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

HOW CAN GENDER INFLUENCE RESPONSE TO PSYCHOTROPIC DRUGS? Kinetics: - Distribution - Clearance Dynamics: - Exposure-response relationship 4

Clearance and distribution are INDEPENDENT of each other

T1/2 =

0.693 ×𝑉𝑑 𝐶𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒

𝐷𝑜𝑠𝑖𝑛𝑔 𝑟𝑎𝑡𝑒 Css = 𝐶𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒

5

Drug distribution may be influenced by body size and body composition Gender affects both size and composition

6

Hanley MJ et al. Clin Pharmacokin 2010; 48: 71-87 MALE

FEMALE

Water-soluble

Lipid-soluble

7

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

8

9

200

NHANES DATA

190

MEAN WEIGHT (pounds)

190

180 168

170

160

150

140

130 1960

1970

1980

1990

2000

2010

YEAR 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 – identifying persons at risk. N Engl J Med 2013; 369: 689-691 17

FDA ASSERTIONS: - Women have lower clearance and higher plasma levels of zolpidem at 8 hr after dosage - Plasma levels exceeding 50 ng/mL at 8 hr are associated with a risk of residual sedation - Driving studies show women to have an increased prevalence of impairment at 8 hr due to high plasma levels - To assure safety and reduce risk, young women should take ½ the dose of zolpidem relative to young men (5 vs. 10 mg of IR, 6.25 vs. 12.5 mg of CR, etc.) 18

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 19

Olubodun JO: Br J Clin Pharmacol 2003; 56:297-304

20

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 21

100 MALE FEMALE

ZOLPIDEM AUC/DOSE [(ng/mLxhr)/mg]

80

60

40

20

0 1988

2000

2003

2013

2013

2014

2014 22

Acta Pharm Sinica B 2014; 4: 146-150

23

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) 24

25

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

26

LESSONS: - Mean values obscure what is going on with individuals - There is NO study showing that levels exceeding 50 ng/mL cause impairment

27

ON-ROAD DRIVING STUDIES Verster JC, Roth T: Traffic Injury Prevention 2012; 13: 286-292 Vermeeren A et al: Sleep 2014; 37: 489-496

• NO study evaluates plasma levels in relation to driving proficiency • Driving 4 hours after 10 mg zolpidem is hazardous • No safety signal for driving 8 hours or longer after 10 mg or 12.5 mg zolpidem 28

Sleep 2014; 37:489-496

29

UNTREATED INSOMNIA ALSO CARRIES RISK • Reduced daytime alertness • Impaired psychomotor performance —Driving —Workplace proficiency/safety • Quality of life

30

Clin Pharmacol Drug Devel 2014; 3:167-169

31

DOSE INFLUENCES EFFICACY Minutes to return to sleep: Placebo

ZST−1.75

ZST−3.5

Male

29.0

19.0

12.7

Female

27.7

15.7

8.6

Roth T: Human Psychopharmacology 2014; 29: 25-30

32

• Yes — Zolpidem clearance is lower in women • Yes — Women may have greater sensitivity • No — No evidence of increased risk in women • No — Lower doses for women impair efficacy. Public health may or may not be served. 33