SELECTION OF OPTIMAL PROPHYLACTIC AMINOGLYCOSIDE DOSAGE IN CANCER-PATIENTS - POPULATION PHARMACOKINETIC APPROACHES

We report an alternative dose-finding approach for the selection of op timal prophylactic aminoglycoside dosage in specific (sub)populations of patients. Relative a priori utility of several intervals of gentami cin or tobramycin (AMG) peak and trough serum levels were assigned by a group of pharmacokinetics experts, assuming prophylactic administrat ion for laryngectomy interventions. A group of 2 7 adult patients, wit h normal renal function, undergoing elective surgery for laryngeal pro blems and treated prophylactically with gentamicin (80 mg t.i.d.) or t obramycin (100 mg t.i.d.) was studied. Two blood samples (peak and tro ugh) were drawn at steady-state for AMG assay. Three different methods , standard two-stage (STS), extended least-squares non-linear regressi on [MULTI(ELS)] and non-parametric expected maximization (NEPM), were used to estimate the pharmacokinetic (PK) population parameters. PK si mulations 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 s chedule for this group of patients. There were no statistically signif icant 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. Convers ely, using the individual PK parameters and the mean AMG levels simula ted 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 rel ative utilities for the AMG serum concentrations in the selection of o ptimal 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.