PACTGIMPAACT P1026S Pharmacokinetic Properties Of Antiretroviral Drugs During Pregnancy Mark Mirochn

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PACTG/IMPAACT P1026S   Pharmacokinetic
Properties Of Antiretroviral Drugs During
PregnancyMark Mirochnick, ChairAlice Stek,
Vice-Chair
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PACTG 1026s Primary Objectives

• To describe the pharmacokinetic (PK) parameters
  during pregnancy of selected antiretroviral (ARV)
  drugs currently used in the clinical care of
  pregnant HIV infected women
• To determine if therapeutic dosing regimens of
  these ARV drugs produce adequate drug exposure
  during pregnancy compared to
• historical data from non-pregnant adults and
• the same women in the study cohorts during the
  postpartum period.

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PACTG 1026s Key Elements

• Opportunistic design enroll pregnant women
  already receiving selected ARVs as part of
  clinical care
• Clinical monitoring for toxicity only for drugs
  not dosed as licensed and/or if special concern
• Pk sampling during pregnancy and again postpartum
  
• Rapid turn around of assay results with
  interpretation back to clinician within 2 weeks
• Adjustment of dosing and repeat pk sampling at
  discretion of clinician

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PACTG 1026s Enrollment Schema

• Eligible subjects may enroll in 1 or more arms
• Enrollment in each arm continues until
• 25 third trimester pk evaluations completed
• or
• Miminum of 12 women enrolled and 6 women have
  third trimester AUC lt10 for non-pregnant adults

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P1026s Enrollment by Month
Total Enrollment (6/1/03-11/27/06) 148 women
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1026s Enrollment by Site
24 sites have enrolled patients, and the leaders
are
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Closed
Open
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P1026s 10th Percentile Report
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Abacavir (ABC) Exposure During Pregnancy
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Tenofovir (TFV) Exposure During Pregnancy
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Nevirapine

• 26 women sampled during 2nd or 3rd trimester and
  6-12 weeks postpartum in P1022 and P1026s
• No difference in NVP AUC during pregnancy and
  postpartum (56 13 mcghr/mL AP vs 61 15
  mcghr/mL PP)
• Also not different from non-pregnant adults

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Lopinavir (LPV) Exposure During PregnancyWith
Capsule Formulation (133mg/33mg)
Version 2.0 3rd trimester and 6 wks postpartum
400mg/100mg
Version 3.0 2nd trimester 400mg/100mg 3rd
trimester and 2 wks postpartum 533mg/133mg
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LPV Protein Binding
p .002
p.0001
p .0001
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Nelfinavir (NFV) Exposure During Pregnancy with
625 mg Tablets
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P1026s Manuscripts and Abstracts

• Manuscripts
• Best B, et al. Impact of pregnancy on abacavir
  pk. AIDS 200620553-60.
• Stek A, et al. Reduced lopinavir exposure during
  pregnancy. AIDS 200620193139
• Capparelli E, et al. Effect of pregnancy on
  nevirapine pharmacokinetics during chronic
  therapy. Submitted for publication.
• Mirochnick M, et al. Adequate lopinavir exposure
  achieved with a higher dose during the 3rd
  trimester of pregnancy. In preparation.
• Abstracts
• Stek A, et al. Reduced LPV exposure during
  pregnancy preliminary pk results from PACTG
  1026. XV Int AIDS Conference, Bangkok, Thailand,
  July, 2004.
• Best B, et al. Abacavir pharmacokinetics during
  pregnancy. American College of Clinical
  Pharmacology Annual Meeting, Phoenix, AZ,
  October, 2004.
• Capparelli E, et al. Effect of pregnancy on NVP
  pk during chronic therapy. 6th Int Workshop on
  Clinical Pharmacology of HIV Therapy, Quebec,
  Canada, April 2005
• Mirochnick M, et al. Adequate lopinavir exposure
  achieved with a higher dose during the 3rd
  trimester of pregnancy. 13th CROI, Denver, CO,
  Feb, 2006.
• Read JS, et al. Nelfinavir pharmacokinetics (625
  mg tablets) during the 3rd tri-mester of
  pregnancy and postpartum. 14th CROI, Los Angeles,
  CA, Feb, 2007.
• Aweeka FT, et al. Lopinavir protein binding
  during pregnancy. 14th CROI, Los Angeles, CA,
  Feb, 2007.

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Ideas for New P1026s Arms

• New drugs
• PIs Darunavir
• NNRTIs TMC125
• Entry Inhibitors
• Integrase Inhibitors
• Formulations used at sites outside the US
• Fixed Dose Combination formulations
• Others??