Definitions

In a general sense, pharmacodynamics is the study of dose-response relationships.¹⁶⁸ Thus, any laboratory or clinical study employing different doses of an agent is addressing a pharmacodynamic question. Examples include the exposure of tumor cells in vitro to varying doses of a new agent to evaluate its dose-response relationship, or a Phase I clinical trial to define the maximally tolerated dose and dose-limiting toxicities in patients.

In the clinical setting, the results of treatment depend on both pharmacokinetics and pharmacodynamics (see Figure 46-1). A patient may have excessive toxicity at the “standard” dose for one of two reasons. If the patient's pharmacokinetics are different from those of the typical patient (eg, decreased renal clearance of carboplatin), there may be decreased total body clearance resulting in a higher than expected drug exposure. The second possibility is that the patient might simply be more sensitive to an average drug exposure due to prior therapy, poor nutrition, or other less well-defined reasons. It is important to distinguish between these two possibilities. In the first case, lowering the dose will result in an “average” drug exposure, whereas in the second case lowering the dose will result in a lower-than-average drug exposure. Therefore, in the setting of dose reduction, there is a greater possibility of a response in the patient with abnormal pharmacokinetics than in the “sensitive” patient with abnormal pharmacodynamics.

General Pharmacodynamic Principles

In the most general sense, any drug may be considered to have a maximal effect and a median dose, that is , that required for 50% of the maximal effect. Wagner proposed a generalized sigmoidal model of drug effect (Figure 46-4), derived from the hypothesis that all drug effects require an initial interaction with a receptor.¹⁶⁹

Figure 46-4

Example of E_max model as proposed by Wagner JG. The maximum effect is 100%, and a concentration of 6 results in 50% effect. The exponent H, also known as the Hill constant, determines the shape of the curve and is usually between 1 and 2.

Most studies addressing pharmacodynamic modeling of anticancer agents have addressed phase-specific agents separately.^170,171 It may be adequate to use a simple log-linear model for non-phase-specific agents^170,172:

This may be referred to as a steep dose-response curve, since the effect continues to increase proportionally as the concentration (C) increases. For any K (in equation 8), an increase in C by 2.3/K will result in a 1-log increase in antitumor effect (Figure 46-5A).

Figure 46-5

Pharmacodynamic plots for drugs with nonsaturable (A) and saturable (B) effects. In the simplest pharmacodynamic model (A), there is a linear relationship between dose and log kill. In B, there is a maximal effect, resulting in a plateau in the dose-response (more...)

The dose-response relationships for phase-specific agents, such as the antimetabolites, are much more complicated. By definition, some cells are out of “phase” and therefore not sensitive (or relatively insensitive) to the effects of the drug during the period of drug exposure. This is not necessarily overcome by increasing the dose, but could be overcome by increasing the duration of drug exposure. The result is the appearance of a plateau in the dose-response curve (Figure 46-5B).

The effects of some antineoplastic agents depend on both the drug concentration and the duration of exposure to that concentration. For some agents, the effect is a function of the product of the concentration and exposure time, analogous to the AUC.¹⁷³ However, for antimetabolites and other phase-specific agents, the mathematical relationships are much more complex.^170,171,174 Drug effect tends to be related to duration of exposure above a threshold concentration.

Plasma concentrations may be an inadequate predictor of clinical effect for those agents that undergo intracellular anabolism to active metabolites, such as is the case for ara-C.¹⁷⁵ Plasma ara-C concentrations do not appear to correlate with the rate of cellular ara-CTP accumulation or peak ara-CTP concentration in leukemia cells, although the intracellular concentration of ara-CTP is an important determinant of treatment outcome. Thus, knowledge of the plasma pharmacokinetics of ara-C is not likely to be a useful predictor of treatment outcome for individual patients. Pharmacogenetic evaluation may be potentially useful for modeling relationships between 6-mercaptopurine pharmacokinetics and clinical effects, as this drug's conversion to active intracellular 6-thioguanine metabolites by thiopurine methyltransferase is genetically determined.¹²⁶ Studies in children with acute lymphoblastic leukemia suggest that intracellular levels of 6-thioguanine nucleotides may be an independent predictor of remission duration.¹²⁵

Pharmacodynamic Modeling of Cancer Chemotherapy

The introduction of pharmacodynamic modeling into clinical oncology has been a slow process. The relationship between toxicity subsequent to high-dose MTX and that of delayed MTX clearance has led to the routine use of therapeutic drug monitoring of plasma MTX concentrations to guide leucovorin dosing.¹⁷⁶ However, studies of other drugs have not clearly resulted in a change in clinical practice although there has been a recent increase in clinical research in this area.¹⁷⁷

Most early pharmacodynamic studies addressed relationships between measurements of drug exposure (AUC, C_ss) and toxicity. More recently, investigators have modeled toxicity by using novel pharmacokinetic parameters, such as time above a threshold concentration for etoposide¹⁷⁸ and paclitaxel.^{116,117,179,180} Other investigators have addressed the importance of active metabolites. This is of particular importance for irinotecan, a drug with both complex metabolism and toxicity patterns. However, recent studies have suggested that irinotecan-induced diarrhea is secondary to relative deficiency in the glucuronidation of SN-38, its active metabolite.^181,182 Hematologic toxicity has been easier to model than nonhematologic toxicity as illustrated in Tables 46-4 and 46-5, respectively.

Table 46-4

Selected Pharmacodynamic Studies of Hematologic Toxicity.

Table 46-5

Selected Pharmacodynamic Studies of Nonhematologic Toxicity.

One of the best-characterized drugs is carboplatin, an analog of cisplatin. Unlike cisplatin, the dose-limiting toxicity of carboplatin is thrombocytopenia, which is a function of drug dose, renal function, pretreatment platelet count, and prior therapy.¹⁵¹ The platelet nadir produced by a dose of carboplatin is related to the carboplatin clearance, which is directly proportional to creatinine clearance. Thus, patients at high risk of severe thrombocytopenia following carboplatin therapy can be identified prospectively, and the drug doses can be modified by monitoring creatinine clearance.

Etoposide has also been the subject of extensive evaluation. Pharmacodynamic modeling of etoposide is complicated by the need to either measure free etoposide directly or estimate its concentration on the basis of measured total plasma concentration of etoposide, albumin, and/or bilirubin.^156,158 Many studies have now demonstrated that the extent of leukopenia/neutropenia is correlated with etoposide exposure.^{158,183–190} Furthermore, interpatient pharmacodynamic variability may be significant and needs to be considered in future modeling of etoposide and potentially of other drugs.¹⁵⁸

There is an expanding interest in trying to optimize cancer chemotherapy by individualizing dosing on the basis of measurements of plasma or tissue drug concentrations. One recent example is the titration of carboplatin dosing discussed above. Other investigators have attempted to optimize the dosing of etoposide,^158,191 teniposide,¹⁹² hexamethylene bisacetamide,^193,194 etanidazole,¹⁹⁵ melphalan,¹⁹⁶ and 5-FU¹⁹⁷ by monitoring plasma drug concentrations during treatment, then using the information obtained to modify the total dose of chemotherapy administered in an attempt to avoid severe toxicity.

An important recent study from St. Jude Children's Research Hospital demonstrated that individual dosing of combination chemotherapy can improve survival in children with acute lymphoblastic leukemia.¹⁹⁸ A total of 182 children received standard induction therapy followed by postremission therapy with ara-C, methotrexate, and teniposide. Patients were randomized to standard versus individualized dosing. The latter was based on adjusting the doses to achieve plasma AUCs in the 50th to 90th percentile (based on historical controls). Those receiving individualized therapy had an improvement in the rate of continuous complete remission (76% versus 66%) at 5 years.

The Future Role of Anticancer Pharmacodynamics

Should the clinical oncologist care about pharmacodynamics? Will therapeutic drug monitoring of antineoplastics be as useful as monitoring of theophylline or aminoglycoside dosing? How will these studies improve the therapeutic index? These are important issues that are currently being addressed.

Our true understanding of dosing of most antineoplastic drugs is primitive. Body surface area is generally the only value used to determine initial dosing, and even this has recently been questioned.^199,200 Prior toxicity may be used to adjust dosing for subsequent cycles although doses are more often reduced than escalated, and the magnitude of dose changes is determined empirically and often arbitrarily.

For drugs with a relatively broad therapeutic index and/or minimal interpatient pharmacokinetic or pharmacodynamic variability, these strategies may not be necessary. As an example, therapeutic drug monitoring of tamoxifen in breast cancer is unlikely to be useful. In contrast, therapeutic drug monitoring of doxorubicin in the adjuvant treatment of breast cancer may potentially help to ensure adequate drug exposure and minimize the risk of life-threatening toxicity, since there is an association between dose and relapse rate.²⁰¹

An achievable goal is the individualization of dosing of drugs having polymorphic metabolism. Important examples are 5-fluorouracil,^202,203 6-mercaptopurine,^125,126 amonafide,^127,128 and irinotecan.¹³³ Most of the pharmacodynamic studies to date have focused on toxicity as an end point, primarily due to the patient populations studied: patients with refractory tumors enrolled in Phase I clinical trials. The potential usefulness of this area is underscored by the St. Jude study demonstrating that the adjustment of dose based on plasma concentration decreases the rate of relapse.¹⁹⁸ Prospective evaluation of plasma¹²⁹ or intratumoral²⁰⁴ concentrations in conjunction with Phase II clinical trials may improve our understanding of the relationship between clinical pharmacology and drug efficacy for other tumors as well. Although most studies to date have utilized continuous infusion chemotherapy, recent strategies have been developed with the aim of optimizing dosing after conventional bolus administration.^{175,192,196,205–207} It may eventually become possible to dose routinely toward a target AUC or C_ss (or time above a threshold) using principles of therapeutic drug monitoring to guide dosing.¹⁹⁸

The next challenge will be optimizing the use of combination chemotherapy. As studies of the pharmacodynamics of single agents are completed, it will become possible to evaluate the pharmacodynamics of drug combinations. As an example, it has been demonstrated that carboplatin plus paclitaxel result in less thrombocytopenia than carboplatin as a single agent.²⁰⁸

In conclusion, it is hoped that a better understanding of the clinical pharmacology of antineoplastic agents will improve the care of patients with cancer. At a minimum, clinicians should understand the basic principles, realizing the limitations of our current approaches.