Poster A-682 54th ICAAC Washington, DC September 5-9, 2014 Melinta Therapeutics, Inc, Phone 203-624-5606 [email protected] Pharmacokinetics and Relative Bioavailability of Intravenous and Oral Formulations of Delafloxacin (DLX) in Healthy Subjects R. HOOVER1, L. LAWRENCE1, M. BENEDICT2, S. GUNDA2, D. LI1, E. SUN1, S. CAMMARATA1 1Melinta Therapeutics, Inc., New Haven, CT 2PPD Inc., Austin, TX Abstract Results Background Delafloxacin, a novel fluoroquinolone, has activity against Gram-positive organisms including methicillin-resistant S. aureus (MRSA), and against susceptible Gram-negative organisms. Delafloxacin is currently in Phase 3 development for ABSSSI and uncomplicated gonorrhea. Figure 1. Structure of Delafloxacin O Methods This was a Phase 1, single dose, open-label, randomized, 2-period, 2-sequence crossover study, in which 56 healthy subjects received a single 450-mg dose of oral delafloxacin and a single 300-mg delafloxacin IV infusion in 1 of 2 treatment sequences. Plasma samples were analyzed for delafloxacin concentrations with a validated LC MS/MS method. Pharmacokinetic parameters were calculated using non-compartmental methods. To assess the relative exposures of the oral form (Test) to the IV form (Reference), a linear mixed-effect model was performed on the natural logarithm (ln)transformed values of AUC0-t, AUC0-inf, and Cmax with sequence, treatment, and period as fixed effects and subject nested within sequence as a random effect. F Cl HO Parameter (unit) AUC0-inf (µg•h/mL) AUC0-t (µg•h/mL) Cmax (µg/mL) Treatment N Geometric LS Mean 450 mg Tablet 300 mg Infusion 450 mg Tablet 300 mg Infusion 450 mg Tablet 300 mg Infusion 42 49 55 55 55 55 23.0 26.2 22.2 26.3 5.80 10.5 90% CI of the Ratio (Test/Ref) 87.7 83.6, 92.0 84.4 80.9, 88.2 55.2 51.5, 59.1 F N Equivalence in AUC exposure between the oral and IV forms was concluded since the 90% CIs for the Test-to-Reference ratios of geometric means were entirely contained within the predefined criterion interval of 80% to 125% for AUC0-t and AUC0-inf. Equivalence for Cmax was not concluded. 16 treatment-emergent AEs (TEAE) were reported, the most frequent of which were headache (5.4%), followed by diarrhea (3.6%). 2 TEAEs were considered moderate in severity, but the remainders were considered mild, and none led to study discontinuation. Parameter Treatmenta N (unit) N N Table 3. Statistical Analysis of Plasma Pharmacokinetic Parameters of Delafloxacin Following 450-mg Oral and 300-mg IV Treatments (Pharmacokinetic Population) Figure 2. Mean (+SD) Plasma Concentrations of Delafloxacin (450-mg Oral and 300-mg IV Treatments) Versus Time (Pharmacokinetic Population) OH Results Ratio (%) of Geometric LS Means (Test/Ref) O Results H2N F Introduction Gonorrhea is a sexually transmitted disease (STD) caused by infection with Neisseria gonorrhoeae and is the second most commonly reported notifiable disease in the United States, with more than 320,000 cases of gonorrhea reported to the Centers for Disease Control (CDC) in 2011 (CDC 2012b), and left untreated can cause serious and permanent health problems in both women and men (CDC 2012a; CDC 2013). Delafloxacin is highly active against all strains of N. gonorrhoeae tested to date, including those classified as multidrug-resistant. In a 99-strain susceptibility panel (70% ciprofloxacin-resistant) performed by the CDC in 2010 using US specimens (Lawrence 2013), the MIC100s for delafloxacin and ciprofloxacin were 0.5/64 µg/mL. These data suggest delafloxacin may be effective against N. gonorrhoeae infections that are resistant to currently marketed quinolones and in currently in a Phase 3 clinical study in the US. Methods Clinical Study Design This was a Phase 1, single-dose, open-label, randomized, 2-period, 2-sequence crossover study in 56 healthy subjects. Subjects who met all of the eligibility criteria were randomly assigned in a 1:1 ratio to a single dose of oral delafloxacin (450-mg tablet; Treatment A) and IV delafloxacin (300 mg infused over 1 hour; Treatment B) in 1 of 2 treatment sequences. The study consisted of a screening period (Days –28 to –2), 2 check-ins (Day –1 of each period), 2 treatment periods (Days 1 to 4 of each period), and end-of-study/early termination assessments (Day 4 of Period 2). There was a minimum 7-day washout interval between doses in each period. Safety assessments included monitoring of adverse events (AEs), clinical laboratory test results, vital sign measurements, physical examination findings, and 12-lead electrocardiogram (ECG) results. Serial blood samples for the determination of plasma concentrations of delafloxacin were collected before dosing and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 16, 20, 24, 36, 48, and 72 hours after dosing. Bioanalysis Delafloxacin in plasma were quantitated using a validated LC-MS/MS method. Plasma samples for delafloxacin analysis were processed by SLE extraction. The processed samples were analyzed by an LC-MS/MS method with a calibration range of 5 to 5000 ng/mL. Non-compartmental Pharmacokinetic Analysis Plasma concentration data for delafloxacin were analyzed by non-compartmental methods. Pharmacokinetic parameters determined included Cmax, Tmax, Cmin, AUClast, AUCinf, T1/2, CL and Vz. Actual sample times were used. 22.2 90% CI of the Ratio (%) of Geometric LS Geometric LS Means (A,B) Means (A/B)d AUC0-t (µg•h/mL) A B 55 26.3 (24.9, 27.9) AUC0-inf (µg•h/mL) A 42 23.0 (21.6, 24.4) B 49 26.2 (24.7, 27.8) Cmax A 55 5.80 (5.44, 6.17) (µg/mL) B 55 10.5 (9.87, 11.2) 90% CI of the Ratio (A/B)e (21.0, 23.6) 84.4 87.7 55.2 (80.9, 88.2) (83.6, 92.0) (51.5, 59.1) Abbreviations: CI, confidence interval; CV, coefficient of variation; IV, intravenous; LS, least square. Note: A linear mixed-effect model on the natural logarithms (ln) of AUC0-inf, AUC0-t and Cmax was performed with treatment, sequence, and period as fixed effects and subject nested within sequence as a random effect. a Treatment A = delafloxacin 450-mg tablet; Treatment B = delafloxacin 300 mg infused over 1 hour Conclusions The plasma exposures of both formulations were similar to those observed in previous clinical experience. Delafloxacin doses were well-tolerated, and the pharmacokinetic data provides support for utilizing both formulations in Phase 3 IV-to-oral switch settings. 55 Geometric LS Meansc Table 1. Summary of Subject Demographics and Baseline Characteristics (All Subjects) Table 2. Mean (CV) Plasma Pharmacokinetic Parameters of Delafloxacin (Pharmacokinetic Population) Delafloxacin 450-mg Tablet Delafloxacin 300-mg IV Infusion (n = 55) (n = 55) AUC0-tau (µg•h/mL) 21.2 (29.7) 25.7 (21.5) (n = 56) Min, max 36.2 (10.87) Parameter (unit) 20, 61 Gender, No. (%) Female 28 (50.0) AUC0-t (µg•h/mL) 23.3 (30.1) 26.9 (21.5) Male 28 (50.0) AUC0-inf (µg•h/mL)a 24.2 (26.6) 26.7 (22.6) Cmax (µg/mL) 6.12 (32.0) 10.7 (21.3) Race, No. (%) White 40 (71.4) Tmax (h)b 0.817 (0.50, 4.00) 1.0 (0.75, 1.13) Black or African American 15 (26.8) Kel (1/h)a 0.0588 (43.0) 0.0804 (48.2) 14.1 (42.0) 10.9 (54.6) Asian 1 (1.8) Mean Weight (kg) (SD) Min, max 2 Mean BMI (kg/m ) (SD) t1/2 (h)a 75.3 (11.9) AUC0-tau/Dose (µg•h/mL/mg) 0.0471 (29.7) 0.0856 (21.5) 52.7, 97.7 AUC0-inf/Dose (µg•h/mL/mg)a 0.0538 (26.6) 0.0889 (22.6) AUC0-t/Dose (µg•h/mL/mg) 0.0517 (30.1) 0.0896 (21.5) Cmax/Dose (µg/mL/mg) 0.0136 (32.0) 0.0358 (21.3) 26.5 (3.10) Min, max 19.2, 31.6 Abbreviation: SD, standard deviation. Min, minimum. Max, maximum. BMI, body mass index. Delafloxacin 450-mg Tablet Delafloxacin 300-mg Infusion Preferred Term, No. (%) (n=55) (n=55) Total Number of TEAEs Number of subjects with at least 1 TEAE Gastrointestinal disorders Diarrhoea 5 4 (7.3) 2 (3.6) 2 (3.6) 11 7 (12.7) 2 (3.6) 0 1 (1.8) 0 0 1 (1.8) 0 0 1 (1.8) 1 (1.8) 1 (1.8) 3 (5.5) 1 (1.8) 0 0 2 (3.6) 1 (1.8) 1 (1.8) 0 1 (1.8) 1 (1.8) 0 1 (1.8) 0 0 0 1 (1.8) 1 (1.8) 0 1 (1.8) 0 0 0 1 (1.8) 1 (1.8) 1 (1.8) Abdominal discomfort Infrequent bowel movements Nausea Vomiting Nervous system disorders Headache Dizziness Dysgeusia Sinus headache General disorders and administration site conditions Energy decreased Infections and infestations Vulvovaginal candidiasis Musculoskeletal and connective tissue disorders Myalgia Skin and subcutaneous tissue disorders Pruritus Conclusions • Equivalence in total exposure of delafloxacin was concluded since the 90% CI of the geometric mean ratios was contained within the predefined criterion interval of 80% to 125% for AUC0-t and AUC0-inf. • Median Tmax of delafloxacin occurred at 0.82 hour following the administration of the 450-mg tablet and at 1.00 hour following 300 mg infused over 1 hour. • 16 TEAEs were reported and 11 of 56 subjects (19.6%) experienced at least 1 TEAE. 7 of 55 subjects (12.7%) experienced TEAEs after delafloxacin 300 mg infused over 1 hour, and by 4 of 55 subjects (7.3%) after delafloxacin 450-mg tablet. • The most frequently reported TEAE overall was headache followed by diarrhea. All TEAEs were considered either possibly related (6 subjects, 10.7%) or unrelated (5 subjects, 8.9%) to study drug. Most TEAEs were mild and all TEAEs resolved by the end of the study. There were no deaths, SAEs, or TEAEs leading to study discontinuation. References 1. Abbreviation: CV, coefficient of variation. a Note: Percentages were calculated based on the number of subjects in the safety population within each treatment sequence and overall. System Organ Class Treatment Overall Mean age (years) (SD) Table 4. Treatment-Emergent Adverse Events (TEAEs, Safety Population) n = 42 for Treatment A and n = 49 for Treatment B. Corresponding parameters were not calculated for some of the subjects because a linear regression could not be fitted through the terminal phase. 2. b 4. For Tmax, the median (minimum, maximum) values are presented. 3. 5. Centers for Disease Control and Prevention (CDC). Gonorrhea-CDC Fact Sheet [Internet]. Atlanta: Department of STD Prevention. 2012a [cited 2013 July 05]. Available from: http://www.cdc.gov/std/gonorrhea/gon-fact-sheet-june-2012.pdf. Centers for Disease Control and Prevention (CDC). Sexually Transmitted Disease Surveillance 2011 [Internet]. Atlanta: U.S. Department of Health and Human Services. 2012b [cited 2013 July 05]. Available from: http://www.cdc.gov/std/stats11/Surv2011.pdf. Centers for Disease Control and Prevention (CDC). Update to CDC’s sexually transmitted diseases treatment guidelines, 2010: Oral cephalosporins no longer a recommended treatment for gonococcal infections. MMWR Morb Mortal Wkly Rep. 2012c;61(31):590-4. Centers for Disease Control and Prevention (CDC). CDC Grand Rounds: the growing threat of multidrug-resistant gonorrhea. MMWR Morb Mortal Wkly Rep. 2013;62(6):103-6. Lawrence L. Study report of the antibacterial activity of RX-3341 against Neisseria gonorrhoeae CDC isolates in 2010. 2013, July 11. Melinta Internal Report.
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