The effects of age and chemotherapy on gentamicin pharmacokinetics and dosing in pediatric oncology patients.

We attempted to determine the effects of prior antineoplastic chemotherapy and age on gentamicin pharmacokinetics in children (age 1-18 yrs) with cancer and in controls, and to establish a protocol for gentamicin dosing and monitoring to ensure rapid attainment of therapeutic serum concentrations in these patients. In a prospective controlled study, patients with fever who were receiving empiric gentamicin for confirmed or suspected infections were separated into three groups: 29 with cancer who were receiving a continuing chemotherapy protocol with nonnephrotoxic antineoplastic agents; 23 with cancer who were receiving a continuing chemotherapy protocol with nephrotoxic antineoplastic agents; and 25 control patients who did not have cancer. Three blood samples (one predose, two postdose concentrations), collected between the third and sixth gentamicin doses from each patient, were analyzed by the Emit assay. Pharmacokinetic parameters were calculated and gentamicin dosages recommended based on the Sawchuk-Zaske method of serum level interpretation. When normalized by body weight, there was no significant difference in clearance, volume of distribution, and half-life between the control group and either group of patients with cancer. However, when normalized by body surface area, patients receiving prior nephrotoxic chemotherapy appeared to have a lower mean clearance (98.2 ml/min/1.73 m2) than those exposed to nonnephrotoxic chemotherapy (117.4 ml/min/1.73 m2) and controls (113.3 ml/min/1.73 m2; ANCOVA p = 0.033). When kinetic parameters were normalized by body weight, the effect of advancing age yielded a decrease in both clearance (p < 0.001) and volume of distribution (p = 0.02), and an increase in gentamicin half-life (p < 0.001). When normalized by body surface area, age had no significant effect on clearance (p = 0.579). There was no significant difference in gentamicin daily dose requirements (mg/kg) between the chemotherapy groups, which may be due to the lack of significant effects of chemotherapy on gentamicin's volume of distribution and clearance normalized by body weight. The final maintenance doses (mg/kg/day, mean +/- SD) for patients with cancer were 10.8 +/- 1.8 for those age 1-5 years, 8.9 +/- 1.1 for those age 6-12 years, and 7.9 +/- 1.9 for those age 13-18 years. However, when normalized by body surface area, the age-dependent doses became remarkably similar for children in all three age groups (ANOVA p = 0.932), approximately 250 mg/m2/day. We recommend that pediatric patients with cancer who require treatment for fever and neutropenia be given higher than standard gentamicin dosages to achieve therapeutic serum concentrations promptly. In particular, initial empiric doses of 10 mg/kg/day are appropriate for those age 1-5 years.

Challenges in comparing treatment outcome from a prospective with that of a retrospective study: assessing the merit of gentamicin therapeutic drug monitoring in pediatric oncology.

The objectives of this study were: (a) to assess whether treatment outcome with gentamicin in pediatric oncology patients could be improved by a pharmacy based therapeutic drug monitoring (TDM) service that included pharmacokinetic interpretation; and (b) to describe the challenges in comparing treatment outcome from a prospective to a retrospective study when the merit of gentamicin therapeutic drug monitoring (TDM) was assessed in pediatric oncology patients. Two groups of pediatric oncology patients, aged 1-18 years, received empiric gentamicin therapy for fever and for confirmed or suspected infection, with the same inclusion and exclusion criteria. Group 1 consisted of patients from a prospective gentamicin pharmacokinetic study with a formalized pharmacy-based TDM service (n = 52). Group 2 consisted of patients admitted to the oncology units who had gentamicin levels analyzed in the TDM Laboratory without the formalized TDM Service (n = 25). Gentamicin dosage adjustments were recommended based on three blood samples (one pre- and two postdose concentrations) collected between the third and sixth doses from each patient in the TDM group, utilizing pharmacokinetic principles and the Sawchuk-Zaske method. In the non-TDM group, dosage adjustments based on two routine blood samples (one pre- and post-gentamicin dose) were performed by physicians without the help of the formalized TDM Service. Multiple regression analysis showed that time periods (TDM, non-TDM), duration of neutropenia, intravenous methotrexate, and types of cancer, e.g., hematologic malignancy vs. solid tumor, had significant effects on duration of fever. Initial absolute neutrophil count, insertion of central venous line, intravenous cloxacillin administration, bacteriologic cultures, and initial post gentamicin levels > or = 5 mg/ml had no significant effects on the duration of fever. Mean duration of fever in the TDM group (2.8 +/- 2.4 days) was significantly shorter than that in the non-TDM group (9.0 +/- 8.8 days) (p < 0.001). Therapeutic serum concentrations were achieved more promptly in the TDM group, with significantly fewer patients requiring dose changes and fewer sets of serum concentrations required. One patient from each group had a > 100% increase in serum creatinine on day 5 compared to baseline. No apparent nephrotoxicity was observed in other patients. Although there was an association of shorter duration of fever with prompt achievement of therapeutic gentamicin serum concentrations with the TDM Service, there were several unresolved factors that affected duration of fever. A randomized prospective and controlled study would be required to substantiate the merit of TDM in shortening the duration of fever in pediatric oncology patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Therapeutic monitoring and pharmacokinetic evaluation of procainamide in neonates.

Past experience with the disposition of procainamide hydrochloride (PA) in neonates is restricted to a single case study involving placental transfer. We studied aspects of PA pharmacokinetics in three neonates who received constant-rate infusion therapy. Results indicated that the total serum clearance of PA is similar to the adult value, but elimination half-lives of both PA and N-acetylprocainamide (NAPA) were slightly prolonged and volume of distribution was variable. Pharmacokinetic evaluations in a renally compromised neonate confirmed that total PA clearance and the renal clearance of both PA and NAPA were reduced, although not to the extent expected for the degree of renal impairment. Peritoneal dialysis was used concurrently and may have contributed to the elimination process. We believe that our experience provides important preliminary guidelines for the management of PA therapy in neonates.

Therapeutic monitoring of cyclosporine following pediatric bone marrow transplantation: problems with sampling from silicone central venous lines.

Blood concentrations are commonly used to guide dosing requirements of cyclosporine, due to large variations in pharmacokinetics both between and within individuals. Bone marrow transplant patients at The Hospital for Sick Children are prescribed intravenous cyclosporine as part of the posttransplant immunosuppression protocol. Sampling for blood concentration measurement is generally done via a single-lumen central venous line (CVL). Cyclosporine concentrations sampled by this route were compared with concentrations in peripheral capillary samples taken concurrently. Results from the CVL blood were substantially higher despite appropriate flushing of the CVL between the end of the infusion and the time of sample collection. This discrepancy disappeared once the patient was converted to oral cyclosporine. We conclude that the sampling error is due to drug adsorbed to the silicone CVL catheters during intravenous administration and displaced during blood sample collection.

Caffeine overdose in an adolescent male.

A 16 year old male who ingested an estimated 6-8 grams of caffeine is described. Caffeine is commonly thought to be harmless, but its wide availability has promoted abuse. This patient manifested many of the adverse effects seen in acute caffeine ingestion including hypokalemia, elevated blood glucose, tachycardia, bigeminy and agitation. Respiratory alkalosis and chest pain, which have not been previously reported to our knowledge in caffeine overdose, were also noted in this patient. Three serum caffeine levels were analyzed and an abnormally long elimination half-life of approximately 16 hours was calculated from the results.