Pharmacokinetic Analysis of Gentamicin Thrice and Single Daily Dosage in Pediatric Cancer Patients

Abstract

Fifty-two children suffering from different types of malignancies were included and evaluated for the pharmacokinetics of gentamicin thrice or single daily dosage protocols. All the study population received a total dose of 5 mg/kg daily. Thirty children received gentamicin thrice daily, and 22 were treated using the single daily protocol; all had fever and neutropenia when included. The individual pharmacokinetic parameters were calculated using a one-compartment model for two blood gentamicin samples. The mean (SD) t 1/2 (h), clearance (mL/min/BSA), Vss (L/kg), Cmax (micrograms/mL), and Cmin (micrograms/mL) were 3.05 (1.0) and 3.9 (0.6) h, 136 (61.3) and 99.9 (65.3) mL/min/BSA, 0.4035 (0.167) and 0.457 (0.17) L/kg, 5.2 (2.0) and 11.5 (4.2) micrograms/mL, 0.8 (0.6) and 0.18 (0.1) microgram/mL for thrice and single daily dosage schedules, respectively. The single gentamicin daily dose protocol had a significantly longer t 1/2, shorter clearance normalized to BSA, higher Cmax, and lower Cmin in comparison with the thrice daily schedule. We recommend the use of gentamicin at 5 mg/kg daily delivered as a single daily dose for pediatric cancer patients with fever and neutropenia, in spite of the measured pharmacokinetic differences, which in our opinion have no clinical significance.

Clinical Issues Surrounding Once‐Daily Aminoglycoside Dosing in Children

“…44 Other trials defined failure to respond as persistence of fever and continuing neutropenia after the fifth and fourth days of therapy. 46,47 One group did not report clinical cure rates, only clinical improvement. 48 Four additional studies evaluating clinical efficacy did not compare dosing regimens, but administered aminoglycosides only once/day.…”

“…6,11,[44][45][46][47][48][49][50][51][52][53][54][55][56] This regimen also was investigated in neonates up to 1 month of age but is not discussed here due to the decreased renal function in that patient population. Infectious processes included neutropenic fever, suspected or confirmed gramnegative infections, cystic fibrosis, and suspected or confirmed surgical infections.…”

“…Nine studies evaluated clinical and/or microbiologic efficacy of ODD in approximately 450 children ( Table 2). [44][45][46][47][48][49][50][51] It is important to note that the studies were not adequately powered to show a true statistical difference due to a limited number of subjects.…”

“…[44][45][46][47][48] Three of them examined gentamicin, and one each tobramycin and amikacin. Clinical cure rates ranged from 88-92% and 90-98% in patients receiving once-daily and multiple daily doses, respectively.…”

“…44,45,[47][48][49][50][51][52][53][54][55] Most of them defined nephrotoxicity as a percentage increase in serum creatinine concentration over baseline or a percentage decrease in creatinine clearance from baseline. In addition to creatinine clearance monitoring, 24-hour proteinuria, lysozymuria, and B2 microglobulinuria were measured to determine nephrotoxicity.…”