COMMENTARY

Tumour pharmacokinetics?—we do need to know

This review considers some of the obstacles to successful drug targeting and delivery of therapeutic agents to desired target sites in the body, in the context of the sometimes overblown claims made for nanoparticle and nanosystem based delivery. It covers aspects of issues surrounding the instability of particles in vivo through flocculation and aggregation, their complex flow and adhesion patterns in the capillary network, particle jamming and bridging, the heterogeneity of access of drugs to some sites such as tumours even in their free molecular state, the diffusion of free drug and nanoparticles in tumour tissue and in single cells. There are the fundamental laws of physics and materials, especially in relation to diffusion, adsorption, adhesion and hydrodynamics, which apply and these cannot be denied in our attempts to target carriers to anatomically distant targets, tumours being the archetypal target experiencing most of the barriers which prevent quantitative carrier and hence drug uptake. The paper closes with a discussion of some of the unmet challenges which must be addressed before quantitative delivery and targeting is achieved in many disease states. It is clear that if progress is to be made an International System for testing nanoparticulate delivery systems should be established. In this way data from different laboratories will be comparable. The International protocol should cover both in vitro and in vivo testing.

Cytotoxic chemotherapy is characterised by a low therapeutic index and significant variability in therapeutic and toxic effects. In an attempt to reduce this variability, most chemotherapy doses are individualised according to patient body surface area (BSA). This practice, which was introduced almost 50 years ago, clearly has practical and economic implications for the healthcare system. Furthermore, the clinical value of this approach has, in recent years, been questioned. Despite established practice, chemotherapy dose selection remains complicated, partly because treatment effects are difficult to measure, partly because drugs are used in combination with other treatment modalities, and also because the patient's condition may change with disease progression. Various patient-related factors can affect drug pharmacokinetics (PK) and pharmacodynamics (PD), for example organ function, expression and activity of metabolising enzymes, drug resistance, body size, gender, age, concomitant disease and co-administration of other drugs. These factors may be of clinical significance in chemotherapy dose determination and measures of PK, PD or both feature in attempts to devise more rigorous methods for chemotherapy dosing. Part I of this series of two reviews describes the history and clinical impact of BSA-based chemotherapy, and examines the scientific evidence to support BSA dosing. It evaluates the factors affecting PK and PD for specific drugs that could inform and refine dose determination.

¹⁹Fluorine magnetic resonance spectroscopy (¹⁹F MRS) offers unique possibilities for monitoring the pharmacokinetics of fluoropyrimidines in vivo in tumors and normal tissue in a non-invasive way, both in animals and in patients. This method may therefore be useful for predicting response to fluoropyrimidine-based therapy with or without the effects of modulating agents, and this may be of value for the individualization of anticancer therapy and the strategic development of new anticancer drugs. ¹⁹F MRS has been very valuable in elucidating the basic aspects of fluoropyrimidine metabolism, especially in animal studies. Studies in humans have indicated its clinical potential, but widespread application has been hampered by the relatively low detection sensitivity of the method. The recent introduction of clinical MR scanners with magnetic fields above 1.5 T may stimulate increased clinical use of ¹⁹F MRS.

The potential anti-cancer agent n-[2-(dimethylamino)ethyl]acridine-4-carboxamide, DACA has been labelled with carbon-11. N-[2-¹¹C-methyl]DACA was produced in 73% radiochemical yield from [¹¹C]iodomethane in 40 min from EOB. The average radiochemical yield was 3.2 GBq with specific radioactivity of 41.5 GBq μmol⁻¹ at EOS, corresponding to 24 μg of stable DACA. The position of labelling was confirmed by co-labelling with $\text{[}{}^{\mathrm{<mtext>11</mtext><mtext>13</mtext>}}\text{C}\text{]}\text{iodomethane}$.

PET studies in patients have been performed prior to Phase I trial of DACA and during Phase I trial of DACA. Analysis of serial plasma samples showed that the metabolism of N-[2-¹¹C-methyl]DACA is rapid and extensive in patient plasma.

The tissue distribution and biodynamics of ¹⁸F-labelled 5-fluorouracil (FU) are described and studied for correlation with its in vivo antitumor activity. The in vivo model consisted of Balb/c mice bearing a FU sensitive (Colon 26-10 carcinoma) tumor in the left and a less responsive (Colon 26 carcinoma) tumor in the right abdominal side of the animal. Distribution and efflux of ¹⁸F-label from tumor, blood, and other tissues were determined by obduction at 0.5, 1, 2, 4, and 6 h postintravenous injection. For a comparison, the ¹⁸F-labeled 5-fluoro-6-hydroxy and cis-5-fluoro-6-ethoxy uracil adducts were studied in the same in vivo model. For ¹⁸F-FU it was found that the ¹⁸F-label tumor kinetics rapidly fell into a biphasic mode: a relatively short ¹⁸F beta phase (¹⁸F $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ β 21 ± 3 min), linked with the total body metabolic capacity and clearance of the animal, and a longer ¹⁸F gamma phase, linked with the intrinsic intratumoral FU metabolism (Colon 26-10: ¹⁸F $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ γ 10.3 h; Colon 26: ¹⁸F $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ γ 5.6 h). It is proposed that the observed faster ¹⁸F efflux of the less responsive Colon 26 corresponds to an enhanced breakdown of 5-fluoronucleotides to 5-fluoronucleosides and subsequent elimination from the tumor cells. It is concluded that on PET scanning, measurement of the dynamic ¹⁸F $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ and ¹⁸F $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ β parameter is of prime importance for an insight in the in vivo tumor biology of a patient.