how gender differences can affect the pharmacokinetics and ...
HOW GENDER DIFFERENCES CAN AFFECT THE PHARMACOKINETICS AND PHARMACODYNAMICS OF PSYCHOTROPIC DRUGS David J. Greenblatt, M.D. Tufts University School of Medicine and Tufts Medical Center, Boston MA
1
SEX or GENDER ?
2
3
4
HOW CAN GENDER INFLUENCE RESPONSE TO PSYCHOTROPIC DRUGS? Kinetics: - Distribution - Clearance
Dynamics: - Exposure-response relationship 5
Clearance and distribution are INDEPENDENT of each other
T1/2 = Css =
0.693 Γππ πΆππππππππ
π·ππ πππ πππ‘π πΆππππππππ
6
Drug distribution may be influenced by body size and body composition Gender affects both size and composition
7
Hanley MJ et al. Clin Pharmacokin 2010; 48: 71-87 MALE
FEMALE
Water-soluble
Lipid-soluble
8
Volume of distribution (liters/Kg) Young male Young female Antipyrine
a
0.66
0.58
b
1.34
2.00
18.1
24.0
Midazolam
Imipramine
c
a: J Pharmacol Exp Ther 1982; 220:120-126 b: Anesthesiology 1984;61:27-35 c: J Pharmacol Exp Ther 1985;232:183-188
9
2013
10
Does it make any difference?
11
Gender effects on clearance
12
CYP CYP CYP CYP CYP CYP CYP
1A2 2B6 2C9 2C19 2D6 2E1 3A
13
J Clin Pharmacol 2008; 48: 1350-1355
CYP3A substrates
14
15
RETAIL PHARMACY PRESCRIPTIONS FOR HYPNOTIC DRUGS IN THE UNITED STATES, 2010 Drug
Number of prescriptions (millions)
Zolpidem Immediate-release
29.7
Controlled-release
5.7
Temazepam
10.5
Eszopiclone
5.7
Triazolam
N/A
Flurazepam
N/A
Zaleplon
N/A
[Trazodone
18.8]
Source: Drug Topics, June 2011 16
10 January 2013:
Followed by: Farkas RH, Unger EF, Temple R: Zolpidem and driving Impairment β identifying persons at risk. N Engl J Med 2013; 369: 689-691
17
FDA ASSERTIONS: - Women have lower clearance and higher plasma zolpidem at 8 hr after dosage - Plasma levels exceeding 50 ng/mL at 8 hours: increased risk of residual sedation
18
- Driving studies show women to have an increased prevalence of impairment at 8 hours due to high plasma levels - To assure safety and reduce risk, young women should take Β½ the dose of zolpidem relative to young men (5 vs. 10 mg of IR, 6.25 vs. 12.5 mg of CR, etc.)
19
PLASMA CONCENTRATION (ng/mL)
12
10
8 15 mg
6
10 mg 4 5 mg 2
0 0
2
4
6
8
10
HOURS AFTER DOSAGE 20
Olubodun JO: Br J Clin Pharmacol 2003; 56:297-304
21
J Clin Pharmacol 2014; 54:282-290
PLASMA ZOLPIDEM (ng/mL)
80
3.5 mg sublingual MALE
70
FEMALE 60 50 40 30 20 10
0
2
4
6
8
10
12
HOURS 22
100 MALE FEMALE
ZOLPIDEM AUC/DOSE [(ng/mLxhr)/mg]
80
60
40
20
0 1988
2000
2003
2013
2013
2014
2014 23
24
J Clin Pharmacol 2006; 46: 1469-1480
THREE-WAY SINGLE-DOSE CROSSOVER STUDY: 1. Placebo 2. IR zolpidem, 10 mg 3. MR zolpidem, 12.5 mg n = 70 (38 male, 32 female)
25
26
Plasma zolpidem exceeding 50 ng/mL at 8 hr: After IR-zolpidem 10 mg: 12.5% of women, 0% of men After MR-zolpidem 12.5 mg: 18.8% of women, 8% of men
27
28
29
30
31
LESSONS: - Mean values obscure what is going on with individuals - There is NO study showing that levels exceeding 50 ng/mL cause impairment
32
ON-ROAD DRIVING STUDIES Verster JC, Roth T: Traffic Injury Prevention 2012; 13: 286-292 Vermeeren A et al: Sleep 2014; 37: 489-496
β’ NO study evaluates plasma levels in relation to driving proficiency β’ Driving 4 hours after 10 mg zolpidem is hazardous β’ No safety signal for driving 8 hours or longer after 10 mg or 12.5 mg zolpidem β’ No gender-related safety signal 33
Sleep 2014; 37:489-496
34
UNTREATED INSOMNIA ALSO CARRIES RISK β’ Reduced daytime alertness β’ Impaired psychomotor performance βDriving βWorkplace proficiency/safety β’ Quality of life
35
Clin Pharmacol Drug Devel 2014; 3:167-169
36
DOSE INFLUENCES EFFICACY Minutes to return to sleep: Placebo
ZSTβ1.75
ZSTβ3.5
Male
29.0
19.0
12.7
Female
27.7
15.7
8.6
Roth T: Human Psychopharmacology 2014; 29: 25-30
37
β’ Yes β Zolpidem clearance is lower in women β’ Yes β Women may have greater sensitivity β’ No β No evidence of increased risk in women β’ No β Lower doses for women impair efficacy. Public health may or may not be served. 38
1
SEX or GENDER ?
2
3
4
HOW CAN GENDER INFLUENCE RESPONSE TO PSYCHOTROPIC DRUGS? Kinetics: - Distribution - Clearance
Dynamics: - Exposure-response relationship 5
Clearance and distribution are INDEPENDENT of each other
T1/2 = Css =
0.693 Γππ πΆππππππππ
π·ππ πππ πππ‘π πΆππππππππ
6
Drug distribution may be influenced by body size and body composition Gender affects both size and composition
7
Hanley MJ et al. Clin Pharmacokin 2010; 48: 71-87 MALE
FEMALE
Water-soluble
Lipid-soluble
8
Volume of distribution (liters/Kg) Young male Young female Antipyrine
a
0.66
0.58
b
1.34
2.00
18.1
24.0
Midazolam
Imipramine
c
a: J Pharmacol Exp Ther 1982; 220:120-126 b: Anesthesiology 1984;61:27-35 c: J Pharmacol Exp Ther 1985;232:183-188
9
2013
10
Does it make any difference?
11
Gender effects on clearance
12
CYP CYP CYP CYP CYP CYP CYP
1A2 2B6 2C9 2C19 2D6 2E1 3A
13
J Clin Pharmacol 2008; 48: 1350-1355
CYP3A substrates
14
15
RETAIL PHARMACY PRESCRIPTIONS FOR HYPNOTIC DRUGS IN THE UNITED STATES, 2010 Drug
Number of prescriptions (millions)
Zolpidem Immediate-release
29.7
Controlled-release
5.7
Temazepam
10.5
Eszopiclone
5.7
Triazolam
N/A
Flurazepam
N/A
Zaleplon
N/A
[Trazodone
18.8]
Source: Drug Topics, June 2011 16
10 January 2013:
Followed by: Farkas RH, Unger EF, Temple R: Zolpidem and driving Impairment β identifying persons at risk. N Engl J Med 2013; 369: 689-691
17
FDA ASSERTIONS: - Women have lower clearance and higher plasma zolpidem at 8 hr after dosage - Plasma levels exceeding 50 ng/mL at 8 hours: increased risk of residual sedation
18
- Driving studies show women to have an increased prevalence of impairment at 8 hours due to high plasma levels - To assure safety and reduce risk, young women should take Β½ the dose of zolpidem relative to young men (5 vs. 10 mg of IR, 6.25 vs. 12.5 mg of CR, etc.)
19
PLASMA CONCENTRATION (ng/mL)
12
10
8 15 mg
6
10 mg 4 5 mg 2
0 0
2
4
6
8
10
HOURS AFTER DOSAGE 20
Olubodun JO: Br J Clin Pharmacol 2003; 56:297-304
21
J Clin Pharmacol 2014; 54:282-290
PLASMA ZOLPIDEM (ng/mL)
80
3.5 mg sublingual MALE
70
FEMALE 60 50 40 30 20 10
0
2
4
6
8
10
12
HOURS 22
100 MALE FEMALE
ZOLPIDEM AUC/DOSE [(ng/mLxhr)/mg]
80
60
40
20
0 1988
2000
2003
2013
2013
2014
2014 23
24
J Clin Pharmacol 2006; 46: 1469-1480
THREE-WAY SINGLE-DOSE CROSSOVER STUDY: 1. Placebo 2. IR zolpidem, 10 mg 3. MR zolpidem, 12.5 mg n = 70 (38 male, 32 female)
25
26
Plasma zolpidem exceeding 50 ng/mL at 8 hr: After IR-zolpidem 10 mg: 12.5% of women, 0% of men After MR-zolpidem 12.5 mg: 18.8% of women, 8% of men
27
28
29
30
31
LESSONS: - Mean values obscure what is going on with individuals - There is NO study showing that levels exceeding 50 ng/mL cause impairment
32
ON-ROAD DRIVING STUDIES Verster JC, Roth T: Traffic Injury Prevention 2012; 13: 286-292 Vermeeren A et al: Sleep 2014; 37: 489-496
β’ NO study evaluates plasma levels in relation to driving proficiency β’ Driving 4 hours after 10 mg zolpidem is hazardous β’ No safety signal for driving 8 hours or longer after 10 mg or 12.5 mg zolpidem β’ No gender-related safety signal 33
Sleep 2014; 37:489-496
34
UNTREATED INSOMNIA ALSO CARRIES RISK β’ Reduced daytime alertness β’ Impaired psychomotor performance βDriving βWorkplace proficiency/safety β’ Quality of life
35
Clin Pharmacol Drug Devel 2014; 3:167-169
36
DOSE INFLUENCES EFFICACY Minutes to return to sleep: Placebo
ZSTβ1.75
ZSTβ3.5
Male
29.0
19.0
12.7
Female
27.7
15.7
8.6
Roth T: Human Psychopharmacology 2014; 29: 25-30
37
β’ Yes β Zolpidem clearance is lower in women β’ Yes β Women may have greater sensitivity β’ No β No evidence of increased risk in women β’ No β Lower doses for women impair efficacy. Public health may or may not be served. 38
