IAS–USA From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. Treatment of HCV Coinfection: Navigating the Interactions Jennifer J. Kiser, PharmD Assistant Professor Department of Pharmaceutical Sciences University of Colorado School of Pharmacy From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
28
Embed
IAS–USA From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA. Treatment of HCV Coinfection: Navigating the Interactions Jennifer J. Kiser, PharmD Assistant.
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
IAS–USAFrom JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Treatment of HCV Coinfection:Navigating the Interactions
Jennifer J. Kiser, PharmDAssistant Professor
Department of Pharmaceutical SciencesUniversity of Colorado School of Pharmacy
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 2 of 39
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
a BOC: ketoconazole 400mg BID x 6 days, BOC single 400mg dose TVR: ketoconazole single 400mg dose, TVR single 750mg doseb BOC: EFV 600mg QD x 16 days, BOC 800mg TID x 6 days TVR: EFV 600mg QD x 20 days, TVR 750mg Q8H x 10 days
1Kassserra C, et al. CROI 2011, Abstract 118, 2Garg V, et al. 6th IWCP Hepatitis Therapy, 2011, abstract PK-13, 3van Heeswijk R, 18th CROI 2011, abstract 119, 4boceprevir prescribing information
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 7 of 39
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
BOC and TVR are CYP3A Inhibitors
• TVR a more potent CYP3A inhibitor
Midazolam GMR Atorvastatin GMRAUC Cmax AUC Cmax
BOC AUC12 = 5.31 2.81 2.33 2.73
TVR AUC24 = 9.02 2.92 7.94 10.64
1BOC: midazolam single 4mg oral dose, BOC 800mg TID x 6 days2TVR: midazolam single 2mg oral dose, TVR 750mg Q8H x 11 days,340mg single dose420mg daily
1Kassserra C, et al. CROI 2011, Boston, MA, Abstract 118, 2Garg V, J Clin Pharm 2012 Jan 26 [Epub ahead of print], 3Hulskotte EGJ, et al. HepDART 2011,4Lee JE, et al. AAC 2011;55(1):4569-74
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 8 of 39
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Drug TransportersSystemic Circulation
Sinusoidal Membrane
Bile
NTCP
OAT2
Systemic Circulation
OCT1P-gp
MRP2MRP3
MRP4
BCRP ABCG5/G8
BSEP
MDR3
Canalicular Membrane
OATP1B1
Slide 8 of 39
Slide 9 of 39
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Concept of a Therapeutic Index
Intensity of overall exposure to an antiviral drug
0
20
40
60
80
100
Pro
ba
bili
ty o
f E
ffe
ct (%
) Viral Inhibition
Toxicities
Therapeutic Index
Pharmacokinetic Variability – Food, Genetics, Degree of Liver Damage, Body Weight
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 11 of 39
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Patient Case• 57 yo African American female being considered for triple
therapy for HCV– HIV
• Diagnosed 2005, sexually acquired, CD4 nadir~200• HIV RNA = target not detected, CD4=1000 (40%) (Feb 2013)
– Hepatitis C 1a• Treatment naïve• Biopsy (June 2012)
– grade 2 inflammation, stage 2 fibrosis
• HCV RNA = 3,270,000 (Aug 2012)
– GERD– Hypertension– Chronic Pain– Schizoaffective Disorder– Personality DisorderFrom JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 12 of 39
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 13 of 39
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Antihypertensives• ACE inhibitors and diuretics ok• Metabolized to some extent by CYP3A, so
consider dose reductions– Beta blockers: carvedilol and nebivolol – ARBs: irbesartan and losartan
• Calcium channel blockers– Amlodipine Cmax and AUC increased 1.27-
and 2.79-fold by TVR, so a reduced dose should be considered
Kiser JJ, et al. Hepatology 2012;55(5):1620
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 14 of 39
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Antidepressant Exposures Likely Reduced by BOC and TVR
1Hulskotte EGJ, et al. HepDART 2011 3Best BM, et al. 14th CROI 2007, abstract 5744Sekar V, et al. 8th International Congress on Drug Therapy in HIV Infection 2006, abstract P295
Escitalopram AUC ↓21% by BOC (t1/2 ↓ from 31 to 22 hrs)1
With HIV protease inhibitors, paroxetine and sertraline exposures are reduced.3,4
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 15 of 39
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Antipsychotics
• Quetiapine ↑ 335% with potent CYP3A inhibitor ketoconazole
• Cases of toxicity with HIV PIs
• Avoid quetiapine• Dosage of aripiprazole
and iloperidone should be halved
Kiser JJ, et al. Hepatology 2012;55(5):1620
Grimm SW, et al. Br J Clin Pharmacol 2006;61:58
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 16 of 39
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Kiser JJ, et al. Hepatology 2012;55(5):1620, Kiser JJ, et al. Nature Reviews Gastro & Hepatol [Accepted]
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 18 of 39
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Mean HIV PI PK Profiles
0 2 4 6 8 10 12 0 2 4 6 8 10 12
LPV/r ATV/r
DRV/r fAPV/r
AUC
AUC 47%AUC 40%
AUC 17%
n=19
n=11
n=20n=16
n=12 n=7
n=11n=18
Time (hours)
0
4000
8000
12000
LPV
conc
entr
ation
(ng/
mL)
0 2 4 6 8 10 12
ATV
conc
entr
ation
(ng/
mL)
0 6 12 18 24Time (hours)
4000
3000
2000
1000
0
Time (hours)
DRV
con
cent
ratio
n (n
g/m
L)
6000
4000
2000
0
APV
conc
entr
ation
(ng/
mL)
Time (hours)
4000
3000
2000
1000
0
PI alonePI + TVR
APV = amprenavir
PI alonePI + TVR
PI alonePI + TVR
PI alonePI + TVR
Van Heeswijk R, et al. CROI 2011, Boston, MA, abstract 119
Cmin ↔ Cmin ↑ 85%
Cmin ↓ 56%
Cmin ↓ 42%
Slide 18 of 39
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 19 of 39
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Mean TVR PK Profiles
AUC = area under the curve
AUC 54%
AUC 20%
AUC 32%AUC 35%
TVR alone
TVR + ARV
n=14 n=17 n=16 n=20
n=12 n=14 n=11 n=18
Time (hours)
0
1000
2000
3000
TVR
conc
entr
ation
(ng/
mL)
LPV ATV DRV fAPV
0 2 4 6 8 0 2 4 6 8
0 2 4 6 8 0 2 4 6 8
Van Heeswijk R, et al. CROI 2011, Boston, MA, abstract 119
Cmin ↓ 52% Cmin ↓ 15% Cmin ↓ 32% Cmin ↓ 30%
Slide 19 of 39
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 20 of 39
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
BOC and RTV-boosted PI DDI Study
Coadministration with BOC also decreased the AUC of ritonavir in all three groups with ritonavir AUC decreasing 34%, 22%, and 27% in the ATV, LPV, and DRV cohorts respectively.
Hulskotte EGJ. CROI, March 5-8, 2012, Seattle, WA, abstract 771LB
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 21 of 39
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Summary of Interactions with BOC and TVR and RTV-boosted HIV PI
BOC TVRHIV PI BOC HIV PI TVR
ATV/r ↓ ↔ ↑ ↓DRV/r ↓ ↓ ↓ ↓fAPV/r No data No data ↓ ↓LPV/r ↓ ↓ ↔ ↓
• Inconsistent• Unexpected• Difficult to Explain• Possibly Multifactorial
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 22 of 39
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Possible Mechanisms for Interactions with HIV/HCV Protease Inhibitors
1. Enzyme Induction?
2. Decrease in Bioavailability?
3. Altered Protein Binding?
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 23 of 39
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
NNRTI Interactions with BOC and TVR
BOC TVRNNRTI BOC NNRTI TVR
RPV ↑39%1 ↔1 ↑79%2 ↔2
ETV ↓29%3 ↔3 ↔2 ↓25%2
1Rhee E, et al. 20th CROI, 2013 Atlanta, GA2Kakuda TN, et al. 7th Int Workshop on Clin Pharm HIV Therapy, 2012 Barcelona, Spain3Hammond KP, Kiser JJ, JAIDS 2013;62(1):67
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 24 of 39
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
BOC and TVR okay with RAL
TVR1:• RAL and RAL-glucuronide AUC
increased 31% and 37%, respectively by TVR
• Similar changes in RAL-glucuronide suggest no effect of TVR on UGT1A1
• ↑ RAL likely due to P-gp inhibition by TVR
1Van Heeswijk R, et al. 51st ICAAC, Chicago, IL, Sept 17-20, 2011, abstract 1738a2de Kanter CTMM, et al. 19th CROI, Seattle, WA, March 5-8, 2012, abstract 772LB
BOC2:• RAL AUC ↔
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 25 of 39
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Maraviroc Interaction with BOC and TVR vs. HIV PI
Vourvahis M, et al. Int Workshop on Clin Pharm HIV Therapy, Amsterdam, Netherlands, 2013
Co-administered drug (dose)
N
Ratio (90% CI) of maraviroc PK parameters with/without co administered drug ‑
AUCtau, area under the plasma concentration-time curve over the dosage interval; Cmin, minimum plasma concentration; DDI, drug-drug interaction; Cmax, maximum plasma concentration; QD, once daily
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 26 of 39
From JJ Kiser, MD, at Chicago, IL: May 20, 2013, IAS-USA.