Pharmacologic Disposition Difference Between Males and Females

1
Pharmacologic Disposition Difference Between
Males and Females

• Stan Louie
• Associate Professor
• Department of Pharmacy and Pharmaceutical Science
• University of Southern California

2
Patients with the Same Diagnosis
3
Pharmacologic Response to Therapy
4
Consideration of Gender, Ethnicity and
Co-morbidities When Selecting ARVs
Efficacy
Tolerability
Gender1 Ethnicity2 Co-morbidities1

• DHHS Guidelines 2005
• Butcher RO. J Natl Med Assoc 2005 97 1093-1100

5
Interindividual Variation in Trough
Concentrations of SQV, IDV, and NFV
Plasma concentration (ng/mL)
Gibbons, et al. AIDS. 200014(suppl 4)S89.
6
Role of CYP 450 Mediated Metabolism and
P-glycoprotein Interaction and Its Influence on
Absorption
Liver
Adapted from Bailey, DG, et al. Br J Clin
Pharmacol 199846101-110
7
Intestinal Lumen
Pgp
Apical
CYP
Basolateral
BLOOD VESSEL
Pgp
Plasma PI Concentration
CD4
8
Protease Inhibitor Activation of the Xenobiotic
Receptors
PI
Repressor
PXR
RXR
Transcription
9
Ligands
Target Genes
Tissues
Nuclear Receptor
CYP3A4/7 CYP2B6 CYP2C9 MDR1 MRP2 CYP2B6 CYP3A4
CYP2C9 MRP2 MDR1 UGT1A1 SPGP NTCP MRP2 DHEASulfot
ransferase
Rifampin PCN Clotrimazole RU486 Nifedipine Hyperfo
rin TCPOBOP PB Androstanol Bile Acids
Pregnane X Receptor (PXR) Constitutive
Androstane Receptor (CAR) Farnesoid X
Receptor (FXR)
Liver Kidney Small Int. Colon Liver Intestine
Heart Kidney Lung Liver Kidney Small Int. Colon
10
P-Glycoprotein System

• Product of multiple drug resistant-1 (MDR1) gene
• In the family of ATP binding cassette (ABCs)
• Cellular efflux transporter as a part of host
  defense but reducing intracellular accumulation
• Variable expression of these transporters in
  sanctuary sites (CNS, genital tract), gut and
  lymphocytes
• Associated with resistance to cancer chemotherapy
• Known to have genetic polymorphisms that
  influence absorption and activity of
  xenobiotics
• PGP also protects against viral infection,
  including HIV infection
• CD56 cells with high PGP activity are resistant
  to infection by HIV

11
P-Glycoprotein and Antiretroviral Agents

• Ritonavir, saquinavir, indinavir, nelfinavir,
  amprenavir are transported by PGP
• Higher PGP activity would lead to lower
  absorption in GI tract and lower intracellular
  drug levels
• Mutation at C3435T affects PGP activity in gut
• CC mutation more common in West Africans (83)
  and African Americans (61) than Whites (26) or
  Japanese (34)
• Highest PGP activity is in individuals of African
  descent

Schaeffeler E, et al. Lancet 2001 358 383-4
12
Overall PGP Effects

• So, high PGP activity could have opposite effects
  on natural compared to treated history cells may
  be more resistant to infection, but have impaired
  absorption and low drug levels
• High PGP activity could increase serum drug
  levels but decrease intracellular drug levels,
  resulting in lower efficacy

13
Nelfinavir Plasma Levels With Regards to MDR-1
Polymorphism
100
CC
CT
75
TT
Plasma Drug Concentration (percentile)
50
25
0
TT
CT
CC
Fellay J et al Lancet 2000
14
CD4 Count Response with Regards to MDR-1
Polymorphism
400
CC
CT
300
TT
CD4 counts (Cells/mm3)
200
100
0
6
0
1
3
Duration of Antiretroviral Treatment (mo)
Fellay J et al Lancet 2000
15
Effect of PGP 3435 genotype
MDR1 expression (median units IQR) Lo 19
17-21 Med 24 19-24 Hi 28
21-32 P 0.02
PGP genotype TT CT CC
Plasma PI(percentile) 30th 50th 75th P
0.0001
?CD4(cells/µl) 257 165 121 P 0.0048
Fellay J, et al. Lancet 2002 359306
16
Impact of MDR-1 Genotype on Virologic Response
Brumme Z. AIDS 2003 17201-208
17
Functional Pgp PolymorphismExon 26 C3435T
Hoffmeyer S et al Proc Natl Acad Sci 2000
973473-8
18
Ethnic Differences of MDR1 exon 26 C3435T
Polymorphism
CC()
CT() TT() Caucasians
26 48 26 African American
68 31
1 Chinese 32
42 26 Southwest Asian
15 38 47
From Ameyaw MM et al. Pharmacogenetics 2001
11217-221.
19
Biosynthesis and Elimination of Pgp
Pgp
Ub
PXR
RXR
Activation Translocation
Ub
Proteasome Degradation
Transcription
Louie S in Pharmacogenomics
20
Gender Difference
21
Mechanisms Of Sex Based PK Differences

• Women may on the average express lower levels of
  p-glycoprotein
• If drug is pure substrate for P450 3A4 tends to
  have lower concentrations in women
• If substrate for both P450 3A4 and PGP tends to
  have higher levels in women
• Counter-evidence indinavir is a substrate for
  both, and has equivalent concentrations in women
  and men

22
Effect of DEX on the Intestinal and Hepatic
Metabolism of IDV (5 mM) in Rats
Intestinal Metabolism
Hepatic Metabolism
IDV Metabolism pmol/min/mg protein
Lin JH et al DMD1999271187-1193
23
Mean Concentrations of IDV in Systemic
Circulation of Control (A) and DEX-treated (B)
Rats During Portal (E) and Femoral (F) Vein
Infusion at a Constant Rate of 12 mg/min
Control
Dexamethasone
Lin JH et al DMD1999271187-1193
24
Effect of Dexamethasone on Hepatic and Intestinal
Metabolism of Testosterone

• Microsome Treatment Testosterone
• (pmol/min/mg proteins)
• 2b-OH 6b-OH
• Liver Control 64.0 ? 13.7 722 ? 122
• Dexamethasone 736 ? 123 5011 ? 454
• Intestinal Control 0.667 ?0.104 16.3 ?0.6
• Dexamethasone 2.40 ?0.78 50.9 ?3.3
• plt0.001

Lin JH et al DMD1999271187-1193
25
Impact of PI (L754,394) on Metabolic Enzymes
Testosterone 2a Hydroxylation
Testosterone 2b Hydroxylation
Testosterone 16a Hydroxylation
Testosterone 6b Hydroxylation
Nishime J et al DMD 1999 27 972
26
Indinavir Clearance in Females versus Males
27
Sex-Based Pharmacokinetics Differences of NVP,
EFV and SQV
1La Porte et al, 2Burger et al, 4th International
Wksp on Clinical Pharmacology in HIV, March 2003,
10, 15 Fletcher et al, 2nd IAS Conference on
HIV Pathogenesis and Treatment, July 2003, 128
28
PHARMACOKINETIC PROFILES WEEK 4
PHARMACOKINETIC PROFILES WEEK 4
SQV concentration (ng/mL)
4X IC50
Time
(hours)


C
C
C
C
AUC
AUC
last
last


max
max
(0-24h)
(0-24h)
(
(
ng
ng
/
/
mL
mL
)
)
(ng/mL)
(ng/mL)
(ng-h/mL)
(ng-h/mL)


N
N






6
6
6
6
6
6
Min
Min
68 1,720
68 1,720
10,542
10,542
Median
Median
429
429
6,435
6,435
66,920
66,920


Max
Max
1,750 13,400 137,563
1,750 13,400 137,563
Geometric Mean
Geometric Mean
336
336
5,875
5,875
49,777
49,777
J
J
.
Montaner
, DART, December 2000 J.
Montaner
, Focus trial updated at Frankfurt Resistance
Conference, 2001
FOCUS trial E.
Acosta
, 2nd International Workshop on Clinical
Pharmacology of HIV Therapy, 2001.
29
Median Cmin for Men and Women
SQV Cmin Levels (ng/mL)
4X EC50 200 ng/mL
In vivo EC50 50 ng/mL
N34
N15
J Montaner. FOCUS Trial Update at Frankfurt
Resistance Conference, 2001
30
Interaction Between ARV Therapy and Oral
Contraceptives
EE/NET Ethinyl estradiol/norenthindrone NVP
nevirapine EFV efavirenz IDV indinavir
NFV nelfinavir APV amprenavir RTV
ritonavir OCP oral contraceptive
pill. http//www.medscape.com/Medscape/HIV/DrugInt
eractions/index.cfm.
31
Sex and Virologic Response to HAART
Observational Study

• Case-control observational sex comparison
• 162 women matched with 324 men
• All ART-naïve
• Matched by CD4 cell count and VL
• Received 2 NRTIs nelfinavir
• Followed for 2 years

Keiser P, et al. 10th CROI, 2003 Poster 927
32
Sex and Virologic Response to HAART
60
Male
P 0.009
Female
50
Proportion patients withundetectable HIV-1
RNA ()
48
P 0.001
40
43
36
30
25
20
10
0
2 years
1 year
Plasma viral load lt400 copies/mL
Keiser P, et al. 10th CROI, 2003 Poster 927
33
The Pharmacokinetics Of Nelfinavir Are Similar In
Men And Women
Results from a study in African-American patients
with HIV infection receiving nelfinavir 1250 mg
bid
Women (n 15)
Men (n 15)
Parameter
Cmax (mcg/ml)
Cmin (mcg/ml)
t½ (hours)
AUC0-12 (mcg-h/ml)
Vd (L/kg)
Sharma et al. XIV Int AIDS Conf, 2002 abstract
WePeB5970
34
Nelfinavir is Equally Effective in
Women and Men
Proportion lt400 copies/ml at most recent visit.
Nelfinavir-based HAART taken for mean 52.2 (men)
or 47.8 (women) months
ARV-naïve
ARV-experienced
80
80
70
70
60
60
77
75
60
65
50
50


40
40
30
30
20
20
10
10
0
0
Men
Women
Men
Women
n 522
n 167
n 479
n 141
P gt 0.3 for men vs women
Palella et al. 14th IAC, 2002 Abs WePeB5967
Poster.
35
Sex Differencesin Pediatric Populations

• Data from the Women and Infants Transmission
  Study (WITS) indicate that there are sex
  differences in quantitative HIV-1 RNA in children
  of same magnitude and direction as in adults

36
Drug Concentrations In Pregnancy

• Nelfinavir concentrations 40 lower in 27
  pregnant women compared to 48 controls1
• Case report of low NFV concentrations in
  pregnancy returning to normal post-partum2
• Indinavir AUC lower in pregnancy3
• Results not present if indinavir used with
  ritonavir
• Cytochrome P450 activity increased
• Results returned to normal post-partum
• Effect of pregnancy on nelfinavir concentrations
  variable

1Wit et al, 2nd IAS conference, 129 2Angel et
al, AIDS 200115417 3Kosel et al AIDS
2003171195
37
Reduced Lopinavir Plasma Concentrations in
Pregnancy
10
9
8
7
6
Median ( SE) Lopinavir (µg/mL)
5
4
3
2
Protein-adjusted IC50 for LPV
1
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Time Post Dose (hours)
Pregnancy (n 17)
Postpartum (n 8)
Nonpregnant historical controls

• Note also abstract 4644 NVP plasma exposure
  reduced in pregnant vs nonpregnant women

Stek et al. Abstract LBOrB08.
38
Gender Difference Toxicity Towards Pharmacologic
Agents
39
Incidence of Any Toxicity Associated with 5-FU
Containing Therapy
Incidence Rate ()
Sloan JA J Clin Oncol 201491-1498.
40
Incidence of Severe Toxicity Associated with 5-FU
Containing Therapy
Incidence Rate ()
Sloan JA J Clin Oncol 201491-1498.
41
Female-male difference in incidence of grade gt 1
stomatitis.
NCCTG Protocol
MalegtFemale
Femalegt Male
83462 A
83462 B
83462 C
874651 B
884651 A
894651 A
894651 B
894651 C
894651 D
894652 A
894652 B
894652 C
Total
-20
10
20
30
40
-10
0
Difference ()
42
Female-male difference in incidence of any grade
gt 3 toxicity
43
Percentage of Patients with Toxicity for Gradesgt
1 and gt 3
44
Gender Difference in Response to Anti-leukemic
Effect
Adapted from Lilleyman and Lennard. Lancet 1994
343 1188-1190
45
Adverse Effects of Medication

• Body Composition Differences in Older Overweight
  or Obese Women
• Some evidence that d4T use (but not PI use) is
  associated with increased truncal fat and
  decreased extremity fat vs no d4T use
• African American race associated with decreased
  truncal fat and increased extremity fat,
  independent of age, BMI, duration of HIV
  infection, CD4 count and PI use

Howard AA, et al. 10th CROI, 2003 Poster 735
46
Adverse Effects of Medication

• Increased risk of diabetes mellitus in women
  treated with PIs, according to WIHS
• Incidence 2.8 per 100 person-years with
  PI-containing ART vs 1.2 per 100 person-years in
  non-PI-containing ART (P 0.002)
• Women had no prior history of DM, and weight gain
  during study did not explain DM incidence
• Should not dissuade PI use in view of the
  clinical benefits of the class. Investigators
  advocate routine screening for diabetes among
  women treated with PIs instead

Justman JE, et al. JAIDS 2003 32 298-302
47
Gender Difference in the Incidence of Hepatic
Events Related to Viramune (Nevirapine)
Viramune Prescribing information. Boehinger
Ingelheim Pharmaceuticals, Inc
48
CYP2B6 Catalyses The Metabolism Of Efavirenz
(1µm)
1.0
0.8
Efavirenz (mM) remaining in microsomal incubates
0.6
0.4
0.2
0.0
CYP1A2
CYP2A6
CYP2B6
CYP2C8
CYP2C9
CYP2D6
CYP2E1
CYP3A4
CYP3A5
CYP2C19
Inactive mics
CYP450 isoforms
49
Human Metabolism of Efavirenz
(Ward et al., J Pharmacol Exp Ther 2003)
50
Efavirenz Concentration in Relationships with
CYP2B6 Polymorphism
51
CYP2B6 G516T (Exon 4) and Efavirenz Plasma
Levels A5097s
Haas et al, AIDS 2004182391
52
Host Genetics and EfavirenzACTG studies
A5095/5097s)

• Efavirenz Levels
• EFV plasma levels were greater in blacks and
  Hispanics than in whites (Ribaudo et al, 11th
  CROI).
• Median EFV AUC0-24h
• Blacks 58 µghrmL-1
• Hispanics 66 µghrmL-1
• Whites 46 µghrmL-1
• (overall P ? 0.001 for all comparisons)
• There was much overlap in the distribution of PK
  parameters between racial/ethnic populations.

Haas et al, AIDS 2004182391
DW Haas, MD. Presented at IASUSA Atlanta Course,
March 11, 2005.
53
Difference in Expression of CAR and CYP2B6
Lamba V et al JPET 2003
54
Lecture Highlight

• Gender difference may be due to difference in
  absorption and elimination
• Gender difference in outcomes (e.g. viral
  suppression or drug related toxicity) is
  dependent on the substrate
• The role of hormones has not been fully elucidated