A phase I and pharmacokinetic study was carried out with the new ruthenium complex indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019, FFC14A). Seven patients with various types of solid tumours refractory to standard therapy were treated with escalating doses of KP1019 (25-600 mg) twice weekly for 3 weeks. No dose-limiting toxicity occurred. Ruthenium plasma concentration-time profiles after the first dose and under multiple-dose conditions were analysed using a compartmental approach. The pharmacokinetic disposition was characterised by a small volume of distribution, low clearance and long half-life. Only a small fraction of ruthenium was excreted renally. The area under the curve values increased proportionally with dose indicating linear pharmacokinetics.

Oxaliplatin is a promising drug for cancer therapy and the oxaliplatin/5-fluorouracil/leucovorin (FOLFOX) regimen has become the standard adjuvant treatment for colorectal cancer. However, the oxaliplatin-induced neurotoxicity still represents a clinical problem leading to a discontinuation of the therapy. Many strategies have been proposed in order to manage the neurotoxicity, but their effect on antitumoral efficacy is still unclear. In this study, we investigated the effect of reduced glutathione administration on neurotoxicity, oxaliplatin pharmacokinetics, and platinum-DNA (Pt-DNA) adduct formation in patients affected by colorectal cancer treated with FOLFOX4 adjuvant regimen. Twenty-seven patients were randomized to receive GSH 1500 mg/m or saline solution before oxaliplatin infusion. Evaluation of neurotoxicity, pharmacokinetics of plasmatic total and ultrafiltered Pt, and determination of Pt-DNA adduct formation on white blood cells was performed during the 5th, 9th, and 12th cycles. At the end of all cycles of therapy, the patients in the GSH arm showed a statistically significant reduction of neurotoxicity (P=0.0037) compared with the placebo arm. There were no significant differences in the main pharmacokinetic parameters between the two arms except a lower area under the plasma concentration-time curve and a smaller apparent steady-state volume of distribution (Vss) when GSH was coadministered. This difference can be explained by the natural function of GSH in the detoxification of oxaliplatin and by its ability to remove the Pt bound to plasma proteins. The determination of Pt-DNA adduct formation shows no statistically significant differences between the two arms. In conclusion, this study indicates that coadministration of GSH is an effective strategy to reduce the oxaliplatin-induced neurotoxicity without impairing neither the pharmacokinetics of oxaliplatin, nor the Pt-DNA adduct formation.

No abstract

Elevated homocysteine concentrations have been associated with methotrexate-induced neurotoxicity. Based on methotrexate and homocysteine plasma concentrations of 494 children with acute lymphoblastic leukemia treated with high-dose methotrexate in the TOTAL XV study, a pharmacokinetic/pharmacodynamic (PK/PD) model was built with NONMEM. Several compartment and indirect response models were investigated. The pharmacokinetic disposition of methotrexate was best described by a two-compartment model. Homocysteine concentrations were included by an indirect response model where methotrexate inhibition of the homocysteine elimination rate was described by an Emax model. The homocysteine baseline level was found to be age-dependent. Simulations revealed that folinate rescue therapy does not affect peak concentrations of homocysteine but leads to a modestly reduced homocysteine exposure. In conclusion, our PK/PD model describes the increase of methotrexate-induced HCY concentrations with satisfactory precision and can be applied to assess the effect of folinate regimens on the HCY concentration-time course.

No abstract

In this study, we investigated the kinetics of oxaliplatin-DNA adduct formation in white blood cells of cancer patients in relation to efficacy as well as oxaliplatin-associated neurotoxicity. Thirty-seven patients with various solid tumours received 130 mg m À2 oxaliplatin as a 2-h infusion. Oxaliplatin-DNA adduct levels were measured in the first cycle using adsorptive stripping voltammetry. Platinum concentrations were measured in ultrafiltrate and plasma using a validated flameless atomic absorption spectrometry method. DNA adduct levels showed a characteristic time course, but were not correlated to platinum pharmacokinetics and varied considerably among individuals. In patients showing tumour response, adduct levels after 24 and 48 h were significantly higher than in nonresponders. Oxaliplatin-induced neurotoxicity was more pronounced but was not significantly different in patients with high adduct levels. The potential of oxaliplatin-DNA adduct measurements as pharmacodynamic end point should be further investigated in future trials.

No abstract

Atomic oxygen number densities measured by a mass spectrometer with a cryoion source and a 5577‐A night airglow photometer flown in the same rocket pay load are discussed. The airglow data are further compared with the number densities obtained from a number of previous photometer experiments and from another cryomass spectrometer. The volume emission rates of the previous airglow measurements were taken from the literature and converted to O number densities by a new set of rate coefficients. The comparison with the mass spectrometer data indicates that these coefficients yield usable oxygen number densities. The oxygen densities are correlated with several geophysical parameters. A seasonal variation of the peak density of the oxygen layer is found showing a flat summer maximum. The altitude at which the peak of the layer occurs shows a seasonal variation with a minimum in summer. Combination of these two counteracting effects yields two results: (1) it indicates a quasi‐semiannual variation of the 5577‐A light emission of the oxygen layer and (2) by an extrapolation it yields a seasonal variation of the atomic oxygen number density at higher altitudes with a pronounced summer minimum.