an absorbed total body radiation dose of
`75 cGy) preceded by a dosimetric step with the same
`isotope. Unlike ibritumomab tiuxetan that is administered
`at a dose based on body weight, tositumomab requires
`individual dosimetry (i.e. assessment of patient-specific
`dose) given the highly variable (5-fold) clearance rate of
`I-131 (90). Prior to the injections of the radioconjugate
`(dosimetric and therapeutic), 450 mg of unlabelled
`tositumomab is infused to improve biodistribution.
`Pharmacokinetic data of tositumomab are sparse. The
`mean effective half-life has been estimated to be 59.3 h
`(range: 24.6-88.6 h) using a radioactive assay (91). It has to
`be mentionned that the radioactive methodology is not
`specific for estimating the concentrations of the conjugate
`given the dehalogenation of iodine 131. The assay evaluates
`the activity of the radiolabelled antibody and of the free
`radionuclide, but excludes the naked antibody which is
`potentially cytotoxic. However, the half-life of tositumomab
`appears shorter than that of rituximab labelled with I-131
`when estimated by the same methodology (i.e., radioactive
`assay), reflecting the rapid elimination of murine antibodies
`when compared with
`their chimeric or humanised
`counterparts (92).
`
`Alemtuzumab
`
`is a humanised
`Alemtuzumab (or CAMPATH-1H)
`monoclonal antibody against the CD52 antigen abundantly
`expressed on lymphocytes and monocytes (93, 94). It was
`first developed in a murine form (Campath-1M then
`Campath-1G) 25 years ago, as a lymphosuppressive agent.
`
`According to the labelling, alemtuzumab is used for the
`treatment of refractory B-CLL as single agent and is
`administered at a fixed dose (30 mg), 3 times a week for 12
`weeks. Alemtuzumab
`is
`also developed
`as
`an
`immunosuppressive agent with a different dosage regimen.
`The mechanisms of action appear to include immunological
`processes (ADCC, CMC) and induction of apoptosis (94).
`Analytical methods have been published in full (95, 96),
`but the kinetic data in patients with B-CLL have only
`become available recently (16). Alemtuzumab was given
`intravenously to 30 patients (30 mg 3 times weekly) for up
`to 12 weeks. Serum samples were taken before and after the
`dose (15 min). The highest peaks and trough concentrations
`shown a wide variation ranging from 2.8 mg/l to 26.4 mg/l
`and from 0.5 mg/l to 18.3 mg/l, respectively (Table III) (16).
`The estimated mean terminal half-life was 6.1 days when
`determined in 16 patients. The kinetic properties of
`alemtuzumab given as an immunosuppressive have been
`partially documented in patients receiving allogeneic stem
`cell transplantation (Table III) (97, 98). The antibody was
`administered at 10 mg/day for 5 or 10 days to 11 and 5
`patients, respectively (97). The pharmacokinetic profiles
`were determined after the last injection over a sampling
`period of 30 days. In both groups, alemtuzumab serum
`concentrations decreased in a biphasic manner with
`estimated terminal half-lives of 21 and 15 days (97).
`
`Gemtuzumab ozogamicin
`
`immunoconjugate
`is an
`Gemtuzumab ozogamicin
`consisting of a humanised anti-CD33 monoclonal antibody
`that is covalently linked to a derivative of the antitumor
`antibiotic calicheamicin (N-acetyl gamma calicheamicin
`dimethyl hydrazide) (99, 100). The formulation contains
`about 50% of the conjugate, the remainder being the
`naked antibody (101). The CD33 antigen is found on the
`surface of maturing normal and leukemic myeloid cells
`but is absent in stem cells, lymphoid cells and non
`
`2332
`
`6
`
`

`

`Levêque et al: Pharmacokinetics of Monoclonal Antibodies Used in Cancer Therapy
`
`Table V. Pharmacokinetic data for trastuzumab. Results as mean (SD).
`
`No. of
`patients
`
`Dose
`
`Duration of Assay
`study (days)
`
`Cmax
`(mg/l)
`
`45
`6
`3
`3
`6
`476
`15
`
`100mg
`1mg/kg (single dose)
`2mg/kg (single dose)
`4mg/kg (single dose)
`8mg/kg (single dose)
`2mg/kg
`6mg/kg (12th dose)
`
`7
`21
`21
`21
`21
`NR
`21
`
`Elisa
`Elisa
`Elisa
`Elisa
`Elisa
`NR
`Elisa
`
`ND
`19.1 (2.7)
`43.4 (8.5)
`72.4 (17.2)
`169.6 (24.9)
`110
`237
`
`Vd (l)
`calculated
`for 70kg
`
`ND
`3.6 (0.4)
`3.7 (1.4)
`5.2 (0.9)
`4.9 (0.5)
`2.95
`ND
`
`Cl (ml/min)
`calculated
`for 70kg
`
`ND
`16.4 (3.7)
`12.9 (1.6)
`7.5 (1.2)
`6.5 (2.2)
`0.15
`0.14
`
`t1/2
`(days)
`
`Reference
`
`8.3 (5)
`2.7 (0.4)
`3.1(2)
`8.8 (1.3)
`10.4 (3)
`28.5
`18.3
`
`109
`110
`110
`110
`110
`60
`107
`
`Cmax, Concentration peak ; Vd, volume of distribution ; Cl, Clearance ; t1/2, terminal half-life ; NR, not reported ; ND, not determined.
`
`Table VI. Pharmacokinetic data for cetuximab. Results as mean (SD).
`
`No. of
`patients
`
`Dose
`(mg/m2)
`
`Duration of
`study (days)
`
`Assay
`
`7
`6
`10
`3
`3
`7
`8
`8
`7
`8
`7
`
`20
`50
`100
`200
`400
`250 (3rd injection)
`50 (single injection)
`100 (single injection)
`250 (single injection)
`400 (single injection)
`500 (single injection)
`
`28
`28
`28
`28
`28
`7
`21
`21
`21
`21
`21
`
`Biocore assay
`Biocore assay
`Biocore assay
`Biocore assay
`Biocore assay
`Elisa
`NR
`NR
`NR
`NR
`NR
`
`Cmax
`(mg/l)
`
`ND
`ND
`ND
`ND
`ND
`130 (31)
`19.9
`54.7
`158.1
`205.1
`243.2
`
`Vd (l)
`calculated
`for 70kg
`
`Cl (ml/min)
`calculated
`for 70kg
`
`t1/2
`(days)
`
`Reference
`
`4.3
`3.2
`3.2
`ND
`ND
`Vss 3.5 (0.7)
`Vss 6.4
`Vss 4.4
`Vss 5.3
`Vss 4.4
`Vss 5.9
`
`3.6
`1.3
`0.9
`0.5
`0.4
`0.6 (0.15)
`3
`1.4
`0.8
`0.65
`0.65
`
`ND
`ND
`ND
`ND
`ND
`4.4 (1.3)
`1.1
`1.6
`3
`3.1
`5.5
`
`115
`115
`115
`115
`115
`117
`118
`118
`118
`118
`118
`
`Cmax, Concentration peak ; Vd, volume of distribution ; Cl, Clearance ; t1/2, terminal half-life ; NR, not reported ; ND, not determined ; Vss,
`volume of distribution at steady state.
`
`hematopoietic tissues (99). The binding of the conjugate
`to the leukemic cells is followed by internalization and
`release of the calicheamicin derivative after lysosomal
`hydrolysis. After reduction, the reactive derivative causes
`double-stand breaks in DNA leading to eventual cell
`death (102). The cytotoxic action could also be attributed
`to the carrier since a humanised antibody directed to
`CD33 (HuM195) has been shown to exhibit clinical
`antileukemic activity via presumptive ADCC (103).
`Gemtuzumab ozogamicin is indicated as single agent
`therapy for the treatment of patients with acute myeloid
`leukemia (AML) in first relapse who are 60 years of age
`or older and who are not candidates for cytotoxic
`chemotherapy. It is administered at 9 mg/m2 as 2 infusions
`separated by 2 weeks.
`The pharmacokinetics have been characterized in 59
`patients with AML by measuring the plasma concentrations
`of the targeting antibody (re