Evidence that amikacin ototoxicity is related to total perilymph area under the concentration-time curve regardless of concentration.
Previous studies have failed to fully establish whether ototoxicity is related in any way to the levels of an aminoglycoside antibiotic in the perilymph. To study this we exposed guinea pigs to continuously infused amikacin at four different dosing rates under conditions parallel to those used in our previous study which related ototoxicity to total plasma area under the concentration-time curve regardless of the level in plasma. It was found that at all dosing rates, levels in the perilymph and ratios of levels in perilymph/plasma remained constant as the dosing duration increased from nonototoxic to strongly ototoxic. Plasma and perilymph amikacin levels were found to be linear functions of the dosing rate even at ototoxic dosing exposures, and ratios of levels in perilymph/plasma did not differ between dosing rates. The total perilymph area under the concentration-time curve was not different between dosing rates either for a total dose associated with threshold ototoxicity or for one associated with severe ototoxicity. The results suggest that amikacin ototoxicity is related to the integral of the concentration in the perilymph over the total time of amikacin exposure regardless of the level in the perilymph.
Drug Toxicology Division, Health Protection Branch, Ottawa, Ontario, Canada.
A R
AR
Beaubien
E
E
Ormsby
A
A
Bayne
K
K
Carrier
G
G
Crossfield
M
M
Downes
R
R
Henri
M
M
Hodgen
D000583:Amikacin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D006311:Hearing Disorders / Q000139:chemically induced*; D007262:Infusions, Intravenous; D008297:Male; D010498:Perilymph / Q000378:metabolism*; D013216:Reflex, Startle / Q000187:drug effects
D000583:Amikacin