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Updates in Antiretroviral Pharmacology &Dosing during PregnancyBrookie M. Best, PharmD, MASAssociate 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
Indications for Treatment during Pregnancy • 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 andInterventions to Reduce Perinatal HIV Transmission in the United States. Accessed November 1, 2012.
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?
Pharmacokinetics Pharmacodynamics ACTIVATIONDose of drug Drug Drug Pharmacologicadministered concentration concentration Effect in systemic at site of circulation action ABSORPTIONDISTRIBUTION ELIMINATION Drug in tissues of Drug distribution metabolized or excreted
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 concentrationsFletcher CV, Jiang H, Brundage RC, et al. Sex-based differences in saquinavir pharmacology and virologic response in AIDS Clinical TrialsGroup 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 drugmonitoring. Aids 1999;13(15):2083-9.Anderson PL, Kakuda TN, Kawle S, Fletcher CV. Antiviral dynamics and sex differences of zidovudine and lamivudine triphosphateconcentrations in HIV-infected individuals. Aids 2003;17(15):2159-68.
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 • Increased volume – Total body water of distribution increased by 8 liters – Plasma volume • Decreased peak increased by 50% plasma – Increased body fat concentrations stores• Protein Binding • Increased free or – Decreased albumin unbound drug (dilution) – Increased Increased effect competitors in blood – Free fatty acids & steroids
Physiologic Changes in Pregnancy that Affect Drug Elimination• Increased Cardiac • Increased elimination Output of renally cleared – Renal plasma flow drugs increase 25-50% – GFR increases up to • Lower trough 50% concentrations• Cholestasis may reflect changes in transport activity• Changes in drug metabolizing enzyme activity – dependent on isoform
Cytochrome P450 Enzyme Changes % Change in Activity Compared to PostPartum 90 60 30 0 -30 -60 -90 14-18 24-28 36-40 CYP 1A CYP 2D6 CYP 3ATracy 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 300 Lamotrigine Clearance (L/hr) 250 200 150 100 50 0 Pre-conception 1st Tri 2nd Tri 3rd Tri Post Partum WT adjustedPennell PB, Newport DJ, Stowe ZN, Helmers SL, Montgomery JQ, Henry TR. The impact ofpregnancy 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/100mgMirochnick 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/100mgMirochnick M, Stek A, Capparelli E, et al. Pharmacokinetics of increased dose atazanavir with and without tenofovir duringpregnancy. 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/100mgMirochnick 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/100mgMirochnick M, Stek A, Capparelli E, et al. Pharmacokinetics of increased dose atazanavir with and without tenofovir duringpregnancy. 12th International Workshop on Clinical Pharmacology of HIV Therapy, 2011 Apr 13-15, Coral Gables, FL.
PIs: Darunavir/Ritonavir 600/100 mg BIDCapparelli E, Best B, Stek A, et al. Pharmacokinetics of darunavir once or twice daily during pregnancy and postpartum. 3rdInternational Workshop on HIV Pediatrics, 2011 Jul15-16, Rome, Italy.
PIs: Darunavir/Ritonavir 800/100 mg QDCapparelli E, Best B, Stek A, et al. Pharmacokinetics of darunavir once or twice daily during pregnancy and postpartum. 3rdInternational Workshop on HIV Pediatrics, 2011 Jul15-16, Rome, Italy.
PIs: Fosamprenavir/RitonavirCapparelli E, Stek A, Best B, et al. Boosted fosamprenavir pharmacokinetics in pregnancy. CROI 2010. 17thConference on Retroviruses and Opportunistic Infections, 2010 Feb 16 – 19; San Francisco, CA. [abstract 908].
PIs: Indinavir/Ritonavir in Thai womenCressey T, Best B, Achalapong J, et al. Effect of pregnancy on pharmacokinetics of indinavir boosted ritonavir. 13thInternational 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 PregnancyBest B, Capparelli E, Stek A, et al. Raltegravir pharmacokinetics in pregnancy. 50th ICAAC. 2010 Interscience Conferenceon 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