updates in antiretroviral pharmacology & dosing during pregnancy
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Brookie M. Best, PharmD, MAS of UC San Diego presents "Updates in Antiretroviral Pharmacology & Dosing during Pregnancy"TRANSCRIPT
The UC San Diego AntiViral Research Center sponsors weekly presentations by infectious disease clinicians, physicians and researchers. The goal of these presentations is to provide the most current research, clinical practices and trends in HIV, HBV, HCV, TB and other infectious diseases of global significance. The slides from the AIDS Clinical Rounds presentation that you are about to view are intended for the educational purposes of our audience. They may not be used for other purposes without the presenter’s express permission.
AIDS CLINICAL ROUNDS
Updates in Antiretroviral Pharmacology & Dosing during Pregnancy Brookie M. Best, PharmD, MAS Associate Professor of Clinical Pharmacy & Pediatrics
Roadmap • Gender Effects • Pregnancy Effects • IMPAACT P1026s Methods • Findings from Past Several Years • Analyses Underway • Future Plans • Conclusion
When did I get started studying pregnant women?
Pediatric Clinical Pharmacology Research Fellowship: 2000 – 2004
November, 2001
September, 2004
HIV Global Epidemic • As of 2011:
– 34.2 million people worldwide living with HIV infection
– About half are women – Most infected women are of childbearing age
• Women particularly vulnerable – Insufficient knowledge about AIDS, lack of access to
prevention services, inability to negotiate safer sex, lack of female-controlled HIV prevention methods
Indications for Treatment during Pregnancy
• For maternal health, according to same criteria used for non-pregnant adults
• PLUS, to prevent vertical transmission of HIV in basically all other women
• Regimens proven to reduce transmission: – 3 part zidovudine (PACTG 076) – Single maternal/infant nevirapine (HIVNET 012) – Zidovudine/lamivudine oral from 36 weeks through
labor + 1 week in infant (PETRA) – Others
• Observational cohort in U.S. transmission rates – No therapy = 20% – Zidovudine = 10.4% – Combination therapy without protease inhibitors = 3.8% – Combination therapy with protease inhibitors = 1.2%
“Regardless of plasma HIV RNA copy number or CD4-T lymphocyte count, all pregnant HIV-infected women should receive a combination ARV drug regimen antepartum to prevent perinatal transmission. A combination regimen is recommended both for women who require therapy for their own health and for prevention of perinatal transmission, in those who do not yet require therapy.”
Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1 Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. Accessed November 1, 2012.
Indications for Treatment during Pregnancy
Considerations for Therapy during Pregnancy • Does the dose need to be altered? • What is the potential for short or long-term toxic
effects on the fetus (if known)? • How effective are the drugs at reducing perinatal
transmission? • When is elective cesarean section
recommended?
Dose of drug administered
Drug concentration
in systemic circulation
Drug concentration
at site of action
Pharmacologic Effect
Pharmacokinetics Pharmacodynamics
Drug in tissues of
distribution Drug
metabolized or excreted
ABSORPTION
DISTRIBUTION
ELIMINATION
ACTIVATION
Gender Differences in Drug Exposure • Body size and composition differences • Large differences in rodents, less pronounced in
humans • Women have modestly increased concentrations of
efavirenz, enfuvirtide, lopinavir, nevirapine, ritonavir and saquinavir
• Higher ritonavir and saquinavir associated with increased side effects and improved virologic response
• Women have similar NRTI plasma concentrations, but increased intracellular zidovudine and lamivudine triphosphate concentrations
Fletcher CV, Jiang H, Brundage RC, et al. Sex-based differences in saquinavir pharmacology and virologic response in AIDS Clinical Trials Group Study 359. J Infect Dis 2004;189(7):1176-84. Gatti G, Di Biagio A, Casazza R, et al. The relationship between ritonavir plasma levels and side-effects: implications for therapeutic drug monitoring. Aids 1999;13(15):2083-9. Anderson PL, Kakuda TN, Kawle S, Fletcher CV. Antiviral dynamics and sex differences of zidovudine and lamivudine triphosphate concentrations in HIV-infected individuals. Aids 2003;17(15):2159-68.
Pregnancy Effects
Drug Absorption in Pregnancy • Increased progesterone → decreased GI motility,
prolonged gastric emptying and transit times – Effect = Delayed drug absorption and lower peak
concentrations • Nausea and vomiting may limit tolerability • Food intake altered – high fat meals frequently
necessary for optimal protease inhibitor absorption
Changes Affecting Drug Distribution • Body composition
– Total body water increased by 8 liters
– Plasma volume increased by 50%
– Increased body fat stores
• Increased volume of distribution
• Decreased peak plasma concentrations
• Increased free or unbound drug
Increased effect
• Protein Binding – Decreased albumin
(dilution) – Increased
competitors in blood – Free fatty acids
& steroids
Physiologic Changes in Pregnancy that Affect Drug Elimination
• Increased Cardiac Output – Renal plasma flow
increase 25-50% – GFR increases up to
50%
• Cholestasis may reflect changes in transport activity
• Changes in drug metabolizing enzyme activity – dependent on isoform
• Increased elimination of renally cleared drugs
• Lower trough concentrations
Cytochrome P450 Enzyme Changes
14-18 24-28 36-40-90
-60
-30
0
30
60
90% C
hang
e in A
ctivity
Compa
red
to P
ostP
artu
m
CYP 1A CYP 2D6 CYP 3A
Tracy TS, Venkataramanan R, Glover DD, Caritis SN. Temporal changes in drug metabolism (CYP1A2, CYP2D6, and CYP3A activity) during pregnancy. Am J Ob Gyn 2005;192:633-9.
Phase II Enzyme (UGT) Changes
Pre-conception 1st Tri 2nd Tri 3rd Tri Post Partum0
50
100
150
200
250
300
Lamot
rigine
Clear
ance
(L/
hr)
WT adjusted
Pennell PB, Newport DJ, Stowe ZN, Helmers SL, Montgomery JQ, Henry TR. The impact of pregnancy and childbirth on the metabolism of lamotrigine. Neurology 2004;62:292-5.
Challenges to pregnancy research • Women of reproductive age used to be routinely
excluded from clinical trials • Ethical and liability concerns with fetal exposure • Difficult to recruit to rigorous pharmacokinetic studies
Need for pregnancy research • Appropriate dosing is critical:
• Under-dosing • poor viral control, resistance, MTCT
• Over-dosing • maternal and fetal toxicity
IMPAACT P1026s • “Pharmacokinetic properties of antiretroviral drugs during
pregnancy” • Intensive 12 or 24 PK profiles in 3rd trimester and
postpartum (2nd trimester for some drugs) • Opportunistic design, pregnant women already taking
drugs of interest for clinical care • Real-time reporting to clinicians, with comparison to
expected values in non-pregnant adults • Clinical monitoring of off-label doses • Adjustment of dose and repeat PK evaluation available • Opened in 2003, Enrollment as of Sept. 2012:
– 513 pregnant women, 197 infants
Protease Inhibitors (PIs): P1026s: Atazanavir/Ritonavir in Pregnancy
3rd trimester and postpartum: 300mg/100mg
Mirochnick M, Best BM, Stek A, et al. Atazanavir pharmacokinetics with and without tenofovir during pregnancy. JAIDS 2011;56(5):412-9.
PIs: Atazanavir/Ritonavir in Pregnancy
2nd trimester and postpartum: 300mg/100mg 3rd trimester: 400mg/100mg
Mirochnick M, Stek A, Capparelli E, et al. Pharmacokinetics of increased dose atazanavir with and without tenofovir during pregnancy. 12th International Workshop on Clinical Pharmacology of HIV Therapy, 2011 Apr 13-15, Coral Gables, FL.
PIs: Atazanavir/Ritonavir + Tenofovir 3rd trimester and postpartum: 300mg/100mg
Mirochnick M, Best BM, Stek A, et al. Atazanavir pharmacokinetics with and without tenofovir during pregnancy. JAIDS 2011;56(5):412-9.
PIs: Atazanavir/Ritonavir + Tenofovir 2nd trimester and postpartum: 300mg/100mg
3rd trimester: 400mg/100mg
Mirochnick M, Stek A, Capparelli E, et al. Pharmacokinetics of increased dose atazanavir with and without tenofovir during pregnancy. 12th International Workshop on Clinical Pharmacology of HIV Therapy, 2011 Apr 13-15, Coral Gables, FL.
PIs: Darunavir/Ritonavir
Capparelli E, Best B, Stek A, et al. Pharmacokinetics of darunavir once or twice daily during pregnancy and postpartum. 3rd International Workshop on HIV Pediatrics, 2011 Jul15-16, Rome, Italy.
600/100 mg BID
PIs: Darunavir/Ritonavir
Capparelli E, Best B, Stek A, et al. Pharmacokinetics of darunavir once or twice daily during pregnancy and postpartum. 3rd International Workshop on HIV Pediatrics, 2011 Jul15-16, Rome, Italy.
800/100 mg QD
PIs: Fosamprenavir/Ritonavir
Capparelli E, Stek A, Best B, et al. Boosted fosamprenavir pharmacokinetics in pregnancy. CROI 2010. 17th Conference on Retroviruses and Opportunistic Infections, 2010 Feb 16 – 19; San Francisco, CA. [abstract 908].
PIs: Indinavir/Ritonavir in Thai women
Cressey T, Best B, Achalapong J, et al. Effect of pregnancy on pharmacokinetics of indinavir boosted ritonavir. 13th International Workshop on Clinical Pharmacology of HIV Therapy; 2012 Apr 16-18. Barcelona, Spain.
Efavirenz in Pregnancy
Cressey TR, Stek A, Capparelli E, et al. Efavirenz pharmacokinetics during the third trimester of pregnancy and postpartum. J Acquir Immune Defic Syndr. 2012 Mar 1;59(3):245-252.
Integrase Inhibitors: P1026s: Raltegravir in Pregnancy
Best B, Capparelli E, Stek A, et al. Raltegravir pharmacokinetics in pregnancy. 50th ICAAC. 2010 Interscience Conference on Antimicrobial Agents and Chemotherapy, 2010 Sep 12-15; Boston, MA. Abstract H-1668a.
Maternal Fetal Transfer of Study ARVs
Ratio Cord/Maternal Blood • NNRTIs
• Efavirenz 0.49
• PIs • Amprenavir/r 0.23 • Atazanavir/r 0.15 • Darunavir/r 0.25 • Indinavir/r 0.12
• IIs • Raltegravir 1.31
In Progress: Maraviroc
• Abstract submitted to CROI 2013 – stay tuned…
In Progress: Urinary Cortisol Analyses
• Manuscript in preparation…
P1026s Coming Attractions:
• DRV/RTV, 800 or 900/100 mg BID during 3rd trimester • Rilpivirine • Still evaluating: ddI, ETV, MVC, NFV 1875 mg BID, TPVr • ARVs with TB treatment
– EFV, LPVr, or NVP with rifampicin-containing TB regimen
• Uninfected women (Control) with TB treatment • ARVs with postpartum contraception
– LPVr or ATVr with EE-containing COC – LPVr or ATVr with etonogestrel (Implanon)
Conclusions • Many factors alter drug disposition in pregnant
patients and may require alteration in dosing. • Detailed knowledge of drug characteristics can
help predict these differences. • Maintaining consistent and optimal ARV
exposure is critical for long-term treatment success.
• Understanding PK of maternal-infant drug transfer can lead to effective and economical therapies for the prevention of HIV transmission.
Acknowledgements • UCSD Team: Steve Rossi, Rowena Espina, Nina Ilog,
Diane Holland, Edmund Capparelli, Steve Spector, Andrew Hull, Linda Proctor, James Connor, Victor Nizet
• NIAID, NICHD • PACTG/IMPAACT • Pediatric Pharmacology Research Unit
• P1026s Study Team, Clinical Sites and Participants • Many Team & Lab Members, including: Mark Mirochnick, Alice
Stek, Sandy Burchett, Jennifer Read, Betsy Smith, Courtney Fletcher, Jiajia Wang, David Shapiro, Chengcheng Hu, Heather Watts, Fran Aweeka, Patty Lizak, Tim Cressey, Regis Kreitchmann & others
Thank You!