Br. J. clin. Pharmac. (1991), 31, 409412
ADONIS 030652519100079 H
Hearing impairment related to plasma quinine concentration in healthy volunteers GUNNAR ALVAN1, KJELL K. KARLSSON2, URBAN HELLGREN3 & TOMAS VILLEN1 Departments of 'Clinical Pharmacology, 2Audiology and 3Infectious Diseases, Karolinska Institutet, Huddinge University Hospital and Roslagstulls Hospital, Sweden
1 Hearing impairment was investigated in six healthy volunteers who received oral doses of 5, 10 and 15 mg kg-1 quinine single-blind and in random order. 2 The plasma concentration of quinine was followed for 48 h and the time course was fitted by a linear one compartment pharmacokinetic model. 3 Hearing thresholds were measured by pure tone audiometry. There was a delay between impairment in hearing and change in plasma quinine concentration. Thus the method of effect compartment modelling was applied. 4 The effect on hearing (L), measured as a shift in hearing threshold (dB), was used to estimate the rate constant for elimination of drug from the assumed effect compartment (keo) and two parameters specifying the effect model (y and k). The effect model applied was L = 10 (log k + y x log Ce) where Ce is the calculated drug concentration in the effect compartment. This model is a logarithmic transform of a power expression equivalent to the Hill equation at the lower end of the effect range. In all experiments where there was a clear effect on hearing, convergence on a set of parameter estimates occurred, but inter- and intraindividual variability was large. The mean value of keo was 3.32 ± 5.93 h-1 s.d., for y it was 1.73 ± 1.14 s.d. and for k it was 0.59 ± 0.66 s.d.
Keywords hearing loss pharmacodynamics
cochlea
quinine
pharmacokinetics
Introduction
cation except for contraceptives. None had experienced any hearing problems and all were considered normal after a routine ear examination and pure tone- and impedance audiometry tests. Each subject received three oral quinine doses as close as possible to 5, 10 and 15 mg kg-', respectively, using standard tablets of quinine hydrochloride (KabiVitrum, Sweden). The doses were given in randomized order and single-blind at intervals of 1 week. Blood samples were drawn through a heparinised intravenous catheter at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 24, 32 and 48 h after dosage. The study was approved by the Ethics Committee of the Huddinge University Hospital.
It is well known that quinine causes reversible hearing loss (Guder, 1880) and enhances muscle contraction (Santesson, 1892). This is an interesting combination of side effects since new theories on the mechanism of hearing (Flock, 1988) assume that contractile structures in the sensory cells enable the ear to adjust its micromechanical properties according to the stimuli. Quinine induces motile responses in isolated outer hair cells of the mammalian cochlea (Karlsson & Flock, 1990) which could account for the reversible hearing loss. We have previously studied the relationship between the plasma concentration of quinine and loss of hearing in the anaesthetised guinea pig (Alvain et al., 1989). The present study describes the findings after three single oral doses of quinine to healthy volunteers.
Effect measurements Hearing was measured at the time of each blood sampling. Pure tone audiometry of the right ear was performed with the Bekdsy sweep technique (500-8000 Hz) and determined at frequencies of 500, 1000, 1500, 2000, 3000, 4000, 6000 and 8000 Hz. Hearing impairment was calculated as the mean threshold shift over these frequencies. As a test of reproducibility, the hearing
Methods
Subjects and study design Six healthy females, 24-39 years old, participated after giving informed consent. They were taking no medi-
Correspondence: Dr G. Alvan, Department of Clinical Pharmacology, Huddinge University Hospital, S-141 86 Huddinge, Sweden
409
410
G. Alvan et al.
threshold at a fixed frequency of 4000 Hz was determined immediately before and after the full frequency sweep on each occasion. All measurements were made in a sound-proof room and using electronic equipment validated according to audiometric standards. At each test time the subjects were asked to grade their subjective symptoms including tinnitus, hearing loss and dizziness. Hearing measurements and drug analyses were made independently by different individuals.
-i, -
...
.0
.0
a
i.>,59
v
,
20
Quinine assay
2 L
Plasma was separated by centrifugation and stored frozen at -20° C until assayed for quinine by h.p.l.c. (Hellgren et al., 1990). The method had coefficients of variation of 9% and 6% at quinine concentrations of 1 ,umol 1-1 and 25 ,umol 1-1, respectively. The day-to-day variation was 8.6% estimated using a standard concentration of 14.5 ,umol 1-1.
f
e6 ,,..,8;;,'14;.,).:9''t.'4''¢%"'[ i;y 'f i' 1- '~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~'1
9 I
I
-~~5QQ
/1*'
axO
f1X,l b....0
a
I
I
2000
w00
4000
4 ,t,j,},t' f 5..4 U
Th*'
Figure 1 Hearing thresholds vs frequencies before intake of quinine (0) and maximum shift after intake of 15 mg kg-' quinine (U) in subject 1. 16
-
Data analysis
The time course of quinine in plasma was described by a one compartment model with an absorption lag time (Gibaldi & Perrier, 1982) using nonlinear regression analysis (NLIN, 1985). The relationship between hearing impairment and plasma quinine concentration was evaluated using the effect compartment method (Colburn, 1981; Holford & Sheiner, 1981; Sheiner et al., 1979). This method assumes a hypothetical effect compartment in which the time course of drug concentration (Ce) lags behind that in plasma. The rate of equilibration between plasma and the effect compartment is defined by the rate constant keO. The effect model was L = 10 (log k + y log Ce) where the response L is the shift in hearing threshold (dB), k and y are model parameters and the stimulus Ce is quinine concentration with reference to the effect compartment. This expression is equivalent to a logarithmically transformed Hill equation (Hill, 1910) for the special case where the stimulus is close to zero compared with the stimulus that elicits half maximum response (see Appendix).
&12-
8 Z
.,
04 0i
15 20 25 Time (h) Figure 2 The effect of quinine on hearing vs time after 5, 10, and 15 mg kg-' doses in subject 1. The progression of the areas under the curves is consistent with the order of dose size.
The figures show results from a representative subject (no 1). The hearing measurements were highly reproducible, the thresholds at 4000 Hz never differing by more than 2 dB in any case. The pure tone audiograms before and after the highest quinine dose are shown in Figure 1. There was an equal shift over the selected frequency range. Figure 2 shows the graded effect on hearing as the mean threshold shift following each oral dose in subject 1. Figure 3 shows counter clockwise hysteresis of hearing impairment as a function of plasma quinine concentration after different doses in subject 1. In almost all experiments, hearing was not affected at 24 h after dosage. Also, the drug effect was absent or too small to enable any evaluation in half of the cases after the lowest dose of 5 mg kg-'. All subjects experienced mild tinnitus and subjective hearing loss at higher plasma drug concentrations but
10
4
8
16
^12 e"
Results
5
8-
0
12
16
20
Quinine concentration (,umol l-1) Figure 3 Hysteresis plot showing the change in the effectconcentration relationship with time after 5, 10, and 15 mg kg- 1 of quinine (subject 1). The progression of the areas within the loops is consistent with the order of dose size.
essentially no other symptoms. A time lag between plasma quinine concentration and the onset of subjective symptoms made it difficult to analyse their relationship in detail. However, most frequently (9 out of 11 observations) when plasma drug concentration exceeded 15 ,umol 1-1 there was a subjective hearing loss or tinnitus and below 5 ,imol 1-1 there were no symptoms.
Hearing impairment and plasma quinine concentrations
411
the fitting procedure was less successful as indicated by an increase in the residual sum of squares. The applied co ~~~~~~~~~~E power function E = k x C' is thus the simplest model applicable to these observations. The sound amplitude _ \>
ADONIS 030652519100079 H
Hearing impairment related to plasma quinine concentration in healthy volunteers GUNNAR ALVAN1, KJELL K. KARLSSON2, URBAN HELLGREN3 & TOMAS VILLEN1 Departments of 'Clinical Pharmacology, 2Audiology and 3Infectious Diseases, Karolinska Institutet, Huddinge University Hospital and Roslagstulls Hospital, Sweden
1 Hearing impairment was investigated in six healthy volunteers who received oral doses of 5, 10 and 15 mg kg-1 quinine single-blind and in random order. 2 The plasma concentration of quinine was followed for 48 h and the time course was fitted by a linear one compartment pharmacokinetic model. 3 Hearing thresholds were measured by pure tone audiometry. There was a delay between impairment in hearing and change in plasma quinine concentration. Thus the method of effect compartment modelling was applied. 4 The effect on hearing (L), measured as a shift in hearing threshold (dB), was used to estimate the rate constant for elimination of drug from the assumed effect compartment (keo) and two parameters specifying the effect model (y and k). The effect model applied was L = 10 (log k + y x log Ce) where Ce is the calculated drug concentration in the effect compartment. This model is a logarithmic transform of a power expression equivalent to the Hill equation at the lower end of the effect range. In all experiments where there was a clear effect on hearing, convergence on a set of parameter estimates occurred, but inter- and intraindividual variability was large. The mean value of keo was 3.32 ± 5.93 h-1 s.d., for y it was 1.73 ± 1.14 s.d. and for k it was 0.59 ± 0.66 s.d.
Keywords hearing loss pharmacodynamics
cochlea
quinine
pharmacokinetics
Introduction
cation except for contraceptives. None had experienced any hearing problems and all were considered normal after a routine ear examination and pure tone- and impedance audiometry tests. Each subject received three oral quinine doses as close as possible to 5, 10 and 15 mg kg-', respectively, using standard tablets of quinine hydrochloride (KabiVitrum, Sweden). The doses were given in randomized order and single-blind at intervals of 1 week. Blood samples were drawn through a heparinised intravenous catheter at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 8, 24, 32 and 48 h after dosage. The study was approved by the Ethics Committee of the Huddinge University Hospital.
It is well known that quinine causes reversible hearing loss (Guder, 1880) and enhances muscle contraction (Santesson, 1892). This is an interesting combination of side effects since new theories on the mechanism of hearing (Flock, 1988) assume that contractile structures in the sensory cells enable the ear to adjust its micromechanical properties according to the stimuli. Quinine induces motile responses in isolated outer hair cells of the mammalian cochlea (Karlsson & Flock, 1990) which could account for the reversible hearing loss. We have previously studied the relationship between the plasma concentration of quinine and loss of hearing in the anaesthetised guinea pig (Alvain et al., 1989). The present study describes the findings after three single oral doses of quinine to healthy volunteers.
Effect measurements Hearing was measured at the time of each blood sampling. Pure tone audiometry of the right ear was performed with the Bekdsy sweep technique (500-8000 Hz) and determined at frequencies of 500, 1000, 1500, 2000, 3000, 4000, 6000 and 8000 Hz. Hearing impairment was calculated as the mean threshold shift over these frequencies. As a test of reproducibility, the hearing
Methods
Subjects and study design Six healthy females, 24-39 years old, participated after giving informed consent. They were taking no medi-
Correspondence: Dr G. Alvan, Department of Clinical Pharmacology, Huddinge University Hospital, S-141 86 Huddinge, Sweden
409
410
G. Alvan et al.
threshold at a fixed frequency of 4000 Hz was determined immediately before and after the full frequency sweep on each occasion. All measurements were made in a sound-proof room and using electronic equipment validated according to audiometric standards. At each test time the subjects were asked to grade their subjective symptoms including tinnitus, hearing loss and dizziness. Hearing measurements and drug analyses were made independently by different individuals.
-i, -
...
.0
.0
a
i.>,59
v
,
20
Quinine assay
2 L
Plasma was separated by centrifugation and stored frozen at -20° C until assayed for quinine by h.p.l.c. (Hellgren et al., 1990). The method had coefficients of variation of 9% and 6% at quinine concentrations of 1 ,umol 1-1 and 25 ,umol 1-1, respectively. The day-to-day variation was 8.6% estimated using a standard concentration of 14.5 ,umol 1-1.
f
e6 ,,..,8;;,'14;.,).:9''t.'4''¢%"'[ i;y 'f i' 1- '~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~'1
9 I
I
-~~5QQ
/1*'
axO
f1X,l b....0
a
I
I
2000
w00
4000
4 ,t,j,},t' f 5..4 U
Th*'
Figure 1 Hearing thresholds vs frequencies before intake of quinine (0) and maximum shift after intake of 15 mg kg-' quinine (U) in subject 1. 16
-
Data analysis
The time course of quinine in plasma was described by a one compartment model with an absorption lag time (Gibaldi & Perrier, 1982) using nonlinear regression analysis (NLIN, 1985). The relationship between hearing impairment and plasma quinine concentration was evaluated using the effect compartment method (Colburn, 1981; Holford & Sheiner, 1981; Sheiner et al., 1979). This method assumes a hypothetical effect compartment in which the time course of drug concentration (Ce) lags behind that in plasma. The rate of equilibration between plasma and the effect compartment is defined by the rate constant keO. The effect model was L = 10 (log k + y log Ce) where the response L is the shift in hearing threshold (dB), k and y are model parameters and the stimulus Ce is quinine concentration with reference to the effect compartment. This expression is equivalent to a logarithmically transformed Hill equation (Hill, 1910) for the special case where the stimulus is close to zero compared with the stimulus that elicits half maximum response (see Appendix).
&12-
8 Z
.,
04 0i
15 20 25 Time (h) Figure 2 The effect of quinine on hearing vs time after 5, 10, and 15 mg kg-' doses in subject 1. The progression of the areas under the curves is consistent with the order of dose size.
The figures show results from a representative subject (no 1). The hearing measurements were highly reproducible, the thresholds at 4000 Hz never differing by more than 2 dB in any case. The pure tone audiograms before and after the highest quinine dose are shown in Figure 1. There was an equal shift over the selected frequency range. Figure 2 shows the graded effect on hearing as the mean threshold shift following each oral dose in subject 1. Figure 3 shows counter clockwise hysteresis of hearing impairment as a function of plasma quinine concentration after different doses in subject 1. In almost all experiments, hearing was not affected at 24 h after dosage. Also, the drug effect was absent or too small to enable any evaluation in half of the cases after the lowest dose of 5 mg kg-'. All subjects experienced mild tinnitus and subjective hearing loss at higher plasma drug concentrations but
10
4
8
16
^12 e"
Results
5
8-
0
12
16
20
Quinine concentration (,umol l-1) Figure 3 Hysteresis plot showing the change in the effectconcentration relationship with time after 5, 10, and 15 mg kg- 1 of quinine (subject 1). The progression of the areas within the loops is consistent with the order of dose size.
essentially no other symptoms. A time lag between plasma quinine concentration and the onset of subjective symptoms made it difficult to analyse their relationship in detail. However, most frequently (9 out of 11 observations) when plasma drug concentration exceeded 15 ,umol 1-1 there was a subjective hearing loss or tinnitus and below 5 ,imol 1-1 there were no symptoms.
Hearing impairment and plasma quinine concentrations
411
the fitting procedure was less successful as indicated by an increase in the residual sum of squares. The applied co ~~~~~~~~~~E power function E = k x C' is thus the simplest model applicable to these observations. The sound amplitude _ \>
