TOXICODYNAMICS AND TOXICOKINETICS OF AMIKACIN IN THE GUINEA-PIG COCHLEA

An extensive overview of the relationship between cochlear toxicity an d amikacin blood concentrations in the guinea pig is provided which sh ould assist in the clinical application of this class of antibiotic. A data set previously used to relate the incidence of amikacin ototoxic ity to dosing rates and blood concentrations was re-examined to assess the toxicodynamics of amikacin in terms of decibels of hearing loss a cross dosing rate, hearing frequency and time following drug exposure. Animals in this data set had received continuously i.v. infused amika cin over an 8-fold range of dosing rates. Preliminary analysis indicat ed that the data were consistent with a sigmoid relationship between h earing loss (decibels) and area under the amikacin plasma concentratio n vs time curve cumulated over the entire course of drug administratio n (cAUC). The sigmoid model was therefore used as the backbone of a fa r more comprehensive toxicodynamic model which described all the data with a single equation. Testing with this model showed that the cAUC r equired to produce half-maximum hearing loss (cAUC-1/2) was related to dosing rate (P < 0.01), to hearing frequency (P < 0.00001), and to po st-drug interval (P < 0.00001). Maximum hearing loss (difference betwe en upper and lower sigmoid asymptotes) was less than total and was sig nificantly related to frequency (P < 0.00001). No effects could be det ected on the sigmoid slope. Further modelling of the significant effec ts detected by the comprehensive toxicodynamic model was done to deter mine if they could be described by simple relationships or by biologic ally relevant sub-models. Modelling of maximum hearing loss (postulate d to represent loss of mainly outer hair cell function) indicated that this parameter was constant at about 61 decibels for 2-12 kHz and lin early decreased with log frequency for frequencies > 12 kHz. Modelling of cAUC-1/2 on frequency indicated that there was a strong inverse li near relationship to log frequency. Modelling of cAUC-1/2 on post-drug interval indicated that delayed ototoxicity continued at progressivel y slower rates for at least 56 days after drug administration-had ceas ed. Modelling of cAUC-1/2 on dosing rate showed an increased requireme nt for drug as the dosing rate decreased. However, cAUC-1/2 changed no more than 20% across the range of dosing rates compared to the 8-fold difference in mean steady-state plasma concentrations, suggesting tha t plasma concentration is not a primary determinant of ototoxicity. A toxicokinetic model was developed which explained the dosing rate effe ct on cAUC-1/2 very successfully. This model postulated (1) zero order accumulation of drug in the ototoxic pool at a rate directly proporti onal to steady-state amikacin plasma concentration, (2) first order di sappearance kinetics from the ototoxic pool, and (3) that the level of drug accumulation in the ototoxic pool required to produce a given se verity of hearing loss is the same for all dosing rates or plasma conc entrations. The disappearance half-life from the ototoxic pool calcula ted from the fit of this toxicokinetic model to the data was about 80 days. Since the sloping portion of the sigmoid relationship for any on e frequency covered several octaves of differential sensitivity to dru g, it would appear that the slope results principally from row-to-row and to within row differences in drug sensitivity rather than to longi tudinal differences. Cluster analysis of standardized hearing loss val ues (obtained by removing the influence of all significant effects fro m the residuals to the final toxicodynamic model) about a common sigmo id curve indicated that the hearing loss data falls into 4 main cluste rs whose means are about 20 dB apart, presumably corresponding to the loss of 0, 1, 2 or 3 rows of outer hair cells. These results show that , for a limited range of dosing exposures, amikacin-induced hearing lo ss in the guinea pig cochlea is well described as a sigmoid function o f cAUC (R(2) = 0.71 With statistically significant parameters modelled in), and that sensitivity to drug can be expressed as a complex mathe matical function of hearing frequency, dosing rate and post exposure t ime within an expanded sigmoid model. The estimate of a very long disa ppearance half-life of drug at the ototoxic pool has important clinica l implications.