cenicriviroc (cvc) drug –drug interactions with guideline...

CVC STUDIES 104/107/108 and 109

Presented at the 14th International Workshop on Clinical Pharmacology of HIV Therapy. Amsterdam, Netherlands. April 2013. Abstract O_09A / O_09B

Cenicriviroc (CVC) drug–drug interactions with guideline-preferred

HIV antiretrovirals

E. Lefebvre1, J. Enejosa1, W. Chang1, H. Jenkins1, C. Ballow2, M. Willett3, S. Griffith4

1Tobira Therapeutics, Inc., San Francisco, CA, USA; 2Buffalo Clinical Research Center, Buffalo, NY, USA; 3Ready Clinical, Princeton, NJ, USA; 4ClinPharma Resources, San Diego, CA, USA


Cenicriviroc (CVC) characteristics

Oral CCR5/CCR2 receptor antagonist currently in Phase 2b In vitro protein-adjusted IC90 against HIV clinical isolates = 0.25 nM

Inhibits binding of MCP-1 to CCR2, IC50 = 5.9 nM

Additive to synergistic antiviral activity in vitro with NRTIs, NNRTIs, PIs and INSTI

Once-daily dosing Long plasma t½ (30–40 hours)

Drug–drug interaction potential Metabolized via CYP3A4 and CYP2C8 Not a known CYP inducer or inhibitor Substrate and inhibitor of P-gp Not a substrate or inhibitor of OATP1B1/B3 or OCT2

2

CVC STUDIES 104/107/108


Cenicriviroc pharmacokinetics when administered with and without ritonavir,

darunavir/ritonavir or atazanavir/ritonavir





Methodology

Three Phase 1, multiple-dose, open-label, fixed-sequence, crossover studies assessed the PK, safety and tolerability of CVC when administered with and without protease inhibitors (RTV, DRV/r, ATV/r)

20 healthy subjects enrolled in each study (male and female; ≥18 to ≤55 years of age; BMI ≥18 to ≤30 kg/m2)

Subjects received CVC alone during Period 1 (10 days), followed by CVC with a protease inhibitor during Period 2 (10 days)

Serial plasma CVC samples were collected; a 24-hour plasma PK profile was obtained for CVC on Day 10 of each period Ratios of least-squares geometric means (and 90% CI) of the

co-administration of CVC with protease inhibitors relative to CVC alone were calculated for AUC0–24, Cmax and Cmin to assess the magnitude of any potential interaction

4



Study schematic

Full PK profile for CVC (Day 10 for Periods 1 and 2)

Protease inhibitor: Study 104 = Ritonavir (RTV 100 mg) Study 107 = Darunavir with low-dose ritonavir (DRV/r 800/100 mg) Study 108 = Atazanavir with low-dose ritonavir (ATV/r 300/100 mg)

Screening Period 1 Period 2

Days 1–10 Days 1–10 Days −28 to −2

CVC 50 mg q.d.

Protease inhibitor q.d. n=20 in all three studies

5

CVC and protease inhibitor administered immediately after a standardized breakfast



Study Parameter

Period 1 (CVC)

Period 2 (CVC + PI) Ratio of LS

geometric means (90% CI)

[Period 2/Period 1] n LS

geometric means

n LS

geometric means

104 (CVC + RTV)

AUC0−24 (ng·h/mL)

20

1832

18

6536 3.55 (3.1, 4.1)

Cmax (ng/mL) 164 391 2.39 (2.1, 2.7)

Cmin (ng/mL) 34 173 5.24 (4.4, 6.2)

Effect of protease inhibitors on the PK parameters of CVC

108 (CVC + ATV/r)


18

1462

18

5682 3.89 (3.5, 4.3)

Cmax (ng/mL) 120 306 2.55 (2.3, 2.8)

Cmin (ng/mL) 29 169 5.75 (4.9, 6.7)

LS, least-squares

6

107 (CVC + DRV/r)


20

1264

20

3956 3.13 (2.9, 3.4)

Cmax (ng/mL) 105 229 2.17 (2.0, 2.3)

Cmin (ng/mL) 25 103 4.17 (3.7, 4.7)



CVC concentrations: CVC alone vs CVC + RTV M

ean

(±SD

) pla

sma

CVC

co

ncen

trat

ion,

ng/

mL

Postdose, hour

Period 1, Day 10 (CVC alone) Period 2, Day 10 (CVC + RTV)

Study 104

7



CVC concentrations: CVC alone vs CVC + DRV/r M

ean

(±SD

) pla

sma

CVC

co

ncen

trat

ion,

ng/

mL

Period 1, Day 10 (CVC alone) Period 2, Day 10 (CVC + DRV/r)

Study 107

Postdose, hour

8



CVC concentrations: CVC alone vs CVC + ATV/r M

ean

(±SD

) pla

sma

CVC

co

ncen

trat

ion,

ng/

mL

Period 1, Day 10 (CVC alone) Period 2, Day 10 (CVC + ATV/r)

Study 108

Postdose, hour

9



104 107 108 CVC

(n=20) CVC

+ RTV (n=18)

CVC (n=20)

CVC + DRV/r (n=20)

CVC (n=20)

CVC + ATV/r (n=20)

Any AEs 1 8 5 5 2 20

Any treatment-related AEs 0 0 0 3 0 20

Serious AEs 0 0 0 0 0 0

Discontinuation due to an AE 0 0 0 0 0 2

Severe AEs (Grade 3 or higher) 0 0 0 0 0 0

Safety of CVC alone and in combination with protease inhibitors

In Study 108, Period 2: All 20 subjects reported mild jaundice, a common and expected AE with ATV

14 (70%) and 5 (25%) subjects had Grade 3 and 4 hyperbilirubinemia, respectively

2 subjects discontinued due to moderate rash

10



Conclusions

RTV 100 mg, DRV/r 800/100 mg and ATV/r 300/100 mg significantly increased plasma CVC exposure

The magnitude of interaction was comparable for all 3 regimens CVC alone and in combination with RTV, DRV/r or ATV/r was generally

well tolerated and no serious or unexpected AEs were reported In Study 108, mild jaundice was observed in all subjects during

co-administration of ATV/r with CVC, and resolved after completion of dosing

Incidence of Grade 3 and 4 hyperbilirubinemia was similar to that previously observed in healthy volunteer studies conducted with ATV/r1,2

11

1. Sekar et al. Drugs R D 2007;8(4):241–248; 2. NDA 21-567. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-567_Reyataz_BioPharmr_P3.pdf

CVC STUDY 109


Cenicriviroc and efavirenz pharmacokinetic interactions



CVC STUDY 109


Methodology

Phase 1, multiple-dose, open-label, fixed-sequence, crossover study assessed 2-way PK interactions between CVC and efavirenz (EFV)

40 healthy subjects enrolled (male and female; ≥18 to ≤55 years of age; BMI ≥18 to ≤30 kg/m2)

Serial plasma CVC or EFV samples collected; a 24-hour PK profile was obtained for CVC and EFV after the last dose of each period Ratios of least-squares geometric means (and 90% CI) of the concomitant

administration relative to the administration of CVC or EFV alone were calculated for AUC0–24, Cmax and Cmin to assess the magnitude of any potential interaction

13

CVC STUDY 109


Study schematic

Screening Period 1 Period 2 Days 1–10 Days 1–10 Days −28 to −1

CVC 200 mg q.d. EFV 600 mg q.d.

Group 1: 3-period, 3-treatment crossover to evaluate the effect of EFV on CVC PK

a200 mg on Day 1 and 400 mg on Days 2–10

Full PK profile for CVC (after the dose on Day 10) Full PK profile for EFV (after the dose on Day 10)

CVC was administered immediately after dinner EFV was administered at bedtime

Period 3 Days 1–10

CVC 400 mga q.d.

Review PK (~10–14 days)

EFV 600 mg q.d.

Days 1–10 Day −28 to −1 Days 1–10 Screening Period 1 Period 2

EFV 600 mg q.d.

Group 2: 2-period, 2-treatment crossover to evaluate the effect of CVC on EFV PK

CVC 400 mg q.d.

14

n=20 in both groups

CVC STUDY 109


Parameter

Period 1 (CVC 200 mg)

Period 2 (CVC 200 mg + EFV 600 mg)

Ratio of LS geometric means

(90% CI) [Period 2/Period 1] n LS geometric

means n LS geometric means


20

10 673

20

6085 0.57 (0.51, 0.63)

Cmax (ng/mL) 707 544 0.77 (0.70, 0.85)

Cmin (ng/mL) 220 113 0.52 (0.44, 0.60)

Effect of EFV on PK parameters of CVC: Group 1

Parameter

Period 1 (CVC 200 mg)






19

10 915

19

10 676 0.98 (0.85, 1.12)

Cmax (ng/mL) 722 888 1.23 (1.12, 1.35)

Cmin (ng/mL) 227 192 0.85 (0.71, 1.01)

15

CVC STUDY 109


CVC concentrations: Group 1 M

ean

(±SD

) pla

sma

CVC

co

ncen

trat

ion,

ng/

mL

Postdose, hour

Period 1, Day 10 (CVC 200 mg alone) Period 2, Day 10 (CVC 200 mg + EFV 600 mg)

16

0 4 8 12 16 20 24

CVC STUDY 109


CVC concentrations: Group 1 M

ean

(±SD

) pla

sma

CVC

co

ncen

trat

ion,

ng/

mL

Postdose, hour

Period 1, Day 10 (CVC 200 mg alone) Period 2, Day 10 (CVC 200 mg + EFV 600 mg) Period 3, Day 10 (CVC 400 mg + EFV 600 mg)

17

0 4 8 12 16 20 24

CVC STUDY 109


Effect of CVC on PK parameters of EFV: Group 2

Parameter

Period 1 (EFV 600 mg)

Period 2 (EFV 600 mg + CVC 400 mg)





20

77 265

20

77 925 1.01 (0.95, 1.07)

Cmax (ng/mL) 5631 6003 1.07 (0.97, 1.18)

Cmin (ng/mL) 2416 2329 0.96 (0.89, 1.05)

18

CVC STUDY 109


EFV concentrations: Group 2

19

Period 1, Day 10 (EFV 600 mg alone) Period 2, Day 10 (EFV 600 mg + CVC 400 mg)

Postdose, hour

0 4 8 12 16 20

Mea

n (±

SD) p

lasm

a EF

V co

ncen

trat

ion,

ng/

mL

CVC STUDY 109


Group 1 (n=20) Group 2 (n=20) Period 1

(CVC 200 mg) Period 2

(CVC 200 mg + EFV 600 mg)


Period 1 (EFV 600 mg)

Period 2 (EFV 600 mg + CVC 400 mg)

Any AEs 8 15 9 17 4

Any treatment-related AEs 4 11 4 16 2

Serious AEs 0 0 0 0 0

Discontinuation due to an AE 0 0 0 0 0

Severe AEs (Grade 3 or higher) 0 0 0 0 0

Safety of CVC alone and with EFV

Most common AEs included dizziness, headache, abnormal dreams These AEs were reported during EFV dosing

20

CVC STUDY 109


Conclusions

Co-administration of EFV with CVC 200 mg resulted in a significant decrease in CVC exposure, which was offset by doubling the CVC dosage to 400 mg

CVC had no effect on EFV exposure CVC alone and co-administered with EFV was generally well tolerated

No subject discontinued due to an AE No serious or unexpected AEs No clinically relevant laboratory abnormalities

21


Future directions

CVC is currently under evaluation for the treatment of HIV infection (Study 652-2-202; NCT01338883) Week 24 primary analysis met primary endpoints (CROI 2013; Abstract 106LB) Efficacy comparable to EFV, favorable safety and decreases in LDL and sCD14

Formulation optimization underway CVC single tablet and fixed-dose combinations

Phase 3 studies are being planned Evaluate the clinical efficacy and safety of CVC in combination with

guideline-preferred HIV agents Effect on inflammatory and metabolic parameters

Drug–drug interaction studies Effect of CVC on DRV/r and ATV/r Two-way interactions between CVC and dolutegravir (NCT01827540)

22


Acknowledgments

The authors would like to thank all study participants, Dat Mac from Tobira Therapeutics and Yu-Hui (Ann) Fu from KCAS, LLCa for their contribution to these studies Assistance provided by Sandra Whitelaw, Alpharmaxim Healthcare Communications

23

aBioanalytical Laboratory

cenicriviroc (cvc) drug –drug interactions with guideline...

Documents