Selection of optimal prophylactic aminoglycoside dosage in cancer patients: population pharmacokinetic approaches.

We report an alternative dose-finding approach for the selection of optimal prophylactic aminoglycoside dosage in specific (sub)populations of patients. Relative a priori utility of several intervals of gentamicin or tobramycin (AMG) peak and trough serum levels were assigned by a group of pharmacokinetics experts, assuming prophylactic administration for laryngectomy interventions. A group of 27 adult patients, with normal renal function, undergoing elective surgery for laryngeal problems and treated prophylactically with gentamicin (80 mg t.i.d.) or tobramycin (100 mg t.i.d.) was studied. Two blood samples (peak and trough) were drawn at steady-state for AMG assay. Three different methods, standard two-stage (STS), extended least-squares non-linear regression [MULTI(ELS)] and non-parametric expected maximization (NEPM), were used to estimate the pharmacokinetic (PK) population parameters. PK simulations were applied to estimate the AMG steady-state concentrations from the PK population parameters. From these data, relative utility values were calculated, allowing the selection of the optimal dosage schedule for this group of patients. There were no statistically significant differences between the PK population estimates as generated by the three methods. Using the STS estimates, the simulation of several dosages indicated that the optimal dosage is 170 mg every 8 h. Conversely, using the individual PK parameters and the mean AMG levels simulated from them, the dose with best relative utility is 130 mg every 8 h. This important difference points out the relevance of the use of relative utilities for the AMG serum concentrations in the selection of optimal a priori dosage. We propose the use of 120 mg every 8 h as the safer dose for our population. Further studies are needed to validate this proposal in patients similar to ours.

Pharmacokinetic interaction between high-dose methotrexate and amoxycillin.

A case report of toxicity following concurrent administration of high-dose methotrexate and amoxycillin is presented. A 16-year-old male patient was administered 10 high-dose methotrexate cycles for treatment of a fully malignant osteogenic sarcoma. Methotrexate was administered at a dosage of 8 g/m2 and infused intravenously over a 6-h period. The patient received pre- and posttreatment hydration and sodium bicarbonate for alkalinization of urine. Calcium folinate rescue was performed when appropriate. During the 10th cycle, coadministration of amoxycillin (1 g/6 h, p.o.) resulted in prolonged and marked enhancement of methotrexate serum levels. Pharmacokinetic parameters obtained in cycle 10 indicate significant differences for total plasma clearance, mean residence time, and distribution half-life when compared to those in cycles 1-9. Amoxycillin decreased the renal clearance of methotrexate, probably by competition at the common tubular secretion system and by secondary methotrexate-induced renal impairment. The patient experienced acute and subacute toxicity with renal failure, myelosuppression, mucositis, nausea, vomiting, fever, and dermatologic abnormalities. Patients receiving amoxycillin during methotrexate therapy should be closely monitored to avoid severe toxicity.

Administration of oral chloral hydrate to paediatric patients undergoing magnetic resonance imaging.

Sedation is frequently required in children undergoing magnetic resonance imaging (MRI). 172 Paediatric patients (82 female and 90 male, age 42 +/- 26 months, weight 14.7 +/- 5.6 kg) entered an open, non-comparative, prospective study to assess the utilization of oral chloral hydrate. Chloral hydrate syrup (70 mg/ml) was administered 20-30 min prior to the procedure. Effective sedation was reached in 80.3% with an average initial dose of 55 mg/kg and in 93.6% with an average total dose of 65 mg/kg. Significant differences in effectivity were correlated with the dose (54 +/- 11 mg/kg in failure cases versus 66 +/- 16 mg/kg in effective cases; p < 0.05) and diagnosis (effectivity falls to 62.5% and 76.0% in children with medullar tumours and encephalic white matter alterations, respectively; p < 0.01). Average sleep induction time was 30 +/- 19 min, and average duration of sleep was 62 +/- 24 min. Adverse reactions occurred in 4.7%, with nausea, vomiting and stomach pain being the most common side-effects (3.5%). Multivariate statistical analysis selects total dose and age into the discriminant function, with a 100% relative percentage of correct classification. A simple method for optimizing the chloral hydrate dose in children is proposed: the dose in mg/kg is calculated as half the age in months + 50.