10 th International Workshop on Clinical Pharmacology of HIV Therapy Pierre Giguere, B.Pharm., M.Sc. The Ottawa Hospital

1010thth International Workshop International Workshop on Clinical Pharmacology of on Clinical Pharmacology of

HIV TherapyHIV Therapy

Pierre Giguere, B.Pharm., M.Sc.Pierre Giguere, B.Pharm., M.Sc.

The Ottawa HospitalThe Ottawa Hospital

Selection of the AbstractsSelection of the Abstracts

Scientifically soundScientifically sound High rigorous methods…High rigorous methods…

Criteria:Criteria: What made a good impression to the speakerWhat made a good impression to the speaker

AgendaAgenda RaltegravirRaltegravir

PK-PD relationshipPK-PD relationship Interactions Interactions

DRVrDRVr Simplification using vIQ Simplification using vIQ PK, safety, efficacy 900/100mg qd PK, safety, efficacy 900/100mg qd Interaction with EFV Interaction with EFV

Effect of Smoking Effect of Smoking EFVEFV

ATVATV PK/PD from CASTLE PK/PD from CASTLE ATV unboosted + TDFATV unboosted + TDF Another FAM – ATVr – TDF study !Another FAM – ATVr – TDF study !

PregnancyPregnancy MalariaMalaria

RaltegravirRaltegravir

MOA: irreversible binding to the Integrase MOA: irreversible binding to the Integrase preventing strand transfer into host preventing strand transfer into host genomegenome

Metabolized UGT1A1Metabolized UGT1A1 1 study (P_11)failed to show an 1 study (P_11)failed to show an

association due to extreme interpatient association due to extreme interpatient variability (CV 92%)variability (CV 92%)

PK-PD of RALPK-PD of RAL

Cmin poor predictor. AUC ?Cmin poor predictor. AUC ? Model : HOSCD4R5 cells and HIV-1 cell Model : HOSCD4R5 cells and HIV-1 cell

modified to express fluorescence.modified to express fluorescence. Infected cells using bead cells x 30min Infected cells using bead cells x 30min

then wash out. then wash out. Counted fluorescence, which reflects Counted fluorescence, which reflects

occupency at the integrase site.occupency at the integrase site.

Dissociation of RAL from INTDissociation of RAL from INT

Window of 4-12 hrs, time after which Window of 4-12 hrs, time after which integration cannot occurintegration cannot occur

Residency time RA = 5-6 hrsResidency time RA = 5-6 hrs Impact of N155H: increase dissociation by Impact of N155H: increase dissociation by

10-fold10-fold This parameter would be potentially the This parameter would be potentially the

best marker of activitybest marker of activity Analogous to One shot KillAnalogous to One shot Kill

RAL Interaction in HIV+RAL Interaction in HIV+

Atazanavir 400mg OD + RAL 800mg OD Atazanavir 400mg OD + RAL 800mg OD N=15 HIV-infectedN=15 HIV-infected ATV 400mg po x 14 daysATV 400mg po x 14 days

Then + RAL 800mg qdThen + RAL 800mg qd

Molto, IWCPHT2009; Abst 0_13.


Molto, IWCPHT2009; Abst 0_13.No discontinuation due to AE


Atazanavir 200mg BID + RAL 400mg BID Atazanavir 200mg BID + RAL 400mg BID

Ripamonti, IWCPHT2009;Abst 0_14.









RAL interactionRAL interaction Ezetimibe 10 mg qdEzetimibe 10 mg qd

N=20N=20

ResultsResults

ResultsResults

•The variability inraltegravir Cmax andAUC was higherin the presence ofezetimibe.• Six (30%) of thevolunteers had CtroughWhich were lower than the reported IC95 of 15ng/mL.

Darunavir 900/100mgDarunavir 900/100mg

Simplification using vIQSimplification using vIQ 30 pts with VL<50 for >12 weeks30 pts with VL<50 for >12 weeks vIQ (Ctrough / 0.55 x FC IC50) > 2vIQ (Ctrough / 0.55 x FC IC50) > 2 Ranodmized to continue DRV/r 600/100 mg Ranodmized to continue DRV/r 600/100 mg

BID or switch to 900/100mg qdBID or switch to 900/100mg qd If vIQ < 1.5 x 2 values, then switched backIf vIQ < 1.5 x 2 values, then switched back PTs had a medium exposure of 5 PI, and a PTs had a medium exposure of 5 PI, and a

median number protease mutations = 11median number protease mutations = 11

ResultsResults

3 patients switched back to BID due to low 3 patients switched back to BID due to low vIQvIQ

All maintained VL<50 copies/mLAll maintained VL<50 copies/mL DRV Cmin lower in qd group (GMR 0.72 DRV Cmin lower in qd group (GMR 0.72

[0.49-1.06])[0.49-1.06]) TC no different between groupsTC no different between groups TG 159 TG 159 140 mg/dL (p=0.031) 140 mg/dL (p=0.031)

Darunavir 900/100mg qdDarunavir 900/100mg qd

25 pts (48% HCV co-infected)25 pts (48% HCV co-infected) 47% had VL<50 at baseline, the remainder 47% had VL<50 at baseline, the remainder

median 4.2 logmedian 4.2 log ResultsResults

Ctrough= 1.62 [1.06, 1.46]Ctrough= 1.62 [1.06, 1.46] 24/25 had level > 0.55 ug/mL24/25 had level > 0.55 ug/mL All VL<50 at week 24All VL<50 at week 24 No effect of gender, HCV, other ARTNo effect of gender, HCV, other ART

Curran et al. IWCPHIVT 2009, Amsterdam, P_14

DRVr-EFVDRVr-EFV Attractive once daily first-line regimen Attractive once daily first-line regimen PK DRVr 900/100mg + EFV 600mgPK DRVr 900/100mg + EFV 600mg 12 Healthy volunteers12 Healthy volunteers

DRVr 900mg/100mg

Day 0 day10

PK

DRVr 900mg/100mg +

EFV 600mg

Day 11 Day 25

EFV 600mg

Day 26 Day 40

PK

PK

Period 1 Period 2 Period 3

Lee et al. IWCPHIVT 2009, Amsterdam, P_29

Darunavir/r + EFVDarunavir/r + EFV

DRV Period #2DRV Period #2 EFV (Period #3) (2)EFV (Period #3) (2)

AUCAUC GMR=0.86GMR=0.86

[0.75, 0.97][0.75, 0.97]

GM = 0.91GM = 0.91

[0.75, 1.11][0.75, 1.11]

CmaxCmax GMR=0.92GMR=0.92

[0.82, 1.03][0.82, 1.03]

GMR=0.80GMR=0.80

[0.63,1.02][0.63,1.02]

CminCmin 1180ng/mL (1)1180ng/mL (1)

GMR=0.43GMR=0.43

[0.32, 0.57][0.32, 0.57]

GMR 1.01GMR 1.01

[0.81, 1.25][0.81, 1.25]

1. All were > 0.55 ng/mL

2. Half-life higher by 66%Lee et al. IWCPHIVT 2009, Amsterdam, P_29

SmokingSmoking

Known interaction with TheophyllinKnown interaction with Theophyllin Mediated through induction of the CYP1A2Mediated through induction of the CYP1A2

1 abstract showing effect of smoking on 1 abstract showing effect of smoking on EFV levelsEFV levels Cortes (P_04)Cortes (P_04) 219 pts from Chile219 pts from Chile

Also shown to have an inducing effect on Also shown to have an inducing effect on constitutive androstane receptor (CAR) constitutive androstane receptor (CAR) known to regulate 2B6known to regulate 2B6

EFV plasma concentrations grouped EFV plasma concentrations grouped by CYP2B6 G516T polymorphismby CYP2B6 G516T polymorphism

GG GT TT0

5

10

15

CYP2B6 G516T

EFV

pla

sma

conc

entr

atio

n (

g/m

L) <0.0001

<0.0001

<0.0001

2.21 3.13

5.23

Cortes et al. IWCPHIVT 2009, Amsterdam, P_04

EFV plasma concentrations EFV plasma concentrations grouped by smoking statusgrouped by smoking status

Smoking Non smoking 0

5

10

15

Smoking status

EFV

pla

sma

conc

entr

atio

n (

g/m

L)

2.813.32

Cortes et al. IWCPHIVT 2009, Amsterdam, P_04

Atazanavir: PK-PD CASTLEAtazanavir: PK-PD CASTLE

883 treatment naïve 883 treatment naïve patientspatients

Samples at day 1, Samples at day 1, week 4,12,24,36,48week 4,12,24,36,48

Correlation between Correlation between Ctrough and efficacy Ctrough and efficacy or toxicityor toxicity

Zhu. IWCPHIVT 2009, P_19

PK PD CASTLEPK PD CASTLE

No correlation could No correlation could be found between be found between Decline in viral loadDecline in viral load VL<50VL<50

For both ATVr and For both ATVr and LPVrLPVr



Bilirubin was associated with higher trough of Bilirubin was associated with higher trough of ATVrATVr



Nausea was associated with trough but not diarrhea nor TC & TG( not shown)


ATV + TDFATV + TDF

Harris. IWCPHIVT 2009, P_21

ATV + TDFATV + TDF


ATV + TDFATV + TDF


ATV + TDFATV + TDF

CONCLUSIONSDespite low atazanavir trough levels, selected patients may be virologically controlled on regimens including unboosted atazanavir with tenofovir.


ATVr +FAM:ATVr +FAM:Saga Continues !Saga Continues !

Assess ATVr 300/100mg is affected byAssess ATVr 300/100mg is affected by FAM 20mg BIDFAM 20mg BID FAM 40mg BIDFAM 40mg BID 2hrs apart or at same time2hrs apart or at same time With or without TDFWith or without TDF

In HIV-Infected patientsIn HIV-Infected patients

Wang. IWCPHIVT 2009, P_30

ATVr +FAM:ATVr +FAM:With NO TDFWith NO TDF

Fam 20 BID did not decrease CminFam 20 BID did not decrease Cmin Fam 40 BID decreased Cmin by 20% Fam 40 BID decreased Cmin by 20%


ATVr +FAM:ATVr +FAM:With TDFWith TDF

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


ATVr +FAM:ATVr +FAM:Temporal SeparationTemporal Separation

Separation of the dose does not change ATV Separation of the dose does not change ATV Cmin.Cmin.

10 hr separation between doses is still required10 hr separation between doses is still required


PregnancyPregnancy

Several studies reported decrease Several studies reported decrease exposure of PIs in 3exposure of PIs in 3rdrd trimester. trimester.

Some advocate increase doseSome advocate increase dose 60 pregnant women on LPVr, ATV and 60 pregnant women on LPVr, ATV and

NVPNVP Sample each trimester, at delivery, in the cord Sample each trimester, at delivery, in the cord

and post partum (1-2 months)and post partum (1-2 months) Total and free plasma concentrationTotal and free plasma concentration Interim analysis (42 pregnancies)Interim analysis (42 pregnancies)

Fayet. IWCPHIVT 2009, P_57

PregnancyPregnancy LPV: Fu, free and total AUC, Cmin not affectedLPV: Fu, free and total AUC, Cmin not affected ATV: Total AUC and Cmin decreased by 36%, ATV: Total AUC and Cmin decreased by 36%,

while total CL increased. BUT free Cmin and while total CL increased. BUT free Cmin and AUC not affected (Fu tends to increase)AUC not affected (Fu tends to increase)

NVP: Total AUC and Cmin decreased by 32% NVP: Total AUC and Cmin decreased by 32% while total CL tended to increase. Free AUC and while total CL tended to increase. Free AUC and Cmin decreased in parallelCmin decreased in parallel

Cord to mother ratio (C/M)Cord to mother ratio (C/M) LPV and ATV: free C/M ratio were 2-fold; free fraction LPV and ATV: free C/M ratio were 2-fold; free fraction

higher than in mothers plasmahigher than in mothers plasma NVP: free fractions similarNVP: free fractions similar

Fayet. IWCPHIVT 2009, P_57

Malarone PIs - EFVMalarone PIs - EFV

Malarone = atovaquone + proguanilMalarone = atovaquone + proguanil Proguanil is metabolized by 2C19 Proguanil is metabolized by 2C19

to cycloguanil (active moiety)to cycloguanil (active moiety) Atovaquone: likely metabolized Atovaquone: likely metabolized

through glucoronidationthrough glucoronidation PIs and NNRTIS can induce 2C19 PIs and NNRTIS can induce 2C19

(1)(1) LPVr or RTV can induce LPVr or RTV can induce

glucuronidationglucuronidation

However, Proguanil (not However, Proguanil (not cycloguanil) is the synergistic cycloguanil) is the synergistic compound to atovaquone (2)compound to atovaquone (2)

ATV/r

LPV/r

EFV

Health volunteers

HIV

+

1 month

Single dose Malarone

Also looked at 2C19*2 and -*3

van Lui. IWCPHIVT 2009, O_19

1. JAIDS 006, 42:52-60

2. AAC 1999. 43:1334-9

Baseline CharacteristicsBaseline Characteristics

van Lui. IWCPHIVT 2009, O_19

Documents

10 th International Workshop on Clinical Pharmacology of HIV Therapy Pierre Giguere, B.Pharm., M.Sc. The Ottawa Hospital