Ruth Wyllie

Risk factors for ifosfamide nephrotoxicity in children

BACKGROUND Risk factors for long-term nephrotoxicity after ifosfamide for childhood cancers are not fully known. We have studied patient-related and treatment-related risk factors for chronic ifosfamide nephrotoxicity. METHODS A group of 23 children who had received ifosfamide at age 2.1-16.2 years (median 6.9) for various cancers were assessed for nephrotoxicity, at 1-28 (2) months after the end of treatment, by renal function testing, laboratory values, and a grading score (none, mild, moderate, severe). No patient had received cisplatin or undergone nephrectomy. 13 children were reassessed at 10-26 (23) months; eight had died and two were not evaluable. The median total ifosfamide dose was 100.8 (9.0-160.4) g/m2 over a median of 15 courses every 3 weeks as a 48-72 h continuous intravenous infusion (in 22 cases), with mesna and hydration. FINDINGS Glomerular filtration rate was below normal in ten (45%) of 22 evaluable children; their rate was 61-85 mL/min per 1.73 m2. Proximal tubular toxicity led to hypophosphataemic rickets and/or renal tubular acidosis in six children, and distal tubular toxicity caused nephrogenic diabetes insipidus in one. Of the risk factors analysed by multiple regression, only total ifosfamide dose was associated with proximal tubular toxicity. Only two of ten evaluable patients who received under 100 g/m2 developed moderate nephrotoxicity, whereas six of ten who received over this dose had moderate or severe nephrotoxicity. INTERPRETATION High total ifosfamide dose was the only risk factor we identified. Although inter-patient variability was high, cumulative doses of 100 g/m2 or higher should be avoided in children with cancer.

Dose-related nephrotoxicity of carboplatin in children

SummaryThis study investigated changes and the time course of these changes in renal function in children following treatment with carboplatin, and identified risk factors for nephrotoxicity. Glomerular and proximal renal tubular function were investigated before and up to 2 years after treatment in 23 children who received carboplatin. The main findings were reduced glomerular filtration rate (GFR), and increased renal tubular loss of magnesium, manifested by a low serum magnesium (S Mg). The mean fall in GFR was 22 ml min–1 1.73 m–2 (P = 0.012), and in S Mg it was 0.17 mmol l–1 (P = 0.0077). No patient had a clinically important reduction in GFR, and only one patient had symptomatic hypomagnesaemia. GFR and S Mg did not change over time after completion of treatment. Cumulative dose (CD) of carboplatin was inversely related to mean S Mg at the end of treatment (P = 0.031), and directly related to the fall in S Mg (P < 0.001). Calculated cumulative area under the plasma concentration versus time curve (AUC) of carboplatin was inversely related to S Mg after treatment (P = 0.004). Dose intensity (DI) of carboplatin was not shown to be related to S Mg following treatment. CD, AUC and DI of carboplatin were not related to GFR, nor change in GFR, after treatment. High CDs of carboplatin may be associated with evidence of renal damage qualitatively similar to but less severe than that caused by cisplatin. GFR and SMg should be carefully monitored when high CDs of carboplatin are used, or if carboplatin is combined with other nephrotoxic chemotherapy.

Pharmacokinetics and metabolism of cyclophosphamide in paediatric patients

SummaryThe pharmacokinetics and metabolism of cyclophosphamide were studied in nine paediatric patients. Plasma samples were obtained from eight subjects and urine was collected from six children during a 24-h period after drug administration. Cyclophosphamide and its major metabolites phosphoramide mustard (PM), carboxyphosphamide (CX), dechloroethylcyclophosphamide (DCCP) and 4-ketocyclophosphamide (KETO) were determined in plasma and urine using high-performance thin-layer chromatography-photographic densitometry (HPTLC-PD). Cyclophosphamide (CP) was nearly, if not completely, cleared from plasma by 24 h after its administration. The plasma half-life of CP ranged from 2.15 to 8.15 h; it decreased following higher doses and was shorter than that previously reported for adult patients. Both the apparent volume of distribution (0.49±1.4 l/kg) and the total body clearance (2.14±1.4 l m−2 h−1) increased with increasing dose. Renal clearance ranged between 0.12 and 0.58 l/h (mean, 0.43±0.19l/h). Between 5.4% and 86.1% of the total delivered dose was recovered as unchanged drug in the urine. The major metabolites identified in plasma and urine were PM and CX. One patient appeared to be deficient in CX formation. This study suggests that there is interpatient variability in the pharmacokinetics and metabolism of CP in paediatric patients. The shorter half-life and higher clearance as compared with adult values indicate faster CP metabolism in children.

Inaccuracy of glomerular filtration rate estimation from height/plasma creatinine ratio.

Use of a height/plasma creatinine formula to estimate glomerular filtration rate (GFR) is simpler and less invasive than renal or plasma clearance methods. The aim of this study was to determine whether these formulas enabled accurate prediction of GFR measured from the plasma clearance of 51Cr labelled ethylenediaminetetra-acetic acid (51Cr-EDTA). Thirty nine patients underwent GFR measurement at least six months after potentially nephrotoxic chemotherapy. Altman-Bland analysis was performed on the measured GFR and that estimated simultaneously using the original and a modified Counahan-Barratt formula and the Schwartz formula. The limits of agreement of the estimated GFR with the measured GFR were unacceptably wide in each case, despite highly significant correlation coefficients. The bias was smallest for the modified Counahan-Barratt formula. Use of these formulas to estimate GFR in children is insufficiently accurate for research purposes and has limitations in clinical practice. Furthermore, use of correlation coefficients to evaluate different methods of measuring GFR is inappropriate.

Cisplatin pharmacokinetics in children with cancer

Cisplatin is an important drug in the treatment of a number of paediatric cancers yet, despite widespread use, there are only very limited data on the pharmacokinetics of the drug in children. Cisplatin pharmacokinetics were studied in 21 patients following a 24 h infusion of 50-120 mg/m2 cisplatin. Total and free platinum (Pt) levels in plasma and Pt in urine, were measured by atomic absorption spectrophotometry. Pharmacokinetic parameters were determined by non-compartmental and compartmental analyses. There was 3-fold interpatient variability in free drug exposure (area under the plasma concentration versus time curve--AUC) for a given surface area-based dose of cisplatin. The mean (+/- SD) pharmacokinetic parameters for free Pt were: AUC 0.47 +/- 0.13 mg/ml.min/100 mg/m2, Vdss 12.5 +/- 2.7 l/m2, t1/2 39 +/- 9 min, Ke 0.019 +/- 0.006 min-1, Clrenal 62 ml/min/m2, Cltotal 233 +/- 455 ml/min/m2, Cpss 0.31 +/- 0.09 microgram/ml. The total free Pt clearance was 1.5-5.8-fold higher (3.4 +/- 1.0) than the glomerular filtration rate (GFR). The renal clearance of cisplatin was not related to GFR and cisplatin was subject to only limited urinary excretion (27% administered dose 0-48 h), indicating that there are other important pathways of clearance beside renal elimination. Patient and treatment heterogeneity precluded the investigation of pharmacokinetic-pharmacodynamic relationships; however, the degree of interpatient pharmacokinetic variability observed suggests that body surface area-based dosing of cisplatin in children is not satisfactory.

Comparison of continuous infusion and bolus administration of ifosfamide in children

The pharmacological effects of ifosfamide (IFO) are dependent on its metabolism which may vary between different modes of administration. This was studied in 17 patients who received both a continuous infusion (9 g/m2 over 72 h) and repeated bolus administration (3 g/m2 every 24 h for 3 days). Concentrations of IFO and its metabolites were determined in plasma and urine. There was up to 70% less of the dechloroethylated metabolites in plasma following bolus administration compared to continuous infusion. Since dechloroethylation results in the formation of the toxic metabolite chloroacetaldehyde, this difference in metabolism may have an impact on the toxicity of IFO. There were no other consistent differences between the two modes of administration. Auto-induction of IFO metabolism, with an increase in dechloroethylated metabolites, was observed for both modes of administration. In conclusion, apart from dechloroethylation, there is little difference between these two modes of administration. However, during multiple cycles of IFO therapy such differences could have a significant effect.

Intrasubject variation in children of ifosfamide pharmacokinetics and metabolism during repeated administration

Abstract The aim of this study was to investigate intrasubject variability in ifosfamide (IFO) pharmacokinetics and metabolism which may influence clinical effect, since the pharmacology of this drug is dependent on metabolism. A group of 11 patients (ages 1–16 years) were studied on at least two occasions. IFO, 9 gm-2, was administered as a continuous infusion over 72 h. Plasma and urine samples were collected and concentrations of IFO and its metabolites were determined. Comparisons were made between courses in the same subject, allowing for differences in age and prior IFO treatment. There was a wide variation in drug (twofold) and metabolite (up to tenfold) AUCs between courses in the same patient. Although some patients did show an increase in clearance between courses (up to threefold), there was no significant consistent change in overall pharmacokinetics among the different courses studied in the same patient. There was a significant decrease (up to 63%) in the AUC of the inactive metabolite 3-dechloroethylifosfamide (3-DCI) in later courses compared with the first course studied (P=0.032, paired t-test). This was matched by an increase in the AUC of the total dechloroethylated metabolites with course (P=0.015, paired t-test). None of the other metabolites measured showed any consistent change in plasma or urine levels between courses. Overall, the AUC of parent drug correlated with age (r2=0.86, P=0.011), and postinfusion half-life correlated with plasma bilirubin (r2=0.89, P=0.007). This study demonstrated large and seemingly unpredictable intrasubject variability in IFO pharmacokinetics and metabolism during repeated administrations. Investigations relating the clinical effects of IFO to pharmacokinetics and metabolism must take this variation into account.

The effect of treatment with high dose melphalan, cisplatin or carboplatin on levels of glutathione in plasma, erythrocytes, mononuclear cells and urine

Glutathione (GSH) has been implicated as an important factor in the detoxification of many electrophilic xenobiotics, including agents used in cytotoxic chemotherapy. Maintenance of high levels of GSH in normal tissues is believed to be important in the prevention of drug-induced toxicity. Previous studies have indicated that exposure of cells to some toxic electrophiles both in vitro and in vivo can cause a temporary decrease in intracellular levels of GSH. In this paper we report that in a series of 22 children and young adults treated with high dose melphalan (ten courses studied, all 200 mg/m2), cisplatin (eight courses, 80–04 mg/m2) or carboplatin (seven courses, 507–750 mg/m2) there was no significant alteration in the level of plasma, erythrocyte or urine GSH in the period immediately following drug administration. Fluctuations in the level of GSH in mononuclear cells were observed in some patients but did not follow any consistent pattern and were similar to those observed in a series of nine normal adult controls over the same time course. These results suggest that for melphalan, cisplatin and carboplatin, drug-GSH adduct formation is insufficient to cause a measurable decrease in intracellular GSH levels in normal peripheral haematopoietic cells during the course of treatment.

The influence of ifosfamide scheduling on acute nephrotoxicity in children.

Nephrotoxicity is a significant problem in children after treatment with ifosfamide. Acute changes in renal function were compared in 16 children receiving 9 g m(-2) of ifosfamide as a 72-h continuous infusion on one occasion and, on another course, divided into three 1-h infusions on consecutive days. Subclinical acute nephrotoxicity was demonstrated with both schedules, but there were no significant differences in severity.

A balancing act

Corticosteroids were first used in 1948 to successfully treat rheumatoid arthritis.1 They have proven to be very useful in the management of many childhood diseases. However, adverse effects of long-term corticosteroid use are significant, especially in the growing child. Inevitable adverse effects have to be balanced against very valuable benefit. Reducing the chances of serious harm from long-term corticosteroid use involves careful planning, education and surveillance. Two case histories are described to highlight some of the important concerns raised in the management of children treated long-term with corticosteroids. Many of these dilemmas commonly present to general paediatric services, especially out of hours. Generic issues are covered in this article, predominantly drawing on the authors’ experience in paediatric rheumatology. John was diagnosed with systemic onset juvenile idiopathic arthritis (SOJIA) when 4 years old. His disease followed an active course with polyarthritis and frequent exacerbations of systemic features (characterised by fever, typical rash, irritability and on three occasions bilateral pleural effusions). Initial drug treatment was with ibuprofen (at 60 mg/kg/day) and three daily intravenous infusions of methylprednisolone (30 mg/kg/dose). The family met with the paediatric rheumatology team including clinical nurse specialist, physiotherapist, occupational therapist and paediatric rheumatologist. Education including written information was given regarding the disease and treatment options. Referral was made to an ophthalmologist to screen for associated uveitis. As the disease was still active oral prednisolone was started at 2 mg/kg/day alongside oral methotrexate. There was a history of chicken pox and a blood test detected IgG to varicella zoster virus (VZV). Pneumococcal vaccine was administered and annual influenza vaccine recommended. However, his disease remained difficult to control. Polyarthritis persisted with only a two-month transient benefit after intra-articular injections of triamcinolone hexacetonide. Blood tests (raised acute phase reactants and leucocytosis) suggested a high level of inflammation and he had …