ParametersEfavirenz

Mean (CV%)w/o

Rezafunginw/

RezafunginAUC0-t

(pg*h/mL)7898.6(28.7)

8153.2(31.5)

AUC0-∞(pg*h/mL)

15219.3(32.5)

17955.1(46.2)

Cmax

(pg/mL)305.8(22.9)

306.6(20.7)

Tmax

(h)3.00

(2.00-4.05)3.00

(1.00-4.00)t1/2

(h)164.52(46.5)

193.99(51.8)

ParametersCaffeine

Mean (CV%)w/o

Rezafunginw/

RezafunginAUC0-t

(pg*h/mL)17963.8(29.9)

19264.7(31.5)

AUC0-∞(pg*h/mL)

20074.3(36.5)

22333.9(40.9)

Cmax

(pg/mL)2116.0(21.9)

2302.7(26.6)

Tmax

(h)1.00

(0.50-2.00)1.00

(0.50-2.00)t1/2

(h)6.42

(35.2)7.26

(37.6)

ParametersPitavastatinMean (CV%)

w/o Rezafungin

w/ Rezafungin

AUC0-t

(pg*h/mL)86.177(51.4)

89.483(48.3)

AUC0-∞(pg*h/mL)

94.733(49.4)

98.481(47.8)

Cmax

(pg/mL)41.032(56.0)

41.367(53.7)

Tmax

(h)0.75

(0.50-2.00)0.75

(0.50-3.00)t1/2

(h)7.50

(33.2)8.05

(33.9)

ParametersRepaglinideMean (CV%)

w/o Rezafungin

w/ Rezafungin

AUC0-t

(pg*h/mL)22.354(44.9)

24.996(37.1)

AUC0-∞(pg*h/mL)

24.271(42.6)

27.175(34.6)

Cmax

(pg/mL)13.476(53.4)

13.175(40.6)

Tmax

(h)1.00

(0.75-2.00)1.00

(0.50-3.00)t1/2

(h)1.06

(45.7)1.07

(44.9)

ParametersMetformin

Mean (CV%)w/o

Rezafunginw/

RezafunginAUC0-t

(pg*h/mL)7532.22(24.8)

7565.49(28.8)

AUC0-∞(pg*h/mL)

7643.08(24.4)

7674.95(28.2)

Cmax

(pg/mL)1107.48(26.5)

1174.95(31.6)

Tmax

(h)3.00

(2.00-4.00)3.00

(2.00-4.00)t1/2

(h)6.60

(49.3)5.56

(41.8)

No Relevant Pharmacokinetic (PK) Interaction Between Rezafungin and Nine Probe Drugs: Results from a Drug-Drug Interaction (DDI) Study

V. Ong, S. Flanagan, T. SandisonCidara Therapeutics, San Diego, CA

Poster 535Voon Ong, Ph.D.Cidara Therapeutics, Inc.6310 Nancy Ridge Dr., Suite 101San Diego, CA 92121 USAvong@cidara.com

INTRODUCTION METHODS (con’t) RESULTS (con’t) RESULTS (con’t) RESULTS (con’t)Rezafungin (RZF) is a new echinocandin being developed to treat patients with systemic fungal infections and to prevent invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp. in blood and marrow transplant recipients and other patients at high risk of infection. RZF is differentiated by stable and efficacy-driving pharmacokinetics (PK) that allow for once-weekly dosing.

Several in vitro drug-drug interaction (DDI) studies have been conducted to determine the potential of interactions with RZF. RZF inhibition of human CYP isoforms was assessed with recombinant human CYP isoforms and with definitive probe substrates incubated in human liver microsomes. RZF weakly inhibited CYP2C8 and CYP3A4 (IC50 >25 µM). Although inhibition of these CYPs is not expected at therapeutic exposures given unbound peak rezafungin concentrations of approximately 0.3 µM, it was investigated clinically to de-risk the potential interaction.

RZF was found not to be a substrate for the major transporters: P-gp(P-glycoprotein), BCRP (breast cancer resistance protein), or the human solute carrier (SLC) transporters MDR1, MRP2, OATP1B1, OATP1B3, OCT1, OCTN1, or OCTN2. However, RZF in vitro was determined to be an inhibitor (IC50 >6 µM) of OCT1, MATE1, and OATP1B3 transporters. Further, inhibition of P-gp and BCRP could not be definitively ruled out due to sensitivity of the cells to RZF, therefore, these potential interactions were also investigated clinically.

No meaningful PK interactions occurred between RZF and the 9 probe drugs tested. PK exposure of all probe drugs were comparable with or without RZF co-administration. Maximum changes in mean Cmax or AUC were <20% for all drugs when given with or without RZF and unlikely to be clinically significant, providing evidence that no dose adjustment is necessary when these commonly used drugs are co-administered with RZF.

Repaglinide mean plasma concentration profiles without and with RZF are presented with relevant PK parameters for comparison (Fig 2). With RZF, AUC increased by ~12% but lower Cmax suggests RZF likely is not an inhibitor of CYP2C8.

DISCLOSURESV.O., S.F., T.S.: employees and shareholders of Cidara Therapeutics, Inc.

METHODSA Phase 1, single-center, open-label, crossover, inpatient study of 26 healthy subjects was conducted to assess DDIs between RZF (as Rezafungin for Injection) and drugs commonly used as substrates for PK interaction–testing as well as drugs likely to be coadministeredwith RZF.

A loading dose of RZF 600 mg (IV infusion, 1.5 hr) was administered on the first dosing day to approximate a steady-state blood concentration of multiple 400-mg doses, thus enabling DDI testing with the first dose of RZF. Approximately weekly doses of RZF 400 mg (IV infusion, 1 hr) were administered on other dosing days to simulate the highest potential dose and regimen that may be selected for use in Phase 3 clinical studies. Probe drugs were administered as part of a cocktail containing ≥2 drugs, once prior to and once after receiving RZF on a schedule designed to allow for washout between doses and to limit interactions with other drugs (Figure 1).

Tacrolimus mean whole blood–concentration profiles without and with RZF are presented with relevant PK parameters for comparison (Fig 2). Inhibition of CYP3A and P-gp was not observed as exposures decreased slightly and induction would not be expected following a single RZF dose.

CONCLUSION

Plasma (or blood, for tacrolimus) samples were analyzed by validatedLC-MS/MS methods to determine tacrolimus, repaglinide, metformin, rosuvastatin, pitavastatin, caffeine, efavirenz, midazolam and digoxinconcentrations to characterize the PK profile of each analyte. PK exposure parameters (area under curve [AUC] and maximum concentration [Cmax]) were calculated from the plasma/bloodconcentration-time profiles by noncompartmental analysis.

ParametersTacrolimusMean (CV%)

w/o Rezafungin

w/ Rezafungin

AUC0-t

(pg*h/mL)357481.4

(53.1)289461.1

(40.8)AUC0-∞(pg*h/mL)

381681.7(54.4)

309748.1 (42.0)

Cmax

(pg/mL)33762.3(38.5)

31028.5(31.8)

Tmax

(h)1.50

(1.00-4.00)1.00

(0.50-4.00)t1/2

(h)40.44(12.0)

41.87(12.1)

Metformin mean plasma concentration profiles without and with RZF are presented with relevant PK parameters for comparison (Fig 3). Exposures were comparable with and without RZF; RZF is not an inhibitor of transporters MATE1, MATE2K, OCT1, or OCT2.

Pitavastatin mean plasma concentration profiles without and with RZF are presented with relevant PK parameters for comparison (Fig 5). Confirmed no inhibition of OATP1B1/OATP1B3 with RZF co-administration.

Rosuvastatin mean plasma concentration profiles without and with RZF are presented with relevant PK parameters for comparison (Fig 4). Mean exposures increased by ~15%; RZF is a possible weak inhibitor of BCRP transporter.

Caffeine mean plasma concentration profiles without and with RZF are presented with relevant PK parameters for comparison (Fig 6). Negligible change in PK noted; RZF is not a CYP1A2 inhibitor or inducer.

Midazolam mean plasma concentration profiles without and with RZF are presented with relevant PK parameters for comparison (Fig 8). Negligible change in PK noted; RZF is not a CYP3A inhibitor or inducer.

Efavirenz mean plasma concentration profiles without and with RZF are presented with relevant PK parameters for comparison (Fig 7). Negligible change in PK noted; RZF is not a CYP2B6 inhibitor or inducer.

Digoxin mean plasma concentration profiles without and with RZF are presented with relevant PK parameters for comparison (Fig 9). Negligible change in PK noted; RZF is not a P-gp transporter inhibitor.

Day -9 Day 10 (a)

Day 15 (a)

Day 1(a)

≤45 days

Screening Day -15

Day 22 (Check-out)

Day -21

Day -22 (Check-in)

(a) Probe drugs administered at the beginning (≤2 minutes) of the RZF intravenous infusion.

tacrolimus 5 mg (concomitant medication; CYP3A; P-gp), repaglinide 1 mg (CYP2C8 sensitive index substrate; OATP)

caffeine 100 mg (CYP1A2), efavirenz 50 mg (CYP2B6), midazolam 2 mg (CYP3A), digoxin 0.25 mg (P-gp)

Rezafungin for Injection 600 mg

metformin 500 mg (OCT1/2; MATE1/2K), rosuvastatin 5 mg (BCRP; OATP), pitavastatin 2 mg (OATP)

Rezafungin for Injection 400 mg

Figure 1. Study Design and Probe Drugs Used

RESULTS

ACKNOWLEDGEMENTSThe authors would like to acknowledge the contributions from the respective teams at Cidara and Altasciences.

Figure 2. Tacrolimus: Whole Blood Concentration Profiles and RZF PK Parameters

Figure 4. Rosuvastatin: Plasma Concentration Profiles and RZF PK Parameters

ParametersRosuvastatinMean (CV%)

w/o Rezafungin

w/ Rezafungin

AUC0-t

(pg*h/mL)29312.0(42.7)

33769.2(43.2)

AUC0-∞(pg*h/mL)

31051.9(40.5)

35072.9(42.2)

Cmax

(pg/mL)3607.4(43.1)

4030.1(45.1)

Tmax

(h)4.00

(3.00-4.03)4.00

(1.00-4.02)t1/2

(h)8.51

(53.5)13.06(78.9)

Figure 3. Metformin: Plasma Concentration Profiles and RZF PK Parameters

Figure 2. Repaglinide: Plasma Concentration Profiles and RZF PK ParametersParameters

MidazolamMean (CV%)

w/o Rezafungin

w/ Rezafungin

AUC0-t

(pg*h/mL)22.950(42.3)

22.850(38.2)

AUC0-∞(pg*h/mL)

25.123(45.2)

25.158(41.5)

Cmax

(pg/mL)9.602(38.2)

9.097(31.6)

Tmax

(h)0.75

(0.50-2.00)0.75

(0.50-1.00)t1/2

(h)4.08

(19.6)4.28

(19.7)

ParametersDigoxin

Mean (CV%)w/o

Rezafunginw/

RezafunginAUC0-t

(pg*h/mL)12.5

(23.7)14.5

(27.0)AUC0-∞(pg*h/mL)

17.7(21.2)

19.3(19.0)

Cmax

(pg/mL)0.887(28.3)

0.891(35.5)

Tmax

(h)1.00

(0.50-2.00)1.00

(0.50-3.00)t1/2

(h)45.25(20.8)

45.02(15.0)

Figure 5. Pitavastatin: Plasma Concentration Profiles and RZF PK Parameters

Figure 6. Caffeine: Plasma Concentration Profiles and RZF PK Parameters

Figure 7. Efavirenz: Plasma Concentration Profiles and RZF PK Parameters

Figure 8. Midazolam: Plasma Concentration Profiles and RZF PK Parameters

Figure 9. Digoxin: Plasma Concentration Profiles and RZF PK Parameters