Drug Interactions Between Anti-HCV Antivirals Ledipasvir/Sofosbuvir and Integrase Strand

25 Pages·2017·0.51 MB·English

by  Shelu Bhatia

Drug Interactions between Anti-HCV
Antivirals Ledipasvir/Sofosbuvir and
Integrase Strand Transfer Inhibitor-
Based Regimens
Kimberly Garrison, Joseph M. Custodio, Damian McColl,
Phillip S Pang, Moupali Das, FuChih Cheng, Grace Ma, and
Anita Mathias
Gilead Sciences, Foster City, CA
2nd Asia Pacific AIDS and Co-infections Conference (APACC),
1-3 June 2017, Hong Kong
Presentation # 14
Disclosures
▪ Damian McColl, K.L. Garrison, J.M. Custodio, P.S. Pang, M. Das, F.
Cheng, G. Ma, and A. Mathias: Gilead (employment; equity
ownership).
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Background
▪ The introduction of antiretrovirals (ARVs) has significantly reduced
acquired immunodeficiency syndrome (AIDS)-related deaths in human
immunodeficiency virus (HIV)-infected individuals
– However, as HIV-related morbidity and mortality have decreased, liver-
related complications associated with viral hepatitis have become a leading
cause of death in this population1
▪ It is estimated that there are over 4 million HIV/hepatitis C virus (HCV)
coinfected individuals globally
▪ It is a high priority to address this unmet medical need by identifying
well-tolerated treatment options for HIV/HCV coinfected patients
1. BicaI, et al. ClinInfect Dis 2001;32:492-7
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Background
▪ Ledipasvir
LDV
– Once-daily, oral, 90-mg
NS5A
NS5A inhibitor
inhibitor
▪ Sofosbuvir
‒ Once-daily, oral, 400-mg
NS5B inhibitor
SOF
‒ GS-331007, predominant nucleotide
circulating metabolite polymerase
inhibitor
▪ Ledipasvir/Sofosbuvir FDC
– Once-daily, oral, fixed-dose
SSOOF F
(90/400 mg) combination tablet for LDV
SOF
nucleotide
chronic hepatitis C for genotype 1 NS5A nucleotide
SOF
LDV nucleotidpeo lymerase
or 42 inhibitor polymerase
polymenruacislneeho itbiditeo r
NS5A inhibitor
inhibpiotolyrmerase
2. Harvoni[summary of product characteristics]. Cambridge, UK: Gilead Sciences International Ltd.; 2014 inhibitor
inhibitor
FDC, fixed-dose combination; genotype 4: LDV/SOF SPC
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Background (cont’d)
▪ Preclinical data suggest LDV/SOF exhibits limited potential for clinically
significant drug-drug interactions (DDIs)3
Transporters/Enzymes Substrate Inhibitor
LDV
P-gp/BCRP LDV
SOF (not GS-331007)
Slow Oxidative Metabolism* LDV
P-glycoprotein (P-gp); breast cancer resistance protein (BCRP)
*unknown pathway
▪ LDV and SOF are not substrates for or clinically relevant inhibitors of organic cation
transporter (OCT)-1 or -2, organic anion transporter polypeptide (OATP)-1B1 or -
1B3, bile salt export pump (BSEP), or organic anion transporter (OAT)-1 or -3
▪ GS-331007 is not a substrate for OAT1, OAT3, or OCT2
▪ LDV or SOF are not turned over by major CYP isoforms in vitro
▪ LDV, SOF and GS-331007 are not substrates or clinically relevant inhibitors of
UGT1A1
3. Harvoni[package insert]. Foster City, CA: Gilead Sciences, Inc.; 2015;
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Potential of Clinically Significant DDIs by ARVs4-8
Transporters/Enzymes Substrate Inhibitor (or Inducer‡)
P-gp/BCRP/
TAF, DTG†, TDF† COBI
OATP1B1/1B3
OCT2/MATE1 DTG
CYP3A4 EVG, COBI, DTG COBI
CYP2D6 COBI
CYP2C9 EVG‡
UGTs* EVG, DTG
▪ Emtricitabine (FTC) and TAF (and TFV as a major metabolite of TAF) exhibit
limited clinically relevant DDI potential
▪ TAF is not an inhibitor/inducer of CYP3A4 in vivo, nor a substrate of OAT1 or 3;
TDF does not inhibit major CYP isoforms
▪ DTG is not a clinically relevant inhibitor of OAT1 or 3, and is not expected to
impact the pharmacokinetics (PK) of drugs that are substrates of CYPs,
UGT1A1/2B7, P-gp, BCRP, BSEP, OATP1B1/1B3, OCT1, and multidrug-
resistance‒associated proteins 2/4
4. Bam RA, et al. Antivir Ther 2014;19:687-92;
*Elvategravir(EVG) is a substrate for UGT1A1/1A3; dolutegravir(DTG) is a substrate for UGT1A1/1A3/1A9;
5. LepistEI, et al. AntimicrobAgents Chemother2012;56:5409-13;
†DTG and tenofovir(TFV) disoproxilfumarate(TDF) are substrates for P-gpand BCRP;
6. Murakami E, et al. AntimicrobAgents Chemother2015;59:3563-9;
‡EVG is a modest inducer; COBI, cobicistat; MATE1, multidrug and toxin extrusion protein 1; 7. Stribild[package insert]. Foster City, CA: Gilead Sciences, Inc.; 2014;
TAF, tenofoviralafenamidefumarate 8. Tivicay[package insert]. Research Triangle Park, NC: ViiV
9. Healthcare; 2014;
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Objectives
Primary
▪ To evaluate the DDIs between LDV/SOF and integrase strand transfer
inhibitor‒based regimens: EVG/COBI/FTC/TAF (E/C/F/TAF;
150/150/200/10 mg) and DTG+FTC/TDF (50 mg + 200/300 mg)
Secondary
▪ To evaluate the safety and tolerability of co-administration of LDV/SOF
and ARVs
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Methods
▪ Two Phase 1 open-label, randomized, six-sequence, multiple-dose (10
days), cross-over DDI studies in healthy volunteers
Treatment Sequence*
Days 1-10 Days 11-20 Days 21-30
LDV/SOF ARVs LDV/SOF + ARVs
LDV/SOF LDV/SOF + ARVs ARVs
ARVs LDV/SOF + ARVs LDV/SOF
ARVs LDV/SOF LDV/SOF + ARVs
LDV/SOF + ARVs ARVs LDV/SOF
LDV/SOF + ARVs LDV/SOF ARVs
*ARVs = E/C/F/TAF (Study 1) and DTG+FTC/TDF (Study 2). All treatments were administered fed.
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Garrison, APACC 2017, Presentation # 14
Methods
▪ Steady-state PK sampling was performed over 24 hours for LDV, SOF,
GS-331007, FTC, and TFV (Studies 1 and 2); EVG, COBI, and TAF (Study 1);
and DTG (Study 2)Plasma concentrations were determined using validated
LC/MS/MS assays
▪ Plasma concentrations were determined using validated liquid
chromatography‒tandem mass spectrometry assays
▪ PK parameters—including area under the plasma concentration-time curve
over the dosing interval (AUC ), maximum plasma concentration (C ), and
 max
plasma concentration at the end of a dosing interval (C )— were estimated

using noncompartmental methods (WinNonlin® 6.3, Pharsight Corp., St Louis,
Missouri, USA)
▪ Geometric least-squares mean ratios (GMRs) and 90% confidence intervals
(CI) were estimated using analysis of variance for AUC , C , and C
 max 
(test vs reference), and compared against lack of PK alteration boundaries of
70‒143%
▪ Adverse event (AE) monitoring, and clinical laboratory, physical examination,
and electrocardiographic evaluations were performed throughout study
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Subject Enrollment and Demographics
Subjects Study 1 Study 2
Enrolled/completed, n 30/30 30/29*
Mean age, y (range) 33 (22, 44) 32 (19, 45)
Mean weight, kg (range) 75 (60, 98) 76 (55, 109)
Sex (male/female), n 20/10 22/8
Race, n (%)
White 20 (67) 17 (57)
Non-white 10 (33) 13 (43)
Ethnicity n (%)
Hispanic/Latino 4 (13) 17 (57)
Non-Hispanic/Latino 26 (87) 13 (43)
*1 subject discontinued due to abnormal liver function test, which resolved within 2 weeks of treatment discontinuation.
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