Pharmacokinetics of Tetra (m-hydroxyphenyl)chlorin in Human Plasma and Individualized Light Dosimetry in Photodynamic Therapy

Glanzmann, Thomas; Hadjur, Christophe; Zellweger, Matthieu; Grosjean, Pierre; Forrer, Martin; Ballini, Jean‐Pierre; Monnier, Philippe; Bergh, Hubert E. van den; Lim, Chang Kee; Wagnières, Georges

doi:10.1111/j.1751-1097.1998.tb09460.x

Cited by 15 publications

(30 citation statements)

References 27 publications

(22 reference statements)

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“…This shows that the clearance of m-THPC is faster than that of Photofrin. Similar pharmacokinetic analyses in humans have determined half-lives as 452 h for Photofrin (Brown et al, 1992) and 30 h for m-THPC (Glanzmann et al, 1998).…”

Section: Discussionmentioning

confidence: 78%

“…Preclinical results indicate that the efficacy of m-THPC is related to both the drug dose and the interval between administration and illumination (Ris et al, 1993a, b). However, the efficacy is also complicated by many in vivo interactions, such as aggregation and protein binding (Glanzmann et al, 1998;Hopkinson et al, 1999). This study aims to correlate m-THPC pharmacokinetics with PDT efficacy and the mechanism of PDT damage.…”

Section: Discussionmentioning

confidence: 99%

“…Another consideration with m-THPC is the unusual human plasma pharmacokinetics. After an intravenous injection, the plasma level initially falls exponentially but at approximately 10 h it begins to rise to a secondary peak at 24 h (Ronn et al, 1996;Glanzmann et al, 1998). This may change the level of m-THPC in the tumour vasculature and the rate of uptake of m-THPC in the tumour giving different PDT responses.…”

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confidence: 99%

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Photodynamic therapy effect of m-THPC (Foscan®) in vivo: correlation with pharmacokinetics

2003

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m-Tetra(hydroxyphenyl)chlorin (m-THPC, Foscan, Temoporfin) has an unusually high photodynamic efficacy which cannot be explained by its photochemical properties alone. In vivo interactions are therefore of critical importance in determining this high potency. The pharmacokinetics of m-THPC in a rat tumour model was determined using 14 C m-THPC in an LSBD 1 fibrosarcoma implanted into BDIX rats. The photodynamic therapy (PDT) efficacy was determined at different drug administrations to light intervals and correlated with the tumour and plasma pharmacokinetic data. The plasma pharmacokinetics of m-THPC can be interpreted by compartmental analysis as having three half-lives of 0.46, 6.91 and 82.5 h, with a small initial volume of distribution, suggesting retention in the vascular compartment. Tissues of the reticuloendothelial system showed high accumulation of m-THPC, particularly the liver. PDT efficacy of m-THPC over the same time course seemed to exhibit two peaks of activity (2 and 24 h), in terms of tumour growth delay with the peak at 24 h postinjection correlating to the maximum tumour concentration. Investigation on tumour cells isolated from m-THPC-treated tumours suggested that the peak PDT activity at 2 h represents an effect on the vasculature while the peak at 24 h shows a more direct response. These results indicate that the in vivo PDT effect of m-THPC occurs via several mechanisms. British Journal of Cancer (2003) Photodynamic therapy (PDT) is becoming accepted as an alternative to conventional cancer treatments for certain indications and other nononcological conditions. It is based on a tumour accumulation of a photosensitiser, which, when activated by light, results in tumour destruction via reactive oxygen species (Ochsner, 1997). The selectivity of PDT relies upon the targeting of the light delivery in combination with the accumulation/retention of the photosensitiser in malignant tissue. The time interval between photosensitiser administration and light delivery is crucial for the optimal clinical efficacy of PDT. The distribution of the photosensitiser both in the tumour as a whole and throughout the tumour compartments is dependent on this interval as well as in vivo interactions that affect photosensitiser aggregation, delivery and uptake (Boyle and Dolphin, 1996). m-Tetra (hydroxyphenyl)chlorin (m-THPC), a second-generation photosensitiser, has already been shown to be more potent than Photofrin (PII). It has been suggested that it is up to 200 times more powerful (Van Geel et al, 1995;Ball et al, 1999). This figure takes into account the drug dose required (0.15 mg kg À1 compared to 10 mg kg À1 for PII) and the lower light doses necessary (30 J cm À1 rather than 150 J cm À1 ) to produce similar PDT results. However, the reason for this effectiveness remains unresolved even considering the advantageous photoproperties of increased molar absorption coefficient and a favourable shift in the wavelength maximum (652 nm rather than 630 nm) (Bonnett et al, 1989).Preclinical studies have alread...

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Photodynamic therapy effect of m-THPC (Foscan®) in vivo: correlation with pharmacokinetics

2003

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“…The initial rapid drug clearance phase, which is seen in rodents, does not occur in humans. Pharmacokinetic profiles for Foscan demonstrate an unusual delayed plasma peak at about 10 h after bolus injection, with subsequent elimination half-lives in the range of 30 -60 h (Braichotte et al, 1995;Glanzmann et al, 1998). The plasma drug concentrations therefore remain at levels of at least 500 ng ml À1 for up to 96 h after a standard dose of 0.15 mg kg À1 Foscan.…”

Section: Discussionmentioning

confidence: 99%

Foscan® uptake and tissue distribution in relation to photodynamic efficacy

et al. 2003

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Clinical photodynamic therapy (PDT) schedules are based on the assumption that optimum drug -light intervals are times at which there is a maximum differential between photosensitiser retention in the tumour and surrounding normal tissue. However, vascularmediated effects contribute to tumour destruction by PDT; therefore, plasma sensitiser levels and endothelial cell drug exposure could also be important determinants of PDT response. The purpose of this study was to investigate the influence of tumour, tissue and plasma concentrations of the photosensitiser Foscan s (meta-tetrahydroxyphenylchlorin, mTHPC) on PDT response. Groups of BalbC nude mice, bearing human mesothelioma xenografts (H-MESO1) were injected (i.v.) with a single dose of 14 C-labelled mTHPC, or with two doses, separated by 72 h. Drug levels in plasma, tumour and normal tissues were measured at 5 min to 120 h after drug administration. The PDT tumour and skin responses were evaluated by illuminating separate groups mice at intervals of 5 min to 120 h after injection of Foscan (nonlabelled). Drug levels in both tumour and skin increased during the first 24 h after a single injection, and remained almost constant for at least 120 h. The second injection produced a further, rapid increase in mTHPC levels in tumours and skin, with steady state being maintained from 20 min to 120 h. By contrast, PDT response of both tumours and skin were maximal for illumination at 1 -3 h after drug, with very little response when illumination was given 48 -120 h after drug. There was no significant correlation between tumour or skin drug level and PDT response. There was, however, a significant correlation between plasma drug levels and tumour or skin response, excluding an initial distribution time of 20 min. These studies demonstrate a pronounced disassociation between tumour drug levels and optimum drug -light intervals for PDT response with Foscan. We suggest that the PDT effect, in both tumours and normal tissues, is largely mediated via vascular damage and that the selectivity of PDT is not based on differential tumour drug uptake.

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“…Photodynamic therapy with meta(tetrahydroxyphenyl)chlorin (mTHPC) has been shown in clinical trials to be a safe and effective treatment of early malignancy in the upper aerodigestive tract, the bronchi and the oesophagus (Grosjean et al, 1996b;Savary et al, 1997). Numerous studies have shown that mTHPC, like other anti-cancer drugs (McLoed and We, 1995), has high inter-patient variability for accumulation of the drug in normal or malignant tissues Glanzmann et al, 1998). This variability is probably a major factor in the large range of tissue responses to PDT in different patients who have undergone treatment under identical conditions (e.g., drug dose, light dose, light dose rate, time delay after drug administration).…”

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confidence: 99%

Uptake and localisation of mTHPC (Foscan®) and its14C-labelled form in normal and tumour tissues of the hamster squamous cell carcinoma model: a comparative study

et al. 2002

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The aim of this study was to evaluate the pharmacokinetics of meta(tetrahydroxyphenyl)chlorin (mTHPC) on different tissues of interest in a hamster tumour model and to confirm our earlier animal studies on semi-quantitative fluorescence microscopy. The results obtained by three different evaluation methods were compared: in vivo spectrofluorometry, ex vivo fluorescence microscopy and chemical extraction of 14 C-labelled mTHPC. Following intracardiac injection of 0.5 mg kg 71 mTHPC, groups of five tumour-bearing animals were used for in situ light-induced fluorescence spectroscopy. Afterwards, the biopsies were taken and snap frozen for fluorescence microscopy. The presence of radioactivity in serum and tissues was determined after chemical digestion in scintillation fluid using a scintillation counter. For each analysed tissue, a good correlation was observed between the three evaluation methods. The highest fluorescence intensity and quantities of mTHPC were observed between 12 and 24 h in liver, kidney, serum, vascular endothelium and advanced neoplasia. The majority of mTHPC was found at around 48 h in smooth muscle and at 96 h in healthy cheek pouch mucosa and early malignant lesions. The lowest level of mTHPC was noted in striated muscle at all times. No selectivity in dye localisation was observed between early squamous cell carcinoma and healthy mucosa. Soon after the injection, a significant selectivity was noted for advanced squamous cell carcinoma as compared to healthy cheek pouch mucosa or striated muscle. A significant difference in mTHPC localisation and quantity was also observed between striated and smooth muscle during the first 48 h following the injection. Finally, this study demonstrated the usefulness of non-invasive in situ spectroscopic measurements to be performed systematically prior to photodynamic therapy as a real-time monitoring for each treated patient in order to individualise and adapt the light dosimetry and avoid over or under treatments.

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Pharmacokinetics of Tetra (m-hydroxyphenyl)chlorin in Human Plasma and Individualized Light Dosimetry in Photodynamic Therapy

Cited by 15 publications

References 27 publications

Photodynamic therapy effect of m-THPC (Foscan®) in vivo: correlation with pharmacokinetics

Photodynamic therapy effect of m-THPC (Foscan®) in vivo: correlation with pharmacokinetics

Foscan® uptake and tissue distribution in relation to photodynamic efficacy

Uptake and localisation of mTHPC (Foscan®) and its14C-labelled form in normal and tumour tissues of the hamster squamous cell carcinoma model: a comparative study

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