10th International Workshop on Clinical Pharmacology of HIV Therapy

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10th International Workshop on Clinical
Pharmacology of HIV Therapy

• Pierre Giguere, B.Pharm., M.Sc.
• The Ottawa Hospital

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Selection of the Abstracts

• Scientifically sound
• High rigorous methods
• Criteria
• What made a good impression to the speaker

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Agenda

• Raltegravir
• PK-PD relationship
• Interactions
• DRVr
• Simplification using vIQ
• PK, safety, efficacy 900/100mg qd
• Interaction with EFV
• Effect of Smoking
• EFV
• ATV
• PK/PD from CASTLE
• ATV unboosted TDF
• Another FAM ATVr TDF study !
• Pregnancy
• Malaria

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Raltegravir

• MOA irreversible binding to the Integrase
  preventing strand transfer into host genome
• Metabolized UGT1A1
• 1 study (P_11)failed to show an association due
  to extreme interpatient variability (CV 92)

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PK-PD of RAL

• Cmin poor predictor. AUC ?
• Model HOSCD4R5 cells and HIV-1 cell modified to
  express fluorescence.
• Infected cells using bead cells x 30min then wash
  out.
• Counted fluorescence, which reflects occupency at
  the integrase site.

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Dissociation of RAL from INT

• Window of 4-12 hrs, time after which integration
  cannot occur
• Residency time RA 5-6 hrs
• Impact of N155H increase dissociation by 10-fold
• This parameter would be potentially the best
  marker of activity
• Analogous to One shot Kill

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RAL Interaction in HIV

• Atazanavir 400mg OD RAL 800mg OD
• N15 HIV-infected
• ATV 400mg po x 14 days
• Then RAL 800mg qd

Molto, IWCPHT2009 Abst 0_13.
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RAL Interaction in HIV
Molto, IWCPHT2009 Abst 0_13.
No discontinuation due to AE
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RAL Interaction in HIV

• Atazanavir 200mg BID RAL 400mg BID

Ripamonti, IWCPHT2009Abst 0_14.
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RAL Interaction in HIV
Ripamonti, IWCPHT2009Abst 0_14.
11
RAL Interaction in HIV
Ripamonti, IWCPHT2009Abst 0_14.
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RAL Interaction in HIV
Ripamonti, IWCPHT2009Abst 0_14.
13
RAL Interaction in HIV
Ripamonti, IWCPHT2009Abst 0_14.
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RAL interaction

• Ezetimibe 10 mg qd
• N20

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Results
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Results

• The variability in
• raltegravir Cmax and
• AUC was higher
• in the presence of
• ezetimibe.
• Six (30) of the
• volunteers had Ctrough
• Which were lower than the reported IC95 of 15
• ng/mL.

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Darunavir 900/100mg

• Simplification using vIQ
• 30 pts with VLlt50 for gt12 weeks
• vIQ (Ctrough / 0.55 x FC IC50) gt 2
• Ranodmized to continue DRV/r 600/100 mg BID or
  switch to 900/100mg qd
• If vIQ lt 1.5 x 2 values, then switched back
• PTs had a medium exposure of 5 PI, and a median
  number protease mutations 11

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Results

• 3 patients switched back to BID due to low vIQ
• All maintained VLlt50 copies/mL
• DRV Cmin lower in qd group (GMR 0.72 0.49-1.06)
• TC no different between groups
• TG 159 ? 140 mg/dL (p0.031)

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Darunavir 900/100mg qd

• 25 pts (48 HCV co-infected)
• 47 had VLlt50 at baseline, the remainder median
  4.2 log
• Results
• Ctrough 1.62 1.06, 1.46
• 24/25 had level gt 0.55 ug/mL
• All VLlt50 at week 24
• No effect of gender, HCV, other ART

Curran et al. IWCPHIVT 2009, Amsterdam, P_14
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DRVr-EFV

• Attractive once daily first-line regimen
• PK DRVr 900/100mg EFV 600mg
• 12 Healthy volunteers

Lee et al. IWCPHIVT 2009, Amsterdam, P_29
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Darunavir/r EFV
DRV Period 2 EFV (Period 3) (2)
AUC GMR0.86 0.75, 0.97 GM 0.91 0.75, 1.11
Cmax GMR0.92 0.82, 1.03 GMR0.80 0.63,1.02
Cmin 1180ng/mL (1) GMR0.43 0.32, 0.57 GMR 1.01 0.81, 1.25

1. All were gt 0.55 ng/mL
2. Half-life higher by 66

Lee et al. IWCPHIVT 2009, Amsterdam, P_29
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Smoking

• Known interaction with Theophyllin
• Mediated through induction of the CYP1A2
• 1 abstract showing effect of smoking on EFV
  levels
• Cortes (P_04)
• 219 pts from Chile
• Also shown to have an inducing effect on
  constitutive androstane receptor (CAR) known to
  regulate 2B6

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EFV plasma concentrations grouped by CYP2B6 G516T
polymorphism
5.23
3.13
2.21
Cortes et al. IWCPHIVT 2009, Amsterdam, P_04
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EFV plasma concentrations grouped by smoking
status
3.32
2.81
Cortes et al. IWCPHIVT 2009, Amsterdam, P_04
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Atazanavir PK-PD CASTLE

• 883 treatment naïve patients
• Samples at day 1, week 4,12,24,36,48
• Correlation between Ctrough and efficacy or
  toxicity

Zhu. IWCPHIVT 2009, P_19
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PK PD CASTLE

• No correlation could be found between
• Decline in viral load
• VLlt50
• For both ATVr and LPVr

Zhu. IWCPHIVT 2009, P_19
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PK PD CASTLE

• Bilirubin was associated with higher trough of
  ATVr

Zhu. IWCPHIVT 2009, P_19
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PK PD CASTLE
Nausea was associated with trough but not
diarrhea nor TC TG( not shown)
Zhu. IWCPHIVT 2009, P_19
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ATV TDF
Harris. IWCPHIVT 2009, P_21
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ATV TDF
Harris. IWCPHIVT 2009, P_21
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ATV TDF
Harris. IWCPHIVT 2009, P_21
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ATV TDF
CONCLUSIONS Despite low atazanavir trough levels,
selected patients may be virologically controlled
on regimens including unboosted atazanavir with
tenofovir.
Harris. IWCPHIVT 2009, P_21
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ATVr FAMSaga Continues !

• Assess ATVr 300/100mg is affected by
• FAM 20mg BID
• FAM 40mg BID
• 2hrs apart or at same time
• With or without TDF
• In HIV-Infected patients

Wang. IWCPHIVT 2009, P_30
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ATVr FAMWith NO TDF

• Fam 20 BID did not decrease Cmin
• Fam 40 BID decreased Cmin by 20

Wang. IWCPHIVT 2009, P_30
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ATVr FAMWith TDF

• Fam 20 BID decreased Cmin by 19
• Fam 40 BID decreased Cmin by 25

Wang. IWCPHIVT 2009, P_30
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ATVr FAMTemporal Separation

• Separation of the dose does not change ATV Cmin.
• 10 hr separation between doses is still required

Wang. IWCPHIVT 2009, P_30
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Pregnancy

• Several studies reported decrease exposure of PIs
  in 3rd trimester.
• Some advocate increase dose
• 60 pregnant women on LPVr, ATV and NVP
• Sample each trimester, at delivery, in the cord
  and post partum (1-2 months)
• Total and free plasma concentration
• Interim analysis (42 pregnancies)

Fayet. IWCPHIVT 2009, P_57
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Pregnancy

• LPV Fu, free and total AUC, Cmin not affected
• ATV Total AUC and Cmin decreased by 36, while
  total CL increased. BUT free Cmin and AUC not
  affected (Fu tends to increase)
• NVP Total AUC and Cmin decreased by 32 while
  total CL tended to increase. Free AUC and Cmin
  decreased in parallel
• Cord to mother ratio (C/M)
• LPV and ATV free C/M ratio were 2-fold free
  fraction higher than in mothers plasma
• NVP free fractions similar

Fayet. IWCPHIVT 2009, P_57
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Malarone PIs - EFV

• Malarone atovaquone proguanil
• Proguanil is metabolized by 2C19 to cycloguanil
  (active moiety)
• Atovaquone likely metabolized through
  glucoronidation
• PIs and NNRTIS can induce 2C19 (1)
• LPVr or RTV can induce glucuronidation
• However, Proguanil (not cycloguanil) is the
  synergistic compound to atovaquone (2)

Also looked at 2C192 and -3

1. JAIDS 006, 4252-60
2. AAC 1999. 431334-9

van Lui. IWCPHIVT 2009, O_19
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Baseline Characteristics
van Lui. IWCPHIVT 2009, O_19
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