Inter- and intraindividual variability in the concentration-effect (sedation) relationship of flunitrazepam.
1. The relationship between plasma flunitrazepam concentrations and the degree of sedation was evaluated in 20 healthy subjects receiving two single oral doses of 1 mg flunitrazepam on two different occasions (1 week apart). The degree of sedation was rated blindly during the two treatment sessions in parallel with blood sampling (48 h). 2. A strong correlation between the concentrations of flunitrazepam in plasma and the degree of sedation was found according to the sigmoid Emax model. The plasma drug concentration producing 50% of maximal effect (EC50) was found to be 7.0 and 6.5 ng ml-1 on the two occasions, respectively. The variability in EC50 between subjects was larger (C.V. 39%) than the variability within subjects (C.V. 27%). 3. The steepness of the concentration-response curve as reflected in the slope factor(s) showed a virtual 'all or none' response to flunitrazepam with s values ranging from 3 to 30 with a mean of about 14. 4. The results in young healthy subjects suggest that the present dosage recommendations for temporary insomnia (1-2 mg) may be inappropriate; the dose can probably be reduced to 0.5 mg in some patients to achieve moderate sedation.
Grahnén
A
A
Professional Medical Consultants AB-PMC, Uppsala, Sweden.
Wennerlund
P
P
Dahlström
B
B
Eckernäs
S A
SA
D004305:Dose-Response Relationship, Drug; D005260:Female; D005445:Flunitrazepam / Q000493:pharmacokinetics / Q000494:pharmacology*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006993:Hypnotics and Sedatives; D007206:Individuality; D008297:Male; D011897:Random Allocation
D006993:Hypnotics and Sedatives; D005445:Flunitrazepam