ANTICANCER RESEARCH 28: 3075-3078 (2008)
`
`Evaluation of Fixed Dosing of New
`Anticancer Agents in Phase I Studies
`DOMINIQUE LEVÊQUE
`Pharmacy, Hôpital Hautepierre, 67000 Strasbourg, France
`
`Abstract. Aim: To assess
`the basis of dosage of
`investigational anticancer agents in adult phase I trials.
`Materials and Methods: All nonpediatric phase I trials
`presented at
`the meetings of
`the American Society of
`Clinical Oncology and of
`the American Society of
`Hematology in 2005 were reviewed. Data regarding the type
`of investigational agent, the route of administration and the
`basis of dosing (fixed, body surface area, body weight) were
`collected. Results: In all, 225 phase I studies were analyzed
`concerning 148 new anticancer agents. Among 225 studies,
`91 (40.4% ) used a fixed dose. Dosages were adjusted to
`body surface area and body weight in 44% (99/225) and
`13.8% (31/225) of all trials, respectively. Regarding drugs
`given orally (n=40), the majority of the trials (62/77; 80% )
`used a fixed dose. By contrast, only 7.5% (9/120) of studies
`involving intravenous agents (n=82) were conducted with a
`fixed dose. Most of
`these trials (71.6% ) used a dose
`adjusted to body surface area. Of the 73 trials involving
`conventional cytotoxics, 70 (96% ) used body surface area
`dosing. On the other hand, 78.5% (62/79) of studies
`investigating
`targeted
`agents
`used
`a
`fixed
`dose.
`Monoclonal antibodies and antisense agents were mainly
`administered on a body weight basis (13/25 and 4/7 trials,
`respectively). Conclusion: A fixed dose was used in a
`minority of the adult phase I trials presented at the ASCO
`and ASH meetings in 2005.
`
`Presented in part at the 97th Annual Meeting of the American
`Association for Cancer Research (AACR), Washington, 1-5 April
`2006 and at the annual meeting of the American Association of
`Pharmaceutical Scientists (AAPS), San Diego, 11-15 November
`2007.
`to: Dominique Levêque, Pharmacy, Hôpital
`Correspondence
`Hautepierre, avenue Molière, 67000 Strasbourg, France. Tel: +33 0
`388128213, Fax: +33 0 388127804, e-mail: dominique.leveque@chru-
`strasbourg.fr
`Key Words: Phase I, anticancer agents, fixed dose, body surface
`area, body weight.
`
`Dosing of anticancer agents in adult patients is traditionally
`adjusted according to estimated body surface area or body
`weight. For example, in France, 80% of approved anticancer
`drugs are administered according to body surface area and
`10% to body weight. This is based on the intuitive belief that
`the capacities of elimination of a drug are related to body
`size in adults. It is assumed that this approach decreases the
`pharmacokinetic and pharmacodynamic interindividual
`variability of agents known to have a narrow therapeutic
`index. This practice is relatively specific to oncology and
`besides anticancer agents, also concerns supportive care
`products such as some hematopoietic growth factors, folinic
`acid, rasburicase, palifermin, voriconazole and glucarpidase.
`Curiously, this approach may be heterogeneous within a
`class of drugs (fixed dose, dose based on body weight or
`body surface area for monoclonal antibodies), or even for a
`single drug such as dacarbazine for which dosing is based on
`body weight as monotherapy or body surface area as
`combination and rituximab for which dosing is adjusted to
`body surface area in the treatment of lymphomas (375
`mg/m2) and is fixed in rhumatoid arthritis (1 g).
`Practically, and when compared with the fixed dose, body
`size-based dosing is a complication necessitating calculations
`that
`can generate prescription and preparation errors.
`Scientifically,
`this practice is mostly either unjustified or
`unvalidated. In fact, body surface area or body weight should
`only be used if it has been demonstrated that they constitute a
`significant
`factor affecting pharmacokinetic and clinical
`variability. When compared to fixed dosing, administration of
`anticancer drugs adjusted to body weight or body surface area
`should lead to improvement of
`therapeutic outcomes.
`Nevertheless, in the last 18 years, numerous reports have
`indicated that several anticancer agents could be administered at
`a fixed dose in adult patients (1-10). In other words, estimated
`body surface area or body weight was not shown to significantly
`correlate with pharmacokinetic or pharmacodynamic variability.
`In addition, in 2002, the abandonment of the use of body surface
`area in dosing of new agents in phase I studies was
`recommended (11). To see if these recommendations were
`effectively implemented, we assessed the basis of dosage of
`investigational anticancer agents in adult phase I trials.
`
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`ANTICANCER RESEARCH 28: 3075-3078 (2008)
`
`Table I. Basis of dosing of investigational anticancer agents in adult phase I trials (n=225).
`Basis of dosing (number of trials)
`Body surface area-based
`Body weight-based
`86
`23
`13
`2
`3
`2
`2
`13
`4
`4
`
`Type of drug (n)
`Intravenous (82)
`Oral (40)
`Subcutaneous/intradermally (16)
`Conventional (45)
`Targeted (42)
`Monoclonal antibody (19)
`Immunomodulator (11)
`Antisense agent (6)
`Vaccine (15)
`
`Fixed dose
`9
`62
`10
`1
`62
`8
`6
`1
`13
`
`70
`13
`4
`2
`2
`
`Not reported
`2
`3
`
`2
`
`2
`
`Total
`120
`77
`16
`73
`79
`25
`12
`7
`15
`
`Materials and Methods
`The nonpediatric phase I trials presented at the meetings of the
`American Society of Clinical Oncology (ASCO) and of the
`American Society of Hematology (ASH) in 2005 were reviewed.
`Abstracts including the terms ‘phase I or phase I/II’ in the title were
`identified by browsing the 20 categories of the 2005 ASCO meeting
`(ASCO.org) and the abstract book of the 2005 ASH meeting.
`Investigational anticancer agents or nononcological licensed drugs
`for which antitumoral activity was tested (e.g. everolimus) were
`included. Anticancer agents that were approved in the European
`Union at the date of the meeting were excluded.
`Data regarding the type of agent (conventional, targeted or
`interfering with transduction pathways, monoclonal antibody,
`vaccine, antisense agent,
`immunomodulator),
`the route of
`administration and the basis of dosing (fixed, body surface area,
`body weight) were collected from the abstract body. Additional
`information concerning the type of agent was sought using PubMed.
`The objective of the study was to assess the rate of fixed dosing of
`new anticancer agents.
`Results
`In all, 225 adult phase I studies were analyzed concerning a
`total of 148 new anticancer agents. Most of the phase I (88% )
`studies were presented at the ASCO meeting. Of 225 trials,
`143 (63.6% ) were conducted for single-agent therapies and
`82 (36.4% ) for associations, mostly with marketed agents.
`Investigational agents were mainly administered intravenously
`(120 trials; 53.3% ), orally (77 trials; 34.2% ), subcutaneously
`or intradermally (16 trials; 7.1% ).
`A total of 91 studies (40.4% ) used a fixed dose. Dosages
`were adjusted to body surface area and body weight in 44%
`(99/225) and 13.8% (31/225) of all trials, respectively. The
`basis of dosing was not mentioned in 5 (2.2% ) abstracts.
`Regarding drugs given orally (n=40), the majority of the
`trials (62/77; 80% ) used a fixed dose. By contrast, only 7.5%
`(9/120) of studies involving intravenous agents (n=82) were
`conducted with a fixed dose. Most of these trials (86/120;
`71.6% ) used a dose adjusted to body surface area (Table I).
`
`Among the 148 investigational compounds, there were 45
`conventional drugs, 42 targeted agents (drugs interfering
`with signal transduction pathways such as enzyme inhibitors
`and antiangiogenic agents), 19 monoclonal antibodies, 15
`vaccines, 6 antisense agents and 11 immunomodulators
`(Table I). Of the 73 trials involving conventional cytotoxics,
`70 (96% ) used body surface area dosing. On the other hand,
`78.5% (62/79) of studies investigating targeted agents used
`a fixed dose. Vaccines were injected at a fixed dose (13/15).
`Monoclonal antibodies and antisense agents were mainly
`administered on a body weight basis (13/25 and 4/7 trials,
`respectively).
`Discussion
`Expression of dosing of investigational anticancer agents was
`heterogeneous. With regard to recommendations published
`in 2002 (11), the fixed dose was used in a minority of the
`adult phase I trials (40% ) presented at the ASCO and ASH
`meetings in 2005. Body surface area and body weight to a
`lesser extent were still used in the expression of dosing but
`with disparities, depending on the route of administration
`and the type of agent.
`Not surprisingly, trials of agents given orally were mainly
`conducted with a fixed dose. Oral fixed dosing is far more
`convenient than that adjusted to body size. In fact, unless a
`liquid oral formulation is available, accurate adjustment to
`body size is not possible with solid forms. Generally, the
`package insert mentions the number of tablets to be taken
`daily for a body surface area range, leading to complex
`dosing regimens such as those of capecitabine or oral
`vinorelbine. It should be mentioned that fixed dosing of a
`drug does not necessarily lead to a reduction of dosage
`presentations. Various dosages are sometimes needed to
`adjust the regimen based on tolerance. For example, sunitinib
`and dasatinib (fixed dose) are available in 3 dosage
`presentations
`(one more when compared with oral
`vinorelbine or capecitabine presentations). On the other
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`Levêque: Fixed Dosing of Investigational Anticancer Agents
`
`hand, the majority (93% ) of trials involving intravenous
`agents being conducted with a dose based on body surface
`area and body weight may be due to the fact that adjustment
`is relatively easy with a liquid formulation.
`Regarding the type of anticancer drug, virtually all trials
`(97% ) involving conventional agents used body surface area-
`based dosing. This probably reflects the habit that clinicians
`have with the dosing of cytotoxics. In addition, 78% (35/45)
`of conventional agents were in an intravenous formulation,
`which may strengthen the lack of willingness of investigators
`to change the basis of dosing. By contrast, the majority of
`studies (79% ) of targeted anticancer agents used a fixed dose,
`perhaps in relation with their low toxicity (when compared
`with cytotoxics) and to the fact that they were primarily oral
`drugs (30/42). Currently, all approved targeted therapies in
`the European Union (imatinib, erlotinib, sunitinib, sorafenib,
`dasatinib, nilotinib, lapatinib, temsirolimus) are administered
`at a fixed dose in adult patients. Dosing of investigational
`monoclonal antibodies was heteregeneous. The three
`modalities of dosing were encountered as for marketed
`antibodies. Body surface area-or body weight-based dosing
`of monoclonal antibodies is rather an oddity since these drugs
`are relatively nontoxic. In addition, they display a very low
`volume of distribution (around 5 l) and their route of
`elimination is unknown (12). They are probably cleared like
`endogenous immunoglobulins via the FcRn receptor whose
`expression (in particular on endothelial cells) is unlikely to
`be related to body weight or body surface area. Rituximab or
`trastuzumab clearances are not related to body surface area
`and body weight,
`respectively (13, 14). However,
`bevacizumab clearance showed a relationship with body
`weight but it has not been demonstrated that the kinetic
`variability has any clinical impact (15). In all, this practice is
`traditional with monoclonal antibodies even beyond oncology
`(infliximab in rhumatoid arthritis or daclizumab in graft
`recipients for example).
`Overall, it has never been proven that dosing of anticancer
`drugs according to body surface area or body weight leads
`to improvement of therapeutic outcomes in adult patients
`when compared to fixed dosing. Numerous marketed
`anticancer agents could be administered at a fixed dose but
`unfortunately it is improbable that their official labellings
`will change. Regarding investigational agents, fixed dosing
`could be used until it is demonstrated that body size or
`another variable (genotypic, phenotypic) is a significant
`factor of clinical variability. Fixed dosing has at least the
`potential to reduce medication errors (16). It was recently
`stated that novel agents were developed with a fixed dose
`(10). Based on our survey, this holds true for targeted agents
`in relation to their
`toxicity spectrum and their oral
`formulation. By contrast, dosing based on body surface area
`remains the rule for conventional agents as underscored by
`the dosing basis of the recently approved ixabepilone.
`
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`
`Received April 8, 2008
`Revised June 26, 2008
`Accepted July 28, 2008
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