Pharmacokinetic Optimisation of Anticancer Therapy

Abstract

It is obvious that there are great problems with pharmacokinetic individualization of anticancer therapy. The strong relationship between dose intensity (total dose/unit time) and response revealed in clinical trials with some tumours provides a strong support for studies seeking relationships between the individual plasma pharmacokinetic profile and response to treatment. Unfortunately, studies that define a therapeutic window are sparse, and trials that prospectively test such models are even rarer. Thus, for most cancer drugs, it is not possible to give any definite advice on how to use pharmacokinetic determinations to establish individualised therapy, and there is therefore a definite need for such studies. It is important, however, that attempts to establish relationships between drug concentrations and therapeutic effects be founded on a sound theoretical base. When drugs, mainly antimetabolites, are extensively metabolised intracellularly and interact with intracellular processes about which there are data showing a strong interindividual heterogeneity, such data must be considered when designing pharmacokinetic investigations. Cytarabine and fluorouracil are good examples of this. The monitoring of intracellular drug/metabolite concentrations or of the direct biochemical events in the tumour cells seems to be a promising approach with such drugs. It also needs to be emphasised that pharmacokinetically guided individualization cannot be achieved before a therapeutic window is established, i.e. a knowledge of the relationship between drug concentration and clinical effects. The investigators in this field accept a great responsibility when clinical studies are undertaken: a poorly designed study showing no benefit from pharmacokinetically guided individualization can impair the possibilities of performing more adequate studies in the future.

Comparative pharmacokinetic and cytotoxic analysis of three different formulations of mitoxantrone in mice

“…With PA-MTO, blood levels were about tenfold lower than those determined for pH-MTO but, because of the better tissue penetration of MTO, cytotoxicity was superior. These results support the statement of Liliemark and Peterson (1991) that a higher plasma concentration does not necessarily correlate with a more pronounced cytotoxic effect. About 18% of the MTO dose administered in its free form is excreted in the faeces within 5 days and approximately 10% was recovered in the urine (Alberts et al, 1985a).…”

Pharmacokinetics of zidovudine phosphorylation in peripheral blood mononuclear cells from patients infected with human immunodeficiency virus

“…The study also investigated the effect that duration of therapy has on pharmacokinetics and thus the changing ability of PBMCs to phosphorylate ZDV over time. This information could lead to improved ZDV dosing regimens and/or individualized management of therapy, similar to how some nucleoside analogs are managed in the treatment of leukemia (13,16).…”

Quality of pharmacokinetic research in oncology

“…In recent years there has been a rapidly growing awareness in oncology of the potential of pharmacologically guided dose adaptation in optimising the use of anti-cancer drugs (Liliemark and Peterson, 1991;Evans, 1993;Lonning, 1993;Weitman et al, 1993;Workman and Graham, 1994). The use of pharmacokinetic principles to individualise drug therapy outside oncology has been accepted practice for many years (Sjoqvist et al, 1980).…”

“…The use of pharmacokinetic principles to individualise drug therapy outside oncology has been accepted practice for many years (Sjoqvist et al, 1980). Complex intracellular events, complex mechanism of action of cytotoxics and drug resistance have been suggested as reducing any possible role of pharmacokinetic dose optimisation in oncology (Liliemark and Peterson, 1991). Nevertheless, there is now firm evidence that area under the plasma drug concentration-time curve or the time during which plasma drug concentrations are maintained above a minimum effective concentration correlates well with normal tissue toxicity and probably also with tumour response (Hande, 1993;Desoize and Robert, 1994;Newell, 1994).…”

“…Nevertheless, there is now firm evidence that area under the plasma drug concentration-time curve or the time during which plasma drug concentrations are maintained above a minimum effective concentration correlates well with normal tissue toxicity and probably also with tumour response (Hande, 1993;Desoize and Robert, 1994;Newell, 1994). As a result, there is an increasing need for further pharmacokinetically guided dosing studies to improve individualisation of drug therapy (Liliemark and Peterson, 1991;Egorin, 1992).…”