Ombitasvir/Paritaprevir/ Ritonavir + Dasabuvir:...

Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir: Drug Interactions with Antiretroviral Agents

Rajeev Menon Ph.D.

AbbVie Inc.

16th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy

Washington D.C., May 26-28, 2015

16TH INTERNATIONAL WORKSHOP ON CLINICAL PHARMACOLOGY OF HIV & HEPATITIS THERAPY 216TH INTERNATIONAL WORKSHOP ON CLINICAL PHARMACOLOGY OF HIV & HEPATITIS THERAPYMenon R

Amit Khatri

Roger Trinh

Haoyu Wang

Thomas Podsadecki

Walid Awni

Sandeep Dutta

Contributing Authors


• All the authors are AbbVie employees and may hold AbbVie stocks/options.

• The design, study conduct, analyses and financial support for the clinical trials were provided by AbbVie.

Disclaimers


• AbbVie’s three direct acting antiviral (3D) regimen (ombitasvir, paritaprevir/r, and dasabuvir) with and without ribavirin has been approved for the treatment of chronic hepatitis virus (HCV) genotype 1 infection in the US and EU.

• Paritaprevir (ABT-450), identified as a lead compound by AbbVie and Enanta, is a HCV NS3/4A protease inhibitor that is co-administered daily (QD) with ritonavir (paritaprevir/r).

• Ombitasvir (ABT-267) is a HCV NS5A inhibitor dosed QD.

• Dasabuvir (ABT-333) is a non-nucleoside inhibitor of HCV NS5B polymerase dosed twice-daily (BID).

• In phase 3 clinical trials with HCV genotype 1-infected patients, the 3D regimen ±ribavirin demonstrated 12-week sustained virologic response (SVR12) in 92% to 100% of cirrhotic and noncirrhotic patients.

• The 2D regimen of ombitasvir/paritaprevir/ritonavir is being developed for in HCV GT4 subjects with ribavirin (GT4 approved in EU). This regimen is also being developed without ribavirin in HCV GT1b subjects and with ribavirin in HCV GT2 subjects in Japan.

Background

16TH INTERNATIONAL WORKSHOP ON CLINICAL PHARMACOLOGY OF HIV & HEPATITIS THERAPY 5

HIV-HCV Co-infection• Patients with HIV/HCV co-infection are 3 times more likely to develop cirrhosis or

liver decompensation than those infected with HCV alone1.

• Unlike the treatment of HIV, for which the goal is viral suppression, treatment of HCV is finite in duration, and the goal is to achieve SVR. Achieving SVR is associated with a significant decrease in subsequent decompensation of liver function, liver cancer, and all-cause mortality in persons with HIV co-infection2.

• Treatment of patients with HIV/HCV co-infection can be complicated by drug interactions between ARTs and HCV DAAs. Understanding drug interactions between ARTs and HCV DAAs are important prior to coadministering these agents.

1. Graham et al, Clin Infect Dis 2001;33(4):562-5692. Limketkai et al, JAMA 2012;308(4):370-378


Regimen evaluated

Nucleoside Reverse Transcriptase Inhibitor(NRTI)

Emtricitabine/Tenofovir*Abacavir/lamivudine

Integrase Inhibitor Raltegravir*Dolutegravir

Protease Inhibitor (PI) Atazanavir (with and without ritonavir)* Darunavir (with and without ritonavir)*Lopinavir/ritonavir*

Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)

Efavirenz/Emtricitabine/TenofovirRilpivirine

ART Evaluated in Drug-Interaction Studies with the AbbVie DAA Regimen

* Also evaluated in the 2D regimen of ombitasvir/paritaprevir/ritonavir. The 2D regimen is being developed for in HCV GT4 subjects with ribavirin (GT4 approved in EU). This regimen is also being developed without ribavirin in HCV GT1b subjects and with ribavirin in HCV GT2 subjects in Japan.


Nucleoside Reverse Transcriptase Inhibitor

Emtricitabine/Tenofovir

Abacavir/Lamivudine


Design: DDI with Emtricitabine/Tenofovir

Days 1-14 Days 15-21

Cohort 1(N=9)

3D 3D + Emtricitabine +Tenofovir disoproxil fumarate

Days 1-7 Days 8-21

Cohort 2(N=9)

Emtricitabine 200 mg QD +Tenofovir disoproxil fumarate 300 mg QD

3D + Emtricitabine +Tenofovir disoproxil fumarate

3D: Paritaprevir/ritonavir (150/100 mg QD)+ ombitasvir (25 mg QD) + dasabuvir (400 mg BID)


Results: DDI with Emtricitabine/Tenofovir

Central Value Ratio with 90% CI0.25 0.5 0.75 1 1.5 2

Tenofovir

Emcitritabine

Dasabuvir

Ombitasvir

Paritaprevir

CmaxAUCCtrough

0.68 (0.42 - 1.11)0.84 (0.59 - 1.17)1.06 (0.83 - 1.35)

1.05 (1.00 - 1.12)1.07 (1.00 - 1.14)1.09 (1.01 - 1.17)

1.07 (0.93 - 1.24)1.13 (1.07 - 1.20)1.24 (1.13 - 1.36)

0.89 (0.81 - 0.97)0.99 (0.93 - 1.05)1.06 (0.83 - 1.35)

0.85 (0.74 - 0.98)0.85 (0.75 - 0.96)0.85 (0.73 - 0.98)

• No dose adjustment is required for the DAAs, emtricitabine or tenofovir when co-administered

16TH INTERNATIONAL WORKSHOP ON CLINICAL PHARMACOLOGY OF HIV & HEPATITIS THERAPY 10Menon R

Design: DDI with Abacavir + Lamivudine

Period 1 Washout Period 2

Days 1-45 days


Abacavir 600 mg QD +

Lamivudine 300 mg QD

3D 3D + Abacavir 600 mg QD +Lamivudine 300 mg QD

N=123D: ombitasvir/paritaprevir/ritonavir (25/150/100 mg QD)+ dasabuvir (250 mg BID)

1


Results: DDI with Abacavir + Lamivudine

Central Value Ratio with 90% CI0.5 0.75 1 1.5 2

Lamivudine

Abacavir

Dasabuvir

Ombitasvir

Paritaprevir

CmaxAUCCtrough

0.84 (0.69 - 1.02)0.82 (0.70 - 0.97)0.73 (0.63 - 0.85)

0.87 (0.78 - 0.98)0.94 (0.90 - 0.99)

0.78 (0.72 - 0.84)0.88 (0.82 - 0.93)1.41 (1.10 - 1.81)

0.82 (0.76 - 0.89)0.91 (0.87 - 0.95)0.92 (0.88 - 0.96)

0.94 (0.86 - 1.03)0.91 (0.86 - 0.96)0.95 (0.88 - 1.02)

• No dose adjustment is required for the DAAs, abacavir or lamivudine when co-administered

1


• No discontinuations due to AEs during combination dosing of 3D regimen with emtricitabine + tenofovir DF or abacavir + lamivudine

• No SAEs or any new or unexpected safety findings were observed.

Safety: Discontinuations due to Adverse events during combination dosing


Integrase Inhibitors

Raltegravir

Dolutegravir


Design and Results: DDI with Raltegravir

Days 1-3 Days 4-17

Raltegravir 3D + Raltegravir

Central Value Ratio with 90% CI0.5 0.75 1 1.5 2 3 4 5

Raltegravir

CmaxAUCCtrough

2.33 (1.66 - 3.27)

2.34 (1.70 - 3.24)

2.00 (1.17 - 3.42)

• Cross-study comparisons indicate that DAA exposures were not affected by raltegravir coadministration

N=9



According to the raltegravir prescribing information in the United States (Isentress®[raltegravir], Merck Prescribing Information, Isentress: European Public Assessment Reports Product Information), co-administration of raltegravir with omeprazole increases the raltegravir exposure 3-fold but no dose adjustment is needed.

No dose adjustment is recommended for raltegravir when co-administered with the DAAs. Raltegravir based regimens were evaluated in the HCV-HIV co-infected study M14-004.

Recommendations with Raltegravir


Design: DDI with DolutegravirPeriod 1 Washout Period 2

Days 1-77 days


Dolutegravir 50 mg QD

3D 3D + Dolutegravir 50 mg QD

Central Value Ratio with 90% CI0.5 0.75 1 1.5 2

Dolutegravir

Dasabuvir

Ombitasvir

Paritaprevir

CmaxAUCCtrough

0.89 (0.69 - 1.14)0.84 (0.67 - 1.04)0.66 (0.59 - 0.75)

1.01 (0.92 - 1.11)0.98 (0.92 - 1.05)0.92 (0.85 - 0.99)

1.21 (1.15 - 1.29)1.38 (1.30 - 1.47)1.36 (1.19 - 1.55)

0.96 (0.89 - 1.03)0.95 (0.90 - 1.00)0.92 (0.87 - 0.98)

• No dose adjustment is required for the DAAs or dolutegravir when co-administered

N=123D: ombitasvir/paritaprevir/ritonavir (25/150/100 mg QD)+ dasabuvir (25 mg BID)


• No discontinuations due to AEs during combination dosing of the 3D regimen with raltegravir or dolutegravir

• No SAEs or any new or unexpected safety findings were observed.



Protease Inhibitors


Atazanavir DDI Study Design


Cohort 1 3D 3D + ATZ or 3D +ATZ/RTV*

Cohort 2 ATZ + RTV 3D + ATZ or 3D + ATZ/RTV*

PI N Dose Dosing

Atazanavir 24 300 Dosed AM

Atazanavir/RTV 24 300/100 Dosed PM

*Additional ritonavir was coadministered when dosed PM



Atazanavir without Ritonavir

Central Value Ratio with 90% CI0.1 1 10

Atazanavir

Dasabuvir

Ombitasvir

Paritaprevir

CmaxAUCCtrough

1.46 (1.06 - 1.99)1.94 (1.34 - 2.81)3.26 (2.06 - 5.16)

0.83 (0.71 - 0.96)0.82 (0.71 - 0.94)0.79 (0.66 - 0.94)

0.91 (0.84 - 0.99)1.01 (0.93 - 1.10)0.90 (0.81 - 1.01)

0.77 (0.70 - 0.85)0.83 (0.74 - 0.94)0.89 (0.78 - 1.02)

Results and Recommendations: Atazanavir with and without RTV

• Atazanavir without additional RTV can be coadministered the 3D regimen. Atazanavir should be coadministered with ombitasvir/ paritaprevir/ritonavir

Atazanavir with Ritonavir

Central Value Ratio with 90% CI

0.1 1 10 100

Atazanavir

Dasabuvir

Ombitasvir

Paritaprevir

CmaxAUCCtrough

2.19 (1.61 - 2.98)3.16 (2.40 - 4.17)12.0 (8.94 - 16.0)

0.81 (0.73 - 0.91)0.81 (0.71 - 0.92)0.80 (0.65 - 0.98)

1.02 (0.92 - 1.13)1.19 (1.11 - 1.28)1.68 (1.44 - 1.95)

0.83 (0.72 - 0.96)0.90 (0.78 - 1.02)1.00 (0.89 - 1.13)


Darunavir with and without RTV


Cohort 1 3D 3D + DRV3D + DRV/RTV*

Cohort 2 DRV + RTV 3D + DRV3D + DRV/RTV

PI N Dose Dosing

Darunavir QD 18 800 Dosed AM

Darunavir/RTV QD 24 800/100 Dosed PM

Darunavir/RTV BID 18 600/100 No RTV with AM dose

*Additional ritonavir was coadministered when dosed PM 3D: Paritaprevir/ritonavir (150/100 mg QD), ombitasvir (25 mg QD), dasabuvir (250 or 400 mg BID)


Results and Recommendations: Darunavir with and without RTV

• Darunavir Ctrough is lower when coadministered with the 3D regimen• Similar Ctrough and Cmax results were observed for darunavir though AUC increased by

34% when darunavir/ritonavir (PM) was administered with the 3D regimen

Darunavir QD

Central Value Ratio with 90% CI0.25 0.5 0.75 1 1.5 2.5

Darunavir

Dasabuvir

Ombitasvir

Paritaprevir

CmaxAUCCtrough

1.54 (1.14 - 2.09)1.29 (1.04 - 1.61)1.30 (1.09 - 1.54)

1.10 (0.88 - 1.37)0.94 (0.78 - 1.14)0.90 (0.76 - 1.06)

0.92 (0.87 - 0.98)0.76 (0.71 - 0.82)0.52 (0.47 - 0.58)

0.86 (0.77 - 0.95)0.86 (0.79 - 0.94)0.87 (0.82 - 0.92)

Darunavir BID

Central Value Ratio with 90% CI

0.25 0.5 0.75 1 1.5 2.5

Darunavir

Dasabuvir

Ombitasvir

Paritaprevir

0.70 (0.43 - 1.12)0.59 (0.44 - 0.79)0.83 (0.69 - 1.01)

0.84 (0.67 - 1.05)0.73 (0.62 - 0.86)0.54 (0.49 - 0.61)

0.87 (0.79 - 0.96)0.80 (0.74 - 0.86)0.57 (0.48 - 0.67)

0.76 (0.65 - 0.88)0.73 (0.66 - 0.80)0.73 (0.64 - 0.83)

(AM)


• Up to 50% lower Ctrough exposures without a significant impact on Cmax or AUC DRV exposures are unlikely to result in a negatively impact HIV treatment efficacy (in the maintenance of plasma HIV-1 RNA suppression for patients on a stable DRV-based ART regimen during treatment with 3D)

• This is being verified in the M14-004 study in HCV-HIV co-infected subjects

• USPI: Coadministration not recommended

• EU SPC: 800 mg once daily administered at the same time as ombitasvir/paritaprevir/ritonavir + dasabuvir can be used in the absence of extensive PI resistance

Can Darunavir be dosed with the 3D regimen?

Ref:PK-PD analyses of darunavir from two Phase 3 trials (ODIN and ARTEMIS) (Sekar V et al., 2008, 15th Conference on Retroviruses and Opportunistic Infections (CROI); Sekar V et al., 2010, 10th International Conference on Drug Therapy in HIV)

Molto J, Valle M, Ferrer E, et al. Reduced darunavir dose is as effective in maintaining HIV suppression as the standard dose in virologically suppressed HIV-infected patients. 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. 19- 21 May 2014. Washington, DC. Abstract O_02


Lopinavir with RTV QD and BID


Cohort 1 3D 3D + LPV/r

Cohort 2 LPV/r 3D + LPV/r

PI N Dose Dosing

Lopinavir/RTV BID 12 400/100 BID

Lopinavir/RTV QD 24 800/200 Dosed PM



Lopinavir BID

Central Value Ratio with 90% CI0.1 1 10

Lopinavir

Dasabuvir

Ombitasvir

Paritaprevir

CmaxAUCCtrough

2.04 (1.30 - 3.20)2.17 (1.63 - 2.89)2.36 (1.00 - 5.55)

0.99 (0.75 - 1.31)0.93 (0.75 - 1.15)0.68 (0.57 - 0.80)

0.87 (0.76 - 0.99)0.94 (0.81 - 1.10)1.15 (0.93 - 1.42)

1.14 (1.01 - 1.28)1.17 (1.07 - 1.28)1.24 (1.14 - 1.34)

Results and Recommendations: LPV/r with and without RTV

• Similar higher paritaprevir AUC values were observed during coadministration with the 800/200 QD dose of LPV/r. Cmax values were not affected while Ctrough values were higher (due to the PM dose of LPV/r)

• Due to higher paritaprevir exposures and higher ritonavir dose, LPV/r is not recommended with the 3D regimen (USPI) or contraindicated (SMPC).

• Coadministration of the 3D or 2D regimen was tolerated in over 100 subjects for 14 days. If considered for coadministration, the possibility of a greater incidence of gastrointestinal AEs due to increased daily dose of ritonavir (300 mg) for 12 to 24 weeks should be considered.



Regimen Number of Subjects in the 3D Cohorts

Discontinuations due to AE on combination (3D + ARV) regimen

ATZ ± RTV* 48 2 (1st degree AV block and macular rash)

DRV ± RTV 60 0

LPV/r 36 0

* Bilirubin elevations occurred commonly during ATZ+ RTV dosing alone and did not worsen during coadministration with 3D regimen. No AE of jaundice reported.

o Elevation in indirect bilirubin without increases in aminotransferases, was the most common laboratory abnormality; however, no premature discontinuation was observed due to bilirubin elevations. No subject met Hy's Law criteria.

• No SAEs or new safety events were identified in these studies


Non-Nucleoside Reverse Transcriptase Inhibitor

Efavirenz/Emtricitabine/Tenofovir

Rilpivirine


Efavirenz/Emtricitabine/Tenofovir


Cohort 1(N=9)

Paritaprevir/ritonavir (150/100 mg QD)+ dasabuvir (400 mg BID)

Paritaprevir/ritonavir + dasabuvir+ Efavirenz/Emtricitabine/Tenofovir

Cohort 2(N=9)

Efavirenz/Emtricitabine/Tenofovir600/200/300 mg QD

Paritaprevir/ritonavir + dasabuvir+ Efavirenz/Emtricitabine/Tenofovir

• Study was discontinued due to safety & tolerability issues: nausea, vomiting, liver enzyme elevations

• Similar results have been reported with other enzyme inducers (rifampin) and LPV/r or Saquinavir/r

• PK profile was not collected as study discontinued

• Efavirenz containing regimens are contraindicated with the 3D (and 2D) regimen


Design: DDI with Rilpivirine


Cohort 1(N=12)

3D 3D + Rilpivirine 25 mg

Cohort 2(N=12)

Rilpivirine 25 mg 3D + Rilpivirine 25 mg

Rilpivirine was administered:• AM with 3D regimen (n=24)• PM before a meal (n=24)• PM after a meal (n=24)

Overall 72 subjects were dosed in the study



• 2 of 72 subjects discontinued due to AEs (maculopapular rash (N=1) and blood creating phosphokinase and AST increase (N=1))

• The reported QTc prolongation associated with 2.6-fold increase in rilpivirine exposure from the rilpivirine 25 mg QD regimen is ~11 msec (Edurant® [rilpivirine], Janssen Prescribing information), co-administration of rilpivirine with the 3-DAA combination is not recommended at the labeled rilpivirine dose of 25 mg QD.

• USPI: not recommended, EU SPC: Rilpivirine should be used cautiously, in the setting of repeated ECG monitoring.

Results: DDI with Rilpivirine

Results from all 3 Arms were similar

Central Value Ratio with 90% CI0.5 0.75 1 1.5 2 3 4 5

Rilpivirine

Dasabuvir

Ombitasvir

Paritaprevir

CmaxAUCCtrough

1.30 (0.94 - 1.81)1.23 (0.93 - 1.64)0.95 (0.84 - 1.07)

1.18 (1.02 - 1.37)1.17 (0.99 - 1.38)1.10 (0.89 - 1.37)

2.55 (2.08 - 3.12)3.25 (2.80 - 3.77)3.62 (3.12 - 4.21)

1.11 (1.02 - 1.20)1.09 (1.04 - 1.14)1.05 (1.01 - 1.08)


Results from Part 1a• SVR12 was achieved by :

o 29 of 31 (94%) in the 12 week arm

o 29 of 32 patients (91%) in the 24 week arms

• Of the 5 patients who did not achieve SVR , only 2 of 63 were true virologic failureso 1 subject with on treatment breakthrough, 1 subject with PT relapse

o 1 subject withdrew consent (HCV RNA <LLOD at TW10),

o 2 patients had clinical history and phylogenetic evidence consistent with HCV reinfection.

Ref: Mark S. Sulkowski et al, Ombitasvir, Paritaprevir Co-dosed With Ritonavir, Dasabuvir, and Ribavirin for Hepatitis C in Patients Co-infected With HIV-1 A Randomized Trial, JAMA. Published online February 23, 2015. doi:10.1001/jama.2015.1328

ART Regimens evaluated in the HCV-HIV Co-infected Study M14-004 (ClinicalTrials.gov Identifier: NCT01939197)

In addition the following HIV-ART regimens were allowed- Tenofovir disoproxil fumarate (TDF) PO- Emtricitabine (FTC) PO- Lamivudine (3TC) PO

Part 1a (N ~60 )Raltegravir based regimenAtazanavir based regimen

Part 1b (N ~ 30) Darunavir based regimen

Part 2 (N=230 )


Regimen evaluated Recommendation

Nucleoside Reverse Transcriptase Inhibitor

Emtricitabine/TenofovirAbacavir/lamivudine

No dose adjustment requiredNo dose adjustment required

Integrase Inhibitors RaltegravirDolutegravirElvitegravir/cobicistat

No dose adjustment requiredNo dose adjustment requiredNot evaluated

Protease Inhibitors Atazanavir DarunavirLopinavir

No dose adjustment required1

No dose adjustment required1,2

Not recommended/Contraindicated3

Non-Nucleoside Reverse Transcriptase Inhibitor

Efavirenz/Emtricitabine/TenofovirRilpivirine

ContraindicatedNot recommended4

Recommendations for ART with the AbbVie 3-DAA Regimen

1Dose PI at the same time as OBV/PTV/RTV without additional RTV 1,2 Not recommended per USPI. Being evaluated in the HCV-HIV coinfected studyNot recommended (USPI) or contraindicated.(EU SPC). Coadministration of the 3D or 2D was tolerated in over 100

subjects for 14 days. 3EU SPC: Rilpivirine should be used cautiously, in the setting of repeated ECG monitoring. Please refer to the SPC for additional details.


Khatri et al, Drug-Drug Interactions of the Direct Acting Antiviral Regimen of ABT-450/r, Ombitasvir and Dasabuvir with HIV Protease Inhibitors, ICAAC 2014 54th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 5-9, 2014, Washington, DC

Khatri et al, Drug-Drug Interactions of the Direct Acting Antiviral Regimen of ABT-450/r, Ombitasvir and Dasabuvir with Emtricitabine + Tenofovir, Raltegravir, Rilpivirine and Efavirenz, ICAAC 2014 54th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 5-9, 2014, Washington, DC

Khatri et al, Drug-Drug Interactions of Ombitasvir/Paritaprevir/r plus Dasabuvir with Dolutegravir or Abacavir plus Lamivudine, 16th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy, May 26-28, 2015

Sulkowski et al, Ombitasvir, paritaprevir co-dosed with ritonavir, dasabuvir, and ribavirin for hepatitis C in patients co-infected with HIV-1: a randomized trial. JAMA. 2015 Mar 24-31;313(12):1223-31. doi: 10.1001/jama.2015.1328.

References


• Volunteers

• Investigators

• Study staff

• AbbVie personnel involved in study conduct, sample analyses, data analyses

Acknowledgements

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