The concentration‐effect relationship of quinine‐induced hearing impairment

Quinine‐induced reversible hearing impairment at the frequencies of 1000 and 2000 Hz was investigated in healthy volunteers to analyze the plasma concentration‐effect relationship of the drug. Six subjects were given two identical oral doses of quinine and a constant rate infusion of quinine over 6 hours (15 mg · kg −1 ) on three separate occasions. A simple pharmacodynamic model, E = k · C γ (in which E is effect, k is a proportionality constant, C is drug concentration, and the exponent γ is a fitting parameter), was found to describe well the relationship between hearing impairment and quinine concentrations in a hypothetical effect compartment. No statistical differences were found in the estimated parameters when the three dosings were compared, indicating that quinine‐induced hearing impairment is independent of route of administration. The first‐order rate constant (k eo ), linking plasma concentrations to the concentrations in the effect compartment, was (mean ± SD) 0.71 ± 0.19 and 0.99 ± 0.37 hr −1 for 1000 and 2000 Hz, respectively. The corresponding values of k were 0.15 ± 0.10 and 0.12 ± 0.19 and the values of γ were 2.13 ± 0.57 and 3.44 ± 1.04 for 1000 and 2000 Hz, respectively. Effect was also analyzed by semiparametric pharmacodynamic modeling, which gave results comparable to those obtained with the link model. We conclude that a simple power function is a reliable pharmacodynamic model for describing quinine‐induced hearing impairment in healthy subjects. Clinical Pharmacology and Therapeutics (1994) 55, 317–323; doi: 10.1038/clpt.1994.32