Cyclophosphamide pharmacokinetics in children (original) (raw)
Related papers
2011
Myeloablative Children NONMEM Pharmacokinetic A B S T R A C T Introduction: In order to better understand the impact of high-dose on the pharmacokinetics and metabolism of cyclophosphamide, a pharmacological study was performed in children with malignant mesenchymal tumours with metastatic disease. Methods: Patients received four courses of chemotherapy including two courses of cyclophosphamide. Plasma concentrations of cyclophosphamide and the metabolites 4-ketocyclophosphamide, dechloroethylcyclophosphamide and carboxyphosphamide were determined on days 1, 2 and 3 of each course. A population pharmacokinetic model for cyclophosphamide was developed using non-linear mixed effects modelling and metabolite AUC values compared between days and courses.
Cyclophosphamide Metabolism in Children
Cancer Research, 1995
The alkylating agent cyclophosphamideis a prodrug which is metabo lized in vivo to produce both therapeutic and toxic effects.Cyclophosph amide metabolism was Investigated in 36 children with various malignan des. Concentrations of cyclophosphamide and Its principal metabolites were measured In plasma and urine using a quantitative bigh-perfor mance ThC method. The results Indicated a high degree of Inter-patient variationin metabolism. In contrastto previousadult studieson urinary metabolites,plasmacarboxyphosphamideconcentrationsdid not support the existenceof polymorphic metabolism. Plasma concentrations of de chlorethylcyclophosphamldeand carboxyphosphamidewerecorrelated in individual patients, suggesting that the activity of both aldehyde dehydro genaseand cytochrome P450enzyme(s)determine carboxyphosphamide production in vivo. The presence of ketocyclophosphamide In plasma was strongly associated with dexainethasone pretreatment and was also ac companiedby a high clearanceofthe parent drug. Interpatlent differences In metabolism reflect Individual levels of enzyme expression and may contribute to variation In clinical effect.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2000
Cyclophosphamide (CPA) has a broad spectrum of activity against solid tumors. Hepatic self-induction of the active metabolite 4-hydroxycyclophosphamide occurs after repeated administration. We evaluated the clinical efficacy of a window regimen that administers fractionated CPA in conjunction with etoposide (VP16) in children with advanced or refractory solid tumors. Seventeen children with advanced (n = 12) or refractory (n = 5) solid tumors were entered onto this phase II window study. The treatment regimen consisted of intravenous (IV) CPA 500 mg/m(2)/d and IV VP16 100 mg/m(2)/d. Both drugs were administered daily by short infusions for 5 consecutive days. A total of 34 courses were administered, with a median of two courses per patient. The median interval between chemotherapy courses was 21 days (range, 17 to 35 days). Thirty-three courses were assessable for toxicity, and all patients were assessable for response. No life-threatening toxicities were observed. The incidence of ...
Decreased half life of cyclophosphamide in patients under continual treatment
European Journal of Cancer (1965), 1979
Plasma levels of c),clophosphamide (Cy) u'ere measured in 16 cancer patients receiving 100 rag/day of Cy for over 1 yr. Oral and intravenous administrations gave similar AUC values, confirming that intestinal absorption is almost complete. When pharmacokinet#s obtained at the first course of therapy were compared with pharmacokinetics measured after more than 6 months continual treatment, T ½ and ~'gt appeared significantly lower in the second population derpite broad variability' among patients.
Chirality, 1999
The complete pharmacokinetics (PK) of (R)-and (S)-cyclophosphamide (CP) and their dechloroethylated (DCE) metabolites have not been reported to date. We collected plasma and urine samples from 12 cancer patients and determined concentrations of both enantiomers of CP and DCE-CP using a chiral GC-MS method. All concentrations of (R)-CP, (S)-CP, (R)-DCE-CP, and (S)-DCE-CP were simultaneously modeled using an enantiospecific compartmental PK model. A population PK analysis was performed. Enantiospecific differences between (R)-and (S)-CP were found for the formation clearance of CP to the DCE metabolites (Cl f : 0.25 (R) vs. 0.14 (S) L/h). No difference was found between enantiomers for Cl 40H , Cld, Cl(m) R , Cl T , or T 1/2 . In contrast to the adolescent and adult group of patients, a child (6 years old) appeared to have a very different PK and metabolic profile (Bayesian control analysis). Proportions of the (R,S)-CP doses transformed to the (R)-DCE-and (S)-DCE-CP were much higher (R: 25 vs. 1.9%, and S: 38 vs. 3.6%), while formation of active metabolites was much lower (R: 42 vs. 74%, and S: 48 vs. 77%). CP appears to be enantioselectively metabolized to the DCE metabolites. This PK model can evaluate the proportion of a CP dose that is transformed to toxic or active metabolites. It may therefore be used to optimize CP treatment, to identify important drug interactions and/or patients with an abnormal metabolic profile.
Pharmacokinetics of etoposide (VP16) in children and adolescents with refractory solid tumors
Cancer research, 1984
The clinical pharmacokinetics of etoposide were studied in eight pediatric patients with refractory solid tumors. The alpha-phase half-life, beta-phase half-life, volume of distribution, and elimination rate constant averaged 0.82 hr, 6.5 hr, 4.0 liters/sq m, and 0.25 hr-1, respectively. Noncompartmental parameters such as systemic clearance, mean residence time, and volume of distribution at steady-state averaged 20.9 ml/min/sq m, 7.8 hr, and 7.2 liters/sq m, respectively. A significant relationship between serum glutamic pyruvic transaminase and systemic clearance was observed, with patients having elevated serum glutamic pyruvic transaminase showing slower systemic clearance of etoposide. Systemic clearance, mean residence time, and beta-phase half-life of etoposide were significantly lower in those patients who had received cisplatin prior to their Phase II etoposide trial. The average pharmacokinetic values derived from these eight pediatric patients with solid tumors did not d...
Investigational New Drugs, 1995
Thirty-six patients were entered on this study to determine the pharmacology, bioavailability, and toxicity of three different oral formulations of cyclophosphamide (Cytoxan | Endoxan | and an investigational direct compression tablet). Patients were randomized with respect to the order in which they received the different oral cyclophosphamide preparations, and received each one for two weeks followed by a two week washout period. Concurrent chemotherapy was allowed provided it remained constant across all 3 courses of cyclophosphamide. Plasma concentrations of cyclophosphamide and phosphoramide mustard were measured by gas chromatography with electron capture detection. Peak plasma cyclophosphamide concentrations and times to peak plasma cyclophosphamide and phosphoramide mustard preparations were significantly greater for Endoxan | than for Cytoxan | and the investigational direct compression tablet. Drug area under the concentration-time curve (AUC), bioavailability, and plasma elimination half-life could not be reliably calculated for Endoxan | but were similar for Cytoxan | and the investigational formulation. Based on AUC comparisons, bioavailability of parent compound (relative to an oral cyclophosphamide solution) was 85% for Cytoxan | and 69% for the investigational formulation. This difference was not significant. There were no significant differences between the 3 formulations with respect to any individual type of toxicity, although the investigational formulation tended to be associated with somewhat less overall toxicity (p = 0.08).
Clinical pharmacology of cyclophosphamide
Cancer research, 1973
The abbreviations used are: NBP, 4-(4-nitrobenzyl)pyridine; CVP, Cyclophosphamide (40 mg/sq m/day for 5 days, p.o. or i.V.), vincristine (1.4 mg/sq m), and prednisone (100 mg/sq m/day for 5 days p.o.); C X T, concentration X time product. 226 CANCER RESEARCH VOL. 33