Comprehensive reviews of the clinical pharmacology of paclitaxel(Drug information on paclitaxel) and docetaxel(Drug information on docetaxel) have been published previously,[47-51] and only limited pharmacologic aspects relevant to dosing and scheduling issues will be discussed here. Paclitaxel and docetaxel share the following pharmacologic characteristics: large volumes of distribution, rapid and sustained uptake by most tissues, long elimination half-lives, and significant hepatic disposition. The pertinent pharmacokinetic parameters of both agents are summarized in Table 1.
Predictions regarding the potential success of various taxane doses and schedules are often based on whether biologically active drug concentrations can be achieved and maintained in human plasma. Such extrapolations may have several pitfalls, particularly in situations in which drug concentrations achieved in plasma and peripheral tissues (or tumors) may be disparate. For both paclitaxel and docetaxel, plasma concentrations achieved with almost any dosing schedule are capable of inducing relevant biologic and cytotoxic effects in vitro (paclitaxel: more than 0.05 µM with 96-hour infusions, more than 0.3 µM with 24-hour infusions, and more than 5 µM with 1- to 3-hour infusions; docetaxel: more than 3 µM with 1-hour infusions).
Despite extensive plasma protein binding, both paclitaxel and docetaxel are readily cleared from plasma. More important, the volumes of distribution of the taxanes are very large, which is most likely attributable to avid and ubiquitous drug binding to tubulin. Tissue distribution studies in animals using radiolabeled drug have revealed high tissue/plasma concentration ratios in virtually all tissues except brain and testes, which are generally considered tumor sanctuary sites.[52-55]
In fact, docetaxel concentrations in mice have been demonstrated to be substantially higher in the implanted tumor tissue than in plasma. Not only are high taxane concentrations achieved in almost all peripheral tissues, but biologically relevant concentrations are maintained for relatively long periods. In both animals and humans, the results of radiolabeled drug distribution studies suggest that there is substantial sequestration of the taxanes in peripheral tissues.[47-55] Approximately 20% of an administered dose is recovered as either parent compound or metabolites from bile and feces collected for 24 hours after treatment. Most of the total administered radioactivity is recovered from feces collected for 1 week following treatment.[52-58] Renal clearance is insignificant for both taxanes, whereas hepatic P450 mixed-function oxidative metabolism, biliary excretion, fecal elimination, and tissue binding are responsible for the bulk of systemic clearance.[47-58]
These pharmacologic characteristics, particularly wide total body distribution, avid tissue binding, and tissue sequestration, indicate that plasma concentrations may underestimate drug concentrations and pharmacologic exposure in peripheral tissues and tumors. This behavior also suggests that short infusion schedules may be as effective as prolonged schedules in saturating peripheral tissues and tumors. The maintenance of effective tissue saturation may also depend on other factors, including the duration of plasma concentrations maintained above a critical threshold, the duration of the infusion, and the total dose of drug, particularly in situations in which tissue binding may not be avid.
Linear vs Nonlinear Pharmacokinetics
The pharmacokinetic behavior of paclitaxel appeared linear in early
studies of prolonged administration schedules. However, the results of
pharmacokinetic studies accompanying a National Cancer Institute of Canada-Clinical
Trials Group (NCIC-CTG) pivotal bifactoral randomized trial (BMS 016 or
Ov.9) demonstrated that the pharmacokinetic behavior of paclitaxel is nonlinear.[48,49]
The NCIC-CTG study observed the effects of paclitaxel (135 vs 175 mg/m²,
3 vs 24 hours with premedication) in women with recurrent or refractory
carcinoma of the ovary. Pharmacokinetic data from subsequent studies that
were performed in both children and adults
have confirmed these results.[48,49]
As with all drugs with nonlinear pharmacokinetic profiles, nonlinear or saturable behavior is accentuated on shorter infusion schedules. Both plasma concentrations and drug exposure increase disproportionately with increasing doses on shorter schedules. In addition, the pharmacokinetics of drugs like paclitaxel, which truly exhibit a nonlinear pharmacokinetic behavior at higher plasma concentrations, are more likely to be appear linear with prolonged infusion schedules that yield low plasma concentrations.
When plasma levels are much lower than Km (the Michaelis-Menten constant), elimination or distribution processes are not saturated and pharmacokinetics appear linear (first-order). Conversely, nonlinear (zero-order) pharmacokinetics become more apparent with shorter infusion schedules, which result in higher plasma concentrations that approach or exceed the Km of the saturable processes.
Pharmacokinetic modeling of paclitaxel plasma concentration data indicates that both saturable distribution and elimination processes account for paclitaxel's nonlinear pharmacokinetic behavior.[48, 49] Physiologically, nonlinear drug elimination is most likely due to saturable hepatic P450 metabolic processes and/or excretion, which accounts for a principal component of drug disposition. Saturable drug distribution, on the other hand, is much more difficult to explain.
Two pharmacokinetic models have been used successfully to describe nonlinear drug distribution. One model assumes that the drug transfer process into peripheral tissues is saturable, resulting in Km distribution kinetics. An alternate, more physiologic model assumes that there is a limited (therefore, saturable) number of drug-binding sites in the peripheral compartment. This model displays a rate constant for transfer of drug to the peripheral compartment, varying directly with the number of unoccupied binding sites in the peripheral compartment.[E.K. Rowinsky, MD, unpublished results] For paclitaxel, the limited number of binding sites may represent binding sites on beta-tubulin.
Paclitaxel's nonlinear pharmacokinetic profile may have several clinical implications. For example, dose escalations, especially on shorter administration schedules, may result in disproportionate increases in both area under the concentration-time curve (AUC) and peak plasma concentration (Cpeak), as well as disproportionate increases in toxicity. Dose reductions may have the opposite effect, resulting in disproportionate decreases in AUC and/or Cpeak, thereby possibly decreasing antitumor activity. In addition, these models predict that tissue sites are effectively saturated at relatively low paclitaxel concentrations (achieved with paclitaxel doses less than 175 mg/m² on a 3-hour schedule), whereas elimination processes are effectively saturated at higher doses (achieved with paclitaxel doses (3 175 mg/m² on a 3-hour schedule).
To characterize tissue saturation as a function of paclitaxel dose, model simulations have been performed using actual plasma concentration data and both types of tissue distribution models, taking saturable elimination processes into account.[E.K. Rowinsky, md, unpublished results] The simulations have demonstrated that the peak drug contents in tissues do not change significantly when paclitaxel doses are increased from 135 to 250 mg/m² on both 3- and 24-hour schedules. In addition, these simulations indicate that tissue saturation is greater with shorter administration schedules for all paclitaxel doses, and the rate that tissues become saturated is also greater with shorter infusion schedules.
Based on this model, peak drug content is approximately 70% of the theoretical maximum at a dose of 135 mg/m², 85% at a dose of 175 mg/m², and greater than 90% at a dose of 250 mg/m² when paclitaxel is administered over 3 hours. Respective tissue saturation values are approximately 35%, 45%, and 55% when paclitaxel is administered over 24 hours. These results suggest that increasing drug content in peripheral tissues and tumors by increasing paclitaxel dose or dose intensity within a clinically relevant dosing range may be tantamount to a situation of diminishing limiting returns as tissue binding sites become progressively saturated.
It should be pointed out, however, that the precise levels of tissue saturation that result in maximal cytocidal or toxicologic effects are not known. There may also be other important determinants of drug effect, such as the duration that any specific degree of tissue saturation is maintained. In other words, a maximal effect may occur with any degree of tissue saturation. In addition, it may be important to consider the duration that any specific degree of tissue saturation is maintained. Therefore, direct comparisons between prolonged and short treatment schedules with respect to the effect of different degrees of tissue saturation on outcome (ie, cytotoxicity, toxicity) cannot be adequately performed until other critical determinants of effect are characterized. However, the notion of a "threshold concentration" or a "threshold dose" due to saturable pharmacokinetic processes may account for the plateauing dose- or concentration-response relationships that have been observed in vitro and in clinical practice.