Busulphan levels in plasma were measured in 27 patients during conditioning therapy (1 mg/kg x 4 for 4 days) before bone marrow transplantation. The mean minimal concentration found in children aged less than 5 years (237 ng ml-1) was lower than that observed in adults or older children (607 and 573 ng ml-1, respectively). The AUC for the last dose was significantly lower in young children (2.315 h ng ml-1) than in adults or older children (6,134 and 5,937 h ng ml-1, respectively). The elimination half-life for the last dose in young children was shorter (2.05 h) than that in either adults (2.59 h) or older children (2.79 h). When the AUC was normalized for body surface area, the difference between young children and the other groups was smaller but remained statistically significant. The total body clearance was significantly higher in young children (7.3 ml min-1 kg-1) as compared with both older children and adults (3.02 and 2.7 ml min-1 kg-1, respectively). The plasma levels of busulphan showed circadian rhythmicity, especially in young children. The concentration measured during the night in some patients was up to 3-fold that observed during daytime. We conclude that the busulphan dosage for children must be reconsidered and that further studies are urgently needed to develop an optimal therapy.
BackgroundCisplatin is a cornerstone anticancer drug with pronounced ototoxicity, whereas oxaliplatin, a platinum derivative with a different clinical profile, is rarely ototoxic. This difference has not been explained.MethodsIn HCT116 cells, cisplatin (20 μM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold), to 3.1-fold induction (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging from 9.3-fold (95% CI = 8.8- to 9.8-fold), to 5.1-fold (95% CI = 4.4- to 5.8-fold). A guinea pig model (n = 23) was used to examine pharmacokinetics. Drug concentrations were determined by liquid chromatography with post-column derivatization. The total platinum concentration in cochlear tissue was determined by inductively coupled plasma mass spectrometry. Drug pharmacokinetics was assessed by determining the area under the concentration–time curve (AUC). Statistical tests were two-sided.ResultsIn HCT116 cells, cisplatin (20 μM)-induced apoptosis was reduced by a calcium chelator from 9.9-fold induction (95% confidence interval [CI] = 8.1- to 11.7-fold to 3.1-fold induction) (95% CI = 2.0- to 4.2-fold) and by superoxide scavenging (from 9.3-fold, 95% CI = 8.8- to 9.8-fold, to 5.1-fold, 95% CI = 4.4- to 5.8-fold). Oxaliplatin (20 μM)-induced apoptosis was unaffected by calcium chelation (from 7.1- to 6.2-fold induction) and by superoxide scavenging (from 5.9- to 5.6-fold induction). In guinea pig cochlea, total platinum concentration (0.12 vs 0.63 μg/kg, respectively, P = .008) and perilymphatic drug concentrations (238 vs 515 μM × minute, respectively, P < .001) were lower after intravenous oxaliplatin treatment (16.6 mg/kg) than after equimolar cisplatin treatment (12.5 mg/kg). However, after a non-ototoxic cisplatin dose (5 mg/kg) or the same oxaliplatin dose (16.6 mg/kg), the AUC for perilymphatic concentrations was similar, indicating that the two drugs have different cochlear pharmacokinetics.ConclusionCisplatin- but not oxaliplatin-induced apoptosis involved superoxide-related pathways. Lower cochlear uptake of oxaliplatin than cisplatin appears to be a major explanation for its lower ototoxicity.
The pharmacokinetics of high-dose busulphan was studied in adult patients with acute myeloblastic leukaemia after oral doses of 1 mg.kg-1 every 6 h for 4 days. The mean steady-state plasma concentration was 1080 ng/ml-1 during the treatment. Individual steady-state concentrations after the last dose on average were 32% lower than those predicted from total AUC measurements following the first dose. Mean elimination half-life in plasma was 2.3 h after the last dose and 3.4 h after the first dose which suggests that busulfan may increase its own metabolic rate on repeated treatment. The cerebrospinal fluid/plasma concentration ratio of busulphan was 1.3. Busulphan showed insignificant protein binding in plasma (7.4%). About 2% of the dose was excreted unchanged in the urine. For the first time sulpholane, 3-hydroxysulpholane and tetrahydrothiophene 1-oxide were identified as urinary metabolites of busulphan in man.
Oxaliplatin is a novel platinum complex used for the treatment of metastatic colorectal carcinoma. The pharmacokinetics of the free fraction of oxaliplatin in blood were evaluated in 10 patients given 85 mg/m2 of oxaliplatin using an infusion time of 2 h. Blood samples were collected during and after the infusion and immediately placed on ice. The samples were ultrafiltrated centripetally and the concentration of oxaliplatin in the ultrafiltrate was determined by liquid chromatography in combination with postcolumn derivatization. The in vitro degradation rate was determined in blood from the patients taken immediately before drug administration. The maximal blood concentration (C(max)) and terminal half-life (t1/2) were 1.44 +/- 0.20 (SD) microg/mL and 14.1 min (range: 10.2-24.5), respectively. The area under the blood concentration time curve (AUC), clearance (CL), and distribution volume (V(ss)) were (means +/- SD) 161 +/- 22 microg min/mL, 32.1 +/- 4.2 L/h/m2, and 0.26 +/- 0.06 L/kg, respectively. There was a significant correlation between the clearance of oxaliplatin in the patients and the degradation rate in whole blood (r = 0.746; p = 0.017). Oxaliplatin has a short elimination half-life, which is in a sharp contrast to previously reported elimination half-lives obtained by analysis of the platinum content in plasma and ultrafiltrate. The correlation between in vivo and in vitro data suggests that the degradation in whole blood plays a role for the elimination of the drug.
[Pt(dach)oxCl]-, a new transformation product of oxaliplatin, has been identified. Its in vitro cytotoxic effect does not appear to exceed that of oxaliplatin.
Busulfan as a high-dose therapy is an important component of many of the myeloablative regimens for both allogeneic and autologous bone marrow transplantation (BMT) in adults and children. During the last decade, several studies have shown a wide inter- and intra-patient variability of busulfan disposition in adults and children. Some of the factors affecting the interpatient-variability were identified as circadian rhythmicity, age, disease, drug interaction, alteration in hepatic function and recently busulfan bioavailability. In adults, pharmacodynamic studies have shown a positive correlation between high-systemic exposure of the drug and venocclusive disease (VOD). However, pharmacodynamic studies in children did not establish any correlation between the systemic exposure and VOD. Drug-monitoring and dose adjustment in adults were used successfully to decrease the occurrence of VOD and mortality. It was observed that about 20% of the busulfan dose crosses the blood brain barrier. The high amount of the drug which enters the brain can probably be involved in the CNS toxicities reported. In children, a low rate of toxicity combined with a high rate of engraftment failure were observed. Several investigators have expressed their concern about the dosage in children and many suggested higher doses based on the body surface area for young children. However, recently it was shown that busulfan bioavailability varied by 2-fold in adults (0.5-1.03) while in children a 6-fold variation was observed (0.22-1.20). The access to an intravenous form of busulfan and a deeper understanding of pharmacodynamics of the drug might be essential to optimize the treatment, reach a successful engraftment and lower the therapy related toxicities.
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