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Editorial |
Duke University Comprehensive Cancer Center, Durham, North Carolina 25510
TDM,2 which entails individual dose adjustment based on systemic pharmacokinetics, is routinely used by clinicians for some antibiotics, antiarrhythmic agents, and various other drugs. By definition, TDM is reserved for drugs with relatively low therapeutic indices. Arguably, one of the most extreme examples of such a class of drugs is high-dose alkylators that are used extensively in the stem cell transplant setting. Further compounding of the safety profile can occur due to inherent aberrations in the pharmacokinetics of these drugs due to saturation of metabolic and/or elimination processes as the doses are escalated.
Studies have previously described correlations between the systemic exposure of alkylating agents such as busulfan (1, 2, 3) , cyclophosphamide (4 , 5) , carmustine (6) , thio-tepa (7) , and cisplatin (8) with toxicity in the high-dose setting. A limited amount of information also has identified associations between interpatient variability in the systemic exposure of busulfan or cyclophosphamide and antitumor efficacy (4 , 5 , 9) . In addition, the busulfan studies have identified a minimal level of exposure that is apparently necessary for hematopoietic engraftment from a matched sibling donor (2) . Additional work demonstrated the feasibility and benefit of conducting TDM in order to maintain a consistent exposure to busulfan among patients, leading to pharmacokinetically-based dose individualization in many bone marrow transplant centers (10) . Unfortunately, relatively little information that demonstrates high-dose individualization strategies for other agents is published.
Obstacles to prospective dose individualization are numerous and include unconducive schedules of administration, prolonged assay turnaround time, and the potential for intraindividual variability, as described in the trial by Nieto et al. (11) in this issue. Pharmacokinetic drug interactions between chemotherapy agents and ancillary drugs, such as antiemetics and anticonvulsants, can occur on a time-dependent basis and, thus, could make the disposition of a drug that is given over several days change with time (12) . This time-dependent metabolic induction or inhibition greatly complicates efforts to predict drug clearance on subsequent doses. Care must be taken when target concentration or area under the curve data are extrapolated to settings where concurrently administered and potentially interacting drugs are dissimilar. For example, most of the published target exposure ranges for busulfan were derived during concomitant therapy with the metabolic inducer phenytoin. Some evidence suggests this interaction is clinically relevant (13) . Despite the obstacles mentioned above, pharmacokinetically-based dose individualization is possible in the high-dose setting and is arguably one of the most important applications of TDM.
Unfortunately, it is difficult to interpret the relationship between pharmacokinetics and pharmacodynamics (outcome) in the study conducted by Nieto et al. (11) due to the heterogeneity in populations, the relatively short follow-up, and lack of primary data such as the relapse rates for the various diseases. It makes most sense to evaluate these relationships in situations least likely to involve drug resistance (early stage disease) and with relatively high response rates. In addition, the investigators do not provide any data on the pharmacokinetics of the other two agents (cisplatin and carmustine) used in the high-dose regimen.
Since the doses of most chemotherapy agents (even in the high-dose setting) are tailored in Phase I studies to produce untoward toxicity in less than one-third of patients, prospective approaches to concentration control in many cases need not target the "average" patient or even the majority of the population. Rather, the goals of such efforts are to identify and intervene on patients who are at the extremes of systemic exposure (e.g., the upper 10–25% or the lower 10–25%). The cyclophosphamide analyses by Nieto et al. (11) take a different, and perhaps less desirable, approach of attempting to forecast results for all patients in a population. In addition, they are focused on the presence or absence of a pattern of induction, rather than the absolute value of the drug clearance for an individual.
Cyclophosphamide is a prodrug, thus evaluation of parent cyclophosphamide levels as a surrogate for the degree of cytotoxic exposure is fraught with difficulties. Parent drug concentrations could be a predictor of active metabolite profiles because the 4-hydroxylation reaction is most likely the rate-limiting step in the activation process. Unfortunately, the capacity of this reaction can be saturated at concentrations achieved in the high-dose setting, which would attenuate the usefulness of parent drug monitoring (14) . Newer analytic methods that require either immediate sample processing or use bedside stabilization techniques have allowed direct measurement of the intermediate cyclophosphamide metabolites (4-OHCY), which are thought to account for the majority of precursor analytes transported intracellularly and subsequently activated into the cytotoxic species (15) . Results of these limited studies have been divergent, with some demonstrating inverse correlations between parent and intermediate metabolite exposures, whereas others show no relationships (14 , 16) . Explanations for such effects may involve differences in saturable metabolism as well as metabolic inhibition by concurrent administration of thio-tepa. More work needs to be conducted in this area, particularly with the cyclophosphamide, cisplatin, carmustine regimen.
With the lack of consistent correlation of 4-OHCY pharmacokinetics with those of cyclophosphamide, it becomes critical to measure the pharmacokinetic profile of the primary activated metabolite. It is true that the extracellular concentration of 4-OHCY will not equal the intracellular concentration of the alkylating phosphoramide mustard spontaneously liberated from 4-OHCY inside the cell. However, the extracellular concentration of 4-OHCY will be the principal determinant of delivery of this agent into the cell, especially because there is no evidence of active transport of 4-HOCY into the cell. Many antitumor agents are further transformed inside the cell, and the variations in such transformation will affect the response in tumor cells. However, such variations in normal cells should be much less so that the extracellular pharmacokinetics of the proximate agent, which enters the cell, should accurately predict toxicity to normal organs.
It is intriguing that the study published in this issue has identified a subgroup of patients in which parent cyclophosphamide metabolism is apparently not perturbed, or even reduced over 2–3 days dosing. This lack of effect could be reflective of pharmacogenetic differences in either P450-mediated metabolism or aldehyde dehydrogenase detoxification (17) . Prospective phenotyping strategies could potentially be useful tools for prediction of cyclophosphamide disposition if either of the latter mechanisms are found to be important.
Cyclophosphamide is a critical component of numerous high-dose regimens with documented anticancer efficacy; thus, we wholeheartedly disagree with the last statement by Nieto et al. (11) , which suggests that alternatives to cyclophosphamide should be used in the high-dose setting simply due to their better potential for real-time TDM. We believe that real-time TDM can be carried out with cyclophosphamide by making the appropriate measurements. Perhaps it is reasonable to explore this potential before abandoning cyclophosphamide.
FOOTNOTES
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 To whom requests for reprints should be addressed, at Duke University Medical Center, Box 3843 (DUMC), Durham, NC 27710; Phone: (919) 684-3377; Fax: (919) 684-5653. 
2 The abbreviations used are: TDM, therapeutic drug monitoring; 4-OHCY, 4-hydroxy cyclophosphamide/aldophosphamide.
Received 2/18/99; accepted 2/22/99.
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