clincal pharmacology of daas - fcarvturin.it · cross-over design with a 2-3 week washout between...

Gianni Di Perri

Clinica di Malattie InfettiveUniversità degli Studi di Torino

Ospedale Amedeo di Savoia

Clincal Pharmacology of DAAs

Ospedale Amedeo di Savoia

ADME

Absorption

Distribution

Metabolism

Elimination

Pharmacokinetic

Bioavailability

What are the pharmacokinetic goals for HCV therapy?

Do plasma concentrations reflect intra-

hepatic concentrations?

The “Statin” Story

• Most HMG Co-A reductase inhibitors (“statins”)

are hydrophilic open acids with low membrane

permeability.

– Systemic bioavailablity ranges from 10-50%.

• Most are subject to high first-pass metabolism.

• Effect compartment is the interior of

hepatocytes (like DAA’s).

• Pushing parent drug into the systemic

circulation is not a goal of treatment.see Bellosta et al., Circulation 2004;109:III-

50

Do plasma concentrations reflect intra-

hepatic concentrations?The Pravastatin Story

• The systemic bioavailability of pravastatin is decreased by

60% (!) when administered at bedtime compared to a

morning dose.

– Already low at approximately 18%.

• Despite this decrease in systemic bioavailability, the

efficacy of pravastatin is marginally more effective

when given at bedtime (as measured by reduction in

total cholesterol) than when given in the morning.

• Does this reflect better hepatic uptake after an evening

dose?

see Bellosta et al., Circulation 2004;109:III-

50

Tmax (hours) Bioavailability (%)

Grazoprevir 2 20 – 40

Glecaprevir 5 ND

Voxilaprevir 4 ND

Elbasvir 3 32

Velpatasvir 3/4 25 - 30

Pibrentasvir 5 + 300 (with GLE)

Sofosbuvir 1 (3 for GS 331007)

ND

ABSORPTION

AUC Cmax

GRAZOPREVIR + 150 % + 210 %

ELBASVIR - 11 % - 15%

High Fat Meal

AUC Cmax

SOF (GS 331007) mf - - 25%

SOF (GS 331007) hf - - 37 %

VELPATASVIR mf + 34 % + 31 %

VELPATASVIR hf + 21 % + 5 %

Moderate (mf) and High Fat Meal (hf)

GLECAPREVIR + 83 /+ 163 %

PIBRENTASVIR + 40 /+ 53%

Moderate to High Fat Meal (Pk Exposure)

AUC Cmax

SOF (GS 331007) - - 19 / - 35 %

VELPATASVIR + 40 – 166 % + 37 /+187 %

VOXILAPREVIR + 112 – 435 % + 147 /+ 680 %

FOOD EFFECT on ABSORPTION

With Food (not specified)

Protein Binding Blood/Plasma ratio T/2

GRAZOPREVIR 98.8 % ND 31 h

ELBASVIR 99.9 % ND 24 h

SOFOSBUVIR 61-65 % 0.7 0.4 h

GS 331007 < 5% ND 27 h

VELPATASVIR > 99% 0.5 – 0.7 15 h

VOXILAPREVIR > 99% 0.5 – 0.8 33 h

GLECAPREVIR 97.5 % 0.57 6 – 9 h

PIBRENTASVIR > 99 % 0.62 23 – 29 h

DISTRIBUTION and ELIMINATION HALF-LIFE

Metabolism (substrate)

Transporters (substrate)

Inducer Inhibitor

GRAZOPREVIR CYP3A OATP1B1/3, Pgp - BCRP,CYP3A (weak)

ELBASVIR CYP3A Pgp - Pgp, BCRP

SOFOSBUVIR CatA, CES1, Hint1, UMP, CMP & NDP

kinase

- - Pgp, BCRP

VELPATASVIR CYP2B6, CYP2C8, CYP3A

Pgp, BCRP, OAT1B1, OAT1B3

- BCRP (mod.),Pgp, OATP1B1/3

(weak)

VOXILAPREVIR CYP3A (slow turnover)

P-gp, BCRP, OATP1B1 and OATP1B3,

- P-gp, BCRP, OATP1B1 and

OATP1B3,

GLECAPREVIR Secondary (CYP3A) Pgp, BCRP, andOATP1B1/3

- Pgp, BCRP, OATP1B1/3

PIBRENTASVIR none Pgp, BCRP (?) - Pgp, BCRP, OATP1B1/3

METABOLISM and TRANSPORTERS

UPTAKE

EXTRUSION

Wang T, et al. EASL 2015 April 22-26 Vienna Austria

Biliary excretion Urinary excretion

GRAZOPREVIR > 90 % < 1 %

ELBASVIR > 90% < 1 %

SOFOSBUVIR 14 % 80 % + 2.5 % expired air

VELPATASVIR 94 % 0.4 %

VOXILAPREVIR 94 % 0 %

GLECAPREVIR 92.1 % 0.7 %

PIBRENTASVIR 96.6 % 0 %

ELIMINATION

Pk/PD of DAAs and Efficacy

No Correlation of SVR With Plasma PK

Tx-Experienced Tx-Naive Median, Quartiles

Data from RESPOND-2 and SPRINT-2. AUC=area under the concentration-time curve; Cmin=minimum observed plasma concentration; PK=pharmacokinetic; SVR=sustained virologic response.

No SVR (n=29) SVR (n=87) No SVR (n=29) SVR (n=87)

The HCV NS3 protease inhibitor SCH 503034 in combination with

PEG-IFNa-2b in the treatment of HCV-1 PEG-IFNa-2b non

responders: antiviral activity and HCV variant analysis. Zeuzem S, et al.

Hepatology 2006; 44 (S2) 35-36.

Patient population: adults who failed PEG-IFNa-2b +/- RBV (< 2 log reduction in HCV-RNA after 12 weeks)

A. SCH 503034 oral capsules (200 or 400 mg QD) as monotherapy for 7 d;B. PEG-IFNa-2b (1.5 ug/Kg/QW) as monotherapy for 14 d;C. PEG-IFNa-2b (1.5 ug/Kg/QW) + SCH 503034 (200 or 400 mg QD) for 14 d, in a 3-way

cross-over design with a 2-3 week washout between treatments.

RESULTS

4/10 patients in the 400 mg combination group (+ PEG-IFNa-2b) became HCV-RNA negative (< 29 IU/mL) during treatment

Mean max log10 reduction in HCV-RNA were:

➢ 2.4 (1 - 4.5) for SCH 503034 200 mg QD +PEG-IFNa-2b

➢ 2.9 (2.3 – 4.1) for SCH 503034 400 mg QD +PEG-IFNa-2b

Incivek, clinical pharmacology review

Available at www.fda.gov

Interpatient variability & PK/PD relationships:

important for interpretation of drug-drug interactions (2)

Compound

Replicon cell line EC50 (nM)

1a 1b 2a 3a 4a 5a 6a

Glecaprevir1 0.85 0.94 2.7 1.6 2.8 0.12 0.86

Paritaprevir2 1.0 0.21 5.3 19 0.09 0.42 0.68

Grazoprevir3,4 0.4 0.5 1.2 35 1.2 0.9 0.89

Simeprevir5 13 9.4 15 472 36

Asunaprevir6 4 1.2 230 1162 52

Voxilaprevir7 3.9 3.3 3.7 6.1 2.9 1.9 1.5

Inhibitors of NS3/4A: Antiviral Activity Across HCV GT1–6 In Vitro

Compound

Replicon cell line EC50 (pM)

1a 1b 2a 2b 3a 4a 5a 6a

Pibrentasvir1 2 4 2 2 2 2 1 3

Ombitasvir1 14 5 12 4 19 2 3 366

Daclatasvir2 22 3 13,000 530 13 5 74

Ledipasvir3 31 4 21,000 16,000 168,000 390 150 1,100

Elbasvir4 4 3 3 3,000 20 3

Velpatasvir5 12 15 9 8 12 9 75 6

Odalasvir6 14 12 ~150

Samatasvir7 8 3 24 17 2 37

Inhibitors of NS5A: Antiviral Activity Across HCV GT1–6 In Vitro

Pk/PD of DAAs and Toxicity

Grazoprevir / Elbasvir

The rate of ALT increase is related to GZV plasma exposure

Less then 1% of ALT increase (> 5 times upper limit) recorded in clinical trials

Higher rate in Females (2%), Asians (2%) and Pts older than 65 years (2%)

No dose-adjustments are required

SOFOSBUVIR / VELPATASVIR

SOFOSBUVIR / VELPATASVIR / VOXILAPREVIR

GLECAPREVIR / PIBRENTASVIR

Asymptomatic ALT and bilirubin increases have been reported in Subjects with high Glecaprevir Pk exposure.

Pk of Anti-HCV DAAs in End-Organ Disease

Medical Definition of end–organ:

of or relating to an organ (as the liver or kidney) that is ultimately affected by a chronic or progressive disease or condition

Medical Dictionary

LIVER FAILURE

A. between esophageal veins (portal) and the azygos vein (systemic)B. between the superior rectal vein (portal) and the lower rectal veins to the IVC (systemic)C. between the paraumbilical veins (portal) and the abdominal epigastricveins (systemic)D. between the colic veins (portal) and the retroperitoenal veins (systemic)

The architecture of intrahepatic shuntThe extrahepatic shunt

The main effect of chronic liver disease on oral drug availability is thought to result from reduced presystemic drug metabolism

Local effects may be very important

Even without complete shunting, sinusoid to hepatocyte delivery may be impaired

Thabut J Hep 2010

HCV, liver disease and transporters

Pharmacokinetics, Efficacy, and Safety of Hepatitis C Virus Drugs in Patients with Liver and/or Renal Impairment Smolders EJ, et al. Drug Saf. 2016; 39: 589–611.

SMV

ASV

DCV

SOF

LDV/SOF

VEL/SOF

GZV/ELB

OMB/PTV/RTV

DAS

RBV

DAS

RBV

Protease Inhibitors and Dasabuvir * contraindicated in case of CHILD > A

* Due to the elevated AUC of dasabuvir (and M1) in CP-C patients, dasabuvir is con-traindicated in these patients.

Paritaprevir PK according toMetavir score (n=24)

n=14n=10

p= 0.007

Paritaprevir PK according toStiffness (n=24)

p= 0.017

TDM Torino – data on file

Drugs can be categorized according to the efficiency of the liver in their removal from the circulation:

High Hepatic Extration Ratio (EH > 0.7)Blood flow limited: rather insensitive to changes in protein binding or enzyme/ transporter activity. Significant impact may result from decrease in blood flow and porto-systemic shunting

Low Hepatic Extration Ratio (EH < 0.3)Mainly influenced by changes in protein binding and in the intrinsic hepatic clearance (CLint). Enzyme/transporter capacity-limited

Intermediate Hepatic Extration Ratio (0.3 < EH < 0.7)May be influenced by changes in either one of its 3 primary determinants (e.g. hepatic blood flow [QH], intrinsic clearance of unbound drug [CLint] and the fraction of unbound drug [fu])

The ratio of the hepatic clearance of a drug to the hepatic blood flow is called the extraction ratio of the drug. Extraction ratio can be generally classified as high (>0.7), intermediate (0.3-0.7) or low (<0.3) according to the fraction of drug removed during one pass through the liver.

High: > 0.7

Intermediate: 0.3 - 0.7

Low: < 0.3

PORTAL SYSTEM

GRAZOPREVIR – ELBASVIR

GZP ELB

42%

ELB

GZP

14%

ELB

+ 1200%

GZP

Normal Moderate (Child A/B) Severe (Child C)

+ 500%

From Pop-Pk study in compensated cirrhosis

+ 165%

Normal Moderate (Child B) Severe (Child C)

226%

118%

243%

109%

SOFOSBUVIR - GS 331007

SOF SOF SOFGS 331007 GS 331007 GS 331007

+ 100%

- 100%

The pharmacokinetics of velpatasvir were studied with a single dose of 100 mg velpatasvirin HCV negative subjects with moderate and severe hepatic impairment (Child-Pugh Class B and C). Velpatasvir plasma exposure (AUCinf) was similar in subjects with moderate hepatic impairment, severe hepatic impairment, and control subjects with normal hepatic function. Population pharmacokinetics analysis in HCV- infected subjects indicated that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on the exposure of velpatasvir

Patients with Impaired LIVER Function

VELPATASVIR

EPCLUSA HIGHLIGHTS OF PRESCRIBING INFORMATION, revised 06/2016

NO cirrhosis COMP. cirrhosis DECOMP. cirrhosis

AUC controls - 7% - 14 %

Cmax controls - 27% - 41%

C 24h controls + 41% + 54%

STEADY-STATE PHARMACOKINETICS OF SOFOSBUVIR AND VELPATASVIR IN HCV-INFECTED SUBJECTS WITHOUT CIRRHOSIS, WITH COMPENSATED CIRRHOSIS, OR WITH DECOMPENSATED CIRRHOSIS IN THE PHASE 3 ASTRAL STUDIESErik Mogalian , Di An , Yanni Zhu , Yvonne Maruca , Cara Casey , John McNally , John Ling , Anita MathiasEASL LiverTree™. Mogalian E. Apr 15, 2016; 125563

Original Article

Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated CirrhosisMichael P. Curry, M.D., et al. N Engl J Med 2015; 373 (27); 2618-2628

Treatment with sofosbuvir–velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir–velpatasvir for 24 weeks resulted in high rates of sustained virologicresponse in patients with HCV infection and decompensated cirrhosis.


VOXILAPREVIR

VOSEVI HIGHLIGHTS OF PRESCRIBING INFORMATION, revised 09/2017

No dose adjustment of Vosevi is required for patients with mild hepatic impairment (CPT Class A). Vosevi is not recommended in patients with moderate or severe hepatic impairment (CPT Class B or C).

The pharmacokinetics of voxilaprevir were studied with a single dose of 100 mg voxilaprevir in HCV negative patients with moderate and severe hepatic impairment (CPT Class B and C). Relative to patients with normal hepatic function, the voxilaprevirAUCinf was 299% and 500% higher in patients with moderate and severe hepatic impairment, respectively. The unbound fraction of voxilaprevir was approximately 2-fold higher in severe hepatic impairment compared with moderate hepatic impairment or normal hepatic function. Population pharmacokinetic analysis in HCV-infectedpatients indicated that patients with cirrhosis (CPT Class A) had 73% higher exposure of voxilaprevir than those without cirrhosis

Child A Child B Child C

VOXILAPREVIR + 73 % + 299 % + 500 %


GLECAPREVIR / PIBRENTASVIR

Pharmacokinetics and Safety of Glecaprevir/Pibrentasvir in Adults With Chronic Genotype 1-6 Hepatitis C Virus Infection and Compensated Cirrhosis: An Integrated AnalysisGane E, et al. EASL 2017 April 19-21 Amsterdam Netherlands

Cirrhotic status N. Glecaprevir Pibrentasvir

Non-cirrhotic 1804 4800 (198) 1430 (63)

Compensated cirrhosis 288 10700 (124) 1530 (50)

MAVIRET HIGHLIGHTS OF PRESCRIBING INFORMATION, revised 10/2017

Maviret is not recommended in patients with moderate hepatic impairment (Child-Pugh B) and is contraindicated in patients with severe hepatic impairment (Child-Pugh C).

Child A Child B Child C

GLECAPREVIR + 33 % + 100 % + 1200 %

PIBRENTASVIR - + 26 % + 114 %

AUC24h ss (ngh/ml)Geometric Mean (%CV)

• Despite higher GLE exposure in patients with compensated cirrhosis, the safety profile was similar to those in patients without cirrhosis.

• Reported AEs were consistent between patients with and without cirrhosis

Renal failure

No severe renal impairment

Non-dialysis-dependent

Dialysis

Grazoprevir controls + 40% + 10%

Elbasvir “” “” + 46% + 25%

Patients with Impaired Renal Function

ZEPATIER HIGHLIGHTS OF PRESCRIBING INFORMATION, revised 01/2016

GRAZOPREVIR – ELBASVIR

9994

0

20

40

60

80

100

Modifed Full Analysis Set Full Analysis Set

SV

R12 (

%)

115/116 115/122

Elbasvir + Grazoprevir in HCV GT1 and Renal Disease

C-SURFER Study: Results

C-SURFER: SVR12 Results

Source: Roth D, et al. Lancet 2015;386:1537-45.

Modified analysis excluded patients who did not receive ≥1 dose of drug or who died or discontinued early

for reasons unrelated to HCV treatment.

HCV – negative patients AUC0-inf Sofosbuvir AUC0-inf GS-331007

Normal renal function 100 % 100 %

eGFR 80 – 50 ml/min/1.73m2 161 % 155 %

eGFR 50 – 30 ml/min/1.73m2 207 % 188 %

eGFR < 30 ml/min/1.73m2 271 % 551 %

ESRD 1 hr before haemod. 128 % 1380 %

ESRD 1 hr after haemod. 160 % 2170 %

No dose adjustment is required for patients with mild or moderate renal impairment.

The safety of SOVALDI has not been assessed in patients with severe renal impairment or ESRD.

Sovaldi Product Information v1.0 (30 Jun 2014)



EPCLUSA HIGHLIGHTS OF PRESCRIBING INFORMATION, revised 06/2016

The pharmacokinetics of velpatasvir were studied with a single dose of 100 mg velpatasvir in HCV negative subjects with severe renal impairment (eGFR less than 30 mL/min by Cockcroft-Gault). No clinically relevant differences in velpatasvirpharmacokinetics were observed between healthy subjects and subjects with severe renal impairment.

VELPATASVIR

No dose adjustment of Epclusa is required for patients with mild or moderate renal impairment.The safety and efficacy of Epclusa has not been assessed in patients with severe renalimpairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2 ) or end stage renal disease (ESRD) requiring haemodialysis. No dosage recommendation can be given for patients with severe renal impairment or ESRD.


VOSEVI HIGHLIGHTS OF PRESCRIBING INFORMATION, revised 09/2017

VOXILAPREVIR

The pharmacokinetics of voxilaprevir were studied with a single dose of 100 mg voxilaprevir in HCV negative patients with severe renal impairment (eGFR < 30 mL/min by Cockcroft-Gault). Relative to subjects with normal renal function, voxilaprevir AUCinf was 71% higher in subjects with severe renal impairment

No dose adjustment of Vosevi is required for patients with mild or moderate renal impairment. The safety and efficacy of Vosevi has not been assessed in patients with severe renal impairment (estimated Glomerular Filtration Rate [eGFR] < 30 mL/min/1.73 m2) or end stage renal disease(ESRD) requiring haemodialysis.


GLECAPREVIR – PIBRENTASVIR

Glecaprevir and pibrentasvir AUC were increased ≤ 56% in non-HCV infected subjects with mild, moderate, severe, or end-stage renal impairment not on dialysis compared to subjects with normal renal function. Glecaprevir and pibrentasvir AUC were similar with and without dialysis (≤ 18% difference) in dialysis-dependent non-HCV infected subjects. In population pharmacokinetic analysis of HCV-infected subjects, 86% higher glecaprevir and 54% higher pibrentasvir AUC were observed for subjects with end stage renal disease, with or without dialysis, compared to subjects with normalrenal function.Larger increases may be expected when unbound concentration is considered.

Overall, the changes in exposures of Maviret in HCV-infected subjects with renal impairment with or without dialysis were not clinically significant.

MAVIRET HIGHLIGHTS OF PRESCRIBING INFORMATION, revised 10/2017

Kosloski MP, et al. Antimicrob Agents Chemother. 2017 Dec 20. pii: AAC.01990-17

Effects of Renal Impairment and Hemodialysis on the Pharmacokinetics and Safety of the Glecaprevir and Pibrentasvir Combination in HCV-Negative Subjects.

G/P in patients with CKD 4/5

Acknowledgments

THE UNIVERSITY

of LIVERPOOL

TORINO:

Stefano Bonora

Antonio D’Avolio

Mauro Sciandra

Marco Siccardi

Lorena Baietto

Cristina Tettoni

Sabrina Audagnotto

Letizia Marinaro

Jessica Cusato

Margherita Bracchi

Laura Trentini

Andrea Calcagno

Marco Simiele

Amedeo De Nicolò

Anna Lucchini

Filippo Lipani

Roberto Bertucci

Agostino Maiello

Bernardino Salassa

Francesco G. De Rosa

Chiara Montrucchio

Chiara Alcantarini

Chiara Cardellino

LIVERPOOL:

David Back

Saye Khoo

Andy Owen

Marco Siccardi

Anna Maria Geretti

LONDON:

Marta Boffito

Margherita Bracchi

Nicole Pagani

ROMA:

Andrea Antinori

Adriana Ammassari

Giuseppe Ippolito

Alessandra Arialdo

Micol Ferrara

Alice Trentalange

Nicole Pagani

Lucio Boglione

Sarah Allegra

Marino Bonasso

Alessandro Turchi

Debora Pensi

Pino Cariti

Paolo Bigliano

Ilaria Motta

Silvia Corcione

Ambra Barco

Maria Laura Stella

Giancarlo Orofino

Valeria Ghisetti

clincal pharmacology of daas - fcarvturin.it · cross-over design with a 2-3 week washout between...

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