Slide 1

Pharmacokinetics in Pregnancy

David Back

University of Liverpool

UK

David Back

University of Liverpool

July 2012

Why worry about Pharmacokinetic

changes in pregnancy?

Absorption

- Alterations in transit time, gastric secretion

Distribution

- Changes in body water, fat, plasma proteins

Metabolism

- Altered hepatic metabolism; increase in liver blood flow

Excretion

- Increased renal blood flow, GFR, CLCR

100%

An oral drug and systemic concentrations

Stomach Small Intestine Liver

Images supplied by Vertex Pharmaceuticals Inc, February 2011.

CYPs Pgp

CYPs

CYP=cytochrome P450; PGP=P-glycoprotein

The importance of CYP enzymes

Proportion of total CYP enzymes

present in human liver

CYP 1A2

CYP 2A6 CYP 2B6

CYP 2C8

CYP 2C9

CYP 2C19

CYP 2D6

CYP 2E1

CYP 3A

Hacker MP, et al. Pharmacology: Principles and Practice. Academic Press 2009

CYP: cytochrome P450

All percentages are approximate. For illustrative purposes,

hepatic CYP enzymes present at <5% are all represented as 3.3%

Abduljalil K et al 2012; Clin Pharmacokinet 51: 365-396

Protein Binding

Albumin

Example: drug bound to albumin

Total drug concentration: 5 Free concentration: 1 Free fraction: 0.2 (ie20%)

Albumin

Example: Reduced protein

PK

Free concentrations are responsible for pharmacologic

activity (PD), and are subject to

systemic clearance (PK)

Key message

Initial ↑ in free

concentrations are

subject to systemic

clearance

Change in protein binding could give reduced total systemic concentration

0

10

20

30

40

50

60

1977 1980 1983 1986 1989 1992 1995 1998 2001 2004 2007 2010

Pu

blic

atio

ns

Year

Number of Oral Contraceptive and HIV Publications

Oral Contraceptive

HIV

Antiretroviral Drug Approval: 1987-2012

0

5

10

15

20

25

30

1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011

Maraviroc

Raltegravir

Etravirine

Darunavir

Tipranavir

Enfuvirtide

Atazanavir

Emtricitabine

Fosamprenavir

Tenofovir

Lopinavir/r

Efavirenz

Abacavir

Nelfinavir

Delavirdine

Ritonavir

Indinavir

Nevirapine

3TC

Saquinavir

d4T ddC

ddl AZT

• NRTI, Nucleoside reverse transcriptase inhibitor;

• NNRTI, Non-nucleoside reverse transcriptase inhibitor;

• PI, protease inhibitor

• Integrase Inhibitor

• CCR5 Antagonist/Fusion Inhibitor

AZT - zidovudine; ddI - didanosine; ddC - zalcitabine; d4T – stavudine;

3TC - lamivudine

Rilpivirine

Antiretroviral therapy (ART) in Pregnancy:

Antiretroviral therapy is required in HIV-infected

pregnant women for:

- Maternal health

- Prevention of mother-to-child transmission (PMTCT)

In vitro susceptibility and target trough

concentrations

[c]

Drug [C] corresponding

to IC50 or IC90

50%

Measured drug

Concentration

IQ 90%

Personal communication: G di Perri

Effect of changing steady state

concentration with time

Decrease in steady state D

rug

Co

nc.

Gestational Age (weeks)

MEC

Antiretroviral therapy in Pregnancy:

Present in pregnancy – new HIV diagnosis

Treatment experienced-

conceiving on ART

Late presentation – women requires

ART for herself

Early presentation – women requires

ART for herself

Women does not require ART for

herself

Immediate ART initiation

ART initiation as soon as possible

Temporary ART initiation ≤ 24 weeks gestation

Continue on ART regimen

Conceive on ART

Exceptions: -PI monotherapy (poor placental transfer, intensify with NRTI) - d4t/ddl (contraindicated)

ART regimens used in pregnancy: -Dual NRTI backbone (ZDV/3TC , TDF/FTC, ABC/3TC) + 3rd agent -Ritonavir boosted PI (ATV/r, LPV/r & DRV/r) -NNRTI [EFV (as of 2012) or NVP(CD4 count <250 cells/µL) + 4th agent (Raltegravir) in women presenting late in pregnancy

Therapeutic Drug Monitoring (TDM) ↔ dose modification (if required)

0

2000

4000

6000

8000

10000

12000

0 2 4 6 8 10 12

Lop

inav

ir (

ng

/mL)

Time (hr)

Trimester 2 (n=6)

Trimester 3 (n=11)

Postpartum (n=5)

↓28% AUC0-12 (T3 vs. T2)

Impact of pregnancy on plasma concentrations of Lopinavir (LPV/r 400/100 mg bid)

↓35% AUC0-12 (T3 vs. PP)

Lopinavir exposure significantly lower in the third trimester, than in the second trimester and at postpartum

Else LJ et al Antimicrob Agents Chemother 2012; 56: 816-824

MEC

0

1000

2000

3000

4000

5000

6000

7000

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Ata

zan

avir

(n

g/m

L)

Time (h)

P10

P25

P50

P75

P90

Trimester 3

Trimester 2

Post partum

MEC

Atazanavir concentrations significantly lower in the third & second trimester compared with postpartum

Impact of pregnancy on plasma concentrations of Atazanavir (ATV/r 300/100 mg qd)

Sparse sampling overlaid on intensive PK

Else LJ et al – in preparation

REYATAZ 300 mg with ritonavir 100 mg may not provide sufficient exposure to

atazanavir, especially when the activity of atazanavir or the whole regimen

may be compromised due to drug resistance. Since there are limited data

available and due to inter-patient variability during pregnancy, Therapeutic

Drug Monitoring (TDM) may be considered to ensure adequate exposure.

Reyataz SPc – July 2012

Postpartum

2nd & 3rd Trimester

Class Drug Pregnancy-associated change in PK

Placental transfer

%Protein bound

Elimination References

PI

LPV/r

↓30% AUC in pregnancy Low <1-20%

98-99% HEPATIC- CYP3A4

Taylor et al, Lancet 2000 Aweeka et al, CROI, 2004 Else et al AAC 2012

PI

ATV/r

Data inconsistent No change ↓28% AUC at T3

Moderate <10-40%

86% HEPATIC- CYP3A4

Ripamonti et al, AIDS, 2007 Mirochnick et al JAIDS, 2011

PI DRV/r Limited data No change in pregnancy ↓24% AUC in T2/T3

Low 10-30%

95% HEPATIC- CYP3A4

Capparelli et al, Rome, 2011 Zorilla et al, CROI, 2012

NRTI ZDV No change High 100-200%

<25% Glucuronidation; renal (ZDV-glu)

Watts et al, J Infect Dis, 1991 Moodley et al, J Infect , 1998

NRTI 3TC No change High 90-150%

10-50% Renal (unchanged)

Moodley et al, J Infect , 1998

NRTI FTC Limited data ↓AUC in pregnancy

High ~100%

<4% Renal (unchanged)

Stek et al, HIV Med, 2012

NRTI TDF Limited data ↓AUC in third trimester vs. post-partum

High >300%

<0.7% Renal (unchanged)

Colbers et al, IWCPHT, 2012

Impact of pregnancy on antiretroviral PK

Class Drug Pregnancy-associated change in PK

Placental transfer

%Protein bound

Elimination References

1st generation NNRTI

NNRTI

NVP

Data inconsistent No change reported in pregnancy (UK) ↓20% AUC in T3 (Uganda)

Moderate

~80%

60% HEPATIC- CYP3A4, 2B6

Taylor et al, Lancet 2000 Aweeka et al, CROI, 2004 Lamorde et al, JAIDS, 2010

NNRTI

EFV

Limited data Ctrough ↓ in third trimester vs. Postpartum. AUC, Cmax: ↔

Moderate

~49%

99% HEPATIC- CYP2B6

Cressey et al, JAIDS, 2012

2nd generation NNRTI

NNRTI ETV Limited PK data No change

Moderate

<40%

99.9% HEPATIC- CYP3A4, 2C9, 2C19

Lzurieta et al, HIV Med, 2011

NNRTI RPV No data studies currently ongoing

Unknown 99.7% HEPATIC- CYP3A -

Impact of pregnancy on antiretroviral PK

Conclusions

Clear evidence of altered PK in pregnancy – but

drug/regimen dependent.

Data gaps in the antiretroviral field

Importance of vaginal drug levels – especially with

more vaginal deliveries (women with undetectable

plasma VL at term).

Integration of PGx with PK possible

ZDV 122%

Equivalent Exposures

Higher Exposures

Lower Exposures

ZDV 224%A:C

A:M ratios (%) C:M ratios (%)

LPV 6%

LPV <0.4%

NVP 60%

ddI 38%

100%

200%

300%

400%

500%

600%

0%

80%

60%

40%

20%

Placenta (Umbilical cord)

Amniotic fluid

ATV 19-20%

d4T 132%

RTV 2%

3TC 100%

d4T 487%A:C

3TC 399%A:C

ddI 114%A:C ABC 103%

ZDV 113%

3TC 140%

ZDV 161%

3TC 106%

3TC 482%

ZDV 92%

TDF 99%

TDF 104%

TDF 65-67%

FTCp 80%

NVP 102%

NVP 75% NVP 75%

NVP 91%

3TC >1000%

ZDV 150%

3TC 93%

ZDV 86%

TDF 600%

NVP 53%

ZDV 420%

TDF >10,000%

LPV 57%

RTV 55%

LPV 20%

SQV 3-4%

LPV 22%

SQV 13%

RTV 31%

SQV 2%

LPV 8%

RTV 1%

SQV <30%

LPV <10%

RTV<20%

NVP 80%

RTV <3%

SQV <6% IDV <8%

APV 27%

ATV 13%

ATV 24%

APV 37%

DRV 15%

DRV 31%

DRV 24%

DRV 11%

DRV 24%

RALn >730%

MVCa,n <1%

RAL 98%

T-20 n ND

ETV <40%

ABC 740%

ZDV 280% TDF 300%

TDF 660%

IDV 100%

T-20 20%

LPV 14%

LPV 9%

APV 20%

RTV 18% RTV 11-15%

LPV 28%

LPV 13%

T-20 1%

NVP 64%

ddI 100%

FTC 117%

ABC 80%

TDF 60%

APV 31%

IDV 65%

TDF 70%

RTV 31%

RTV<20%

2nd Trimester

3rd Trimester

Postpartum

ME

SGC

2nd Trimester

3rd Trimester

Antiretroviral PK:

3rd Trimester/Postpartum

Antiretroviral Ratio of 3rd T/Postpartum drug

exposure

Zidovudine (1)

Lamivudine (2)

Abacavir (3)

Tenofovir (4) 0.80

Nevirapine (5,6) 0.80 – 0.90

Efavirenz (7) (AUC); 0.75 (Ctrough)

Lopinavir/r (8) 0.65

Saquinavir/r (9) 0.44

Atazanavir/r (10) 0.72

1, Rodman JH et al JID 1999; 180: 1844-1850; 2, Moodley J et al JID 1998; 178: 1327-1333; 3, Best BM

et al AIDS 2006; 20: 553-560; 4, Burchett S et al, 14th CROI 2007; Ab 738; 5, Lamorde M et al; JAIDS

2010; 55: 345-350; 6, Capperelli E et al HIV Med 2008; 9: 214-220; 7, Cressey T et al; JAIDS 2012; 59:

245-252; 8, Else LJ et al, AAC 2012; 56: 816-824; 9, Martinez-Rebollar M et al; Ther Drug Monit 2011;

33: 772-777; 10, Mirochnik M et al, JAIDS 2011; 56: 412-419.