10/27/2013. Study Design. Disclosures

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1 /27/23 Disclosures Drug Exposure Limitations of Oral Methotrexate (MTX) at Doses mg May be Overcome by Using a Subcutaneous MTX Auto-Injector in Patients With Rheumatoid Arthritis (RA) M.H. Schiff, L.S. Simon 2, B. Freundlich 3, J. Jaffe 4 MHS is a consultant for Antares Pharma Inc. LSS is a consultant for Affinergy, Abraxis, Alpha Rx, Nuvo Research, Roche, Pfizer, Novartis, PLx Pharma, Hisamitsu, Dr. Reddy s Laboratories, Avanir, Cerimon, Leerink Swann, Alimera, Nomura, Luxor, Parexel, Nitec, Bayer, Rigel, Chelsea, Regeneron, Cypress, Savient, NicOx, Fidelity, Extera, and Antares Pharma Inc. BF is a shareholder of Pfizer and a consultant for Antares Pharma Inc., Celgene, and Bristol-Myers Squibb JJ is an employee of Antares Pharma Inc. Financial support: Antares Pharma Inc. University of Colorado, Denver, CO, USA; 2 SDG LLC Consulting, West Newton, MA, USA; 3 University of Pennsylvania, Philadelphia, PA, USA; 4 Antares Pharma Inc., Ewing, NJ, USA Background Methotrexate (MTX) is recognized as the anchor of therapy for rheumatoid arthritis (RA),2 Oral administration of MTX is common in the US, 3,4 but has some limitations: gastrointestinal (GI) absorption saturability may compromise bioavailability (BA), and GI intolerability may limit dosing -7 Parenteral administration of MTX has demonstrated efficacy 4,8- and tolerability advantages over oral administration in some RA patients 4,9- Dosing MTX for Rheumatoid Arthritis ACR recommends MTX as first-line therapy for RA MTX is commonly initiated with a starting dose of 7. to mg orally once weekly; may be increased to 2 2 mg Variability exists for prescribing MTX in clinical practice 2 A dose-response relationship is seen with lower oral doses of MTX, 3 higher oral doses ( mg once weekly) may not be more effective 4 Higher oral doses of MTX may lead to reduced GI tolerance 3 The odds ratio for reaching MTX > mg or >2 mg was 6-x higher with subcutaneous (SC) vs oral administration (P<.). Smolen JS, et al. Ann Rheum Dis. 2;69: Singh JA, et al. Arthritis Care Res. 22;64: Visser K, van der Heijde D. Ann Rheum Dis. 29;68: Wegrzyn J, et al. Ann Rheum Dis. 24; Hoekstra M, et al. J Rheumatol. 24;3: Godfrey C, et al. Br J Clin Pharmacol. 998;46: Hamilton RA, Kremer JM. Br J Rheumatol. 997;36: Braun J, et al. Arthritis Rheum. 28;8: Bakker MF, et al. Ann Rheum Dis. 2;69: Hameed B, et al. Int J Rheum Dis. 2;3:e Mainman H, et al. Clin Rheumatol. 2;29: American College of Rheumatology Visser K, van der Heijde D. Ann Rheum Dis. 29;68: Furst DE, et al. J Rheumatol. 989;6: Tian H, et al. Bull NYU Hosp Jt Dis. 27;6: Ng B, Chu A. Clin Rheumatol. 23 Aug.. Epub ahead of print. Study Objectives Primary end points Relative bioavailability of MTX measured by area under the curve (AUC) and maximum concentration (C max ) with the following: Oral vs SC MTX administered via an auto-injector (MTXAI) into the abdomen Oral vs administered into the thigh administered into the abdomen vs the thigh Secondary end points Time of peak concentration (t max ) Terminal half life (t /2 ) Safety and local tolerability of MTXAI Study Design Phase 2, randomized, multicenter, open-label, 3-way crossover study Dose levels: mg,, mg, 2 mg, 2 mg Routes: oral, MTXAI in the abdomen, MTXAI in the thigh Each patient was given dose of MTX via each route by site personnel Screening Treatment Follow-up Dose based on Predose and current MTX regimen postdose blood End-of-study visit and RA disease sampling status Randomize -week (n=49) (N=4) to treatment intervals sequence between (n=) treatments Up to day -3 to - Days &2, 8&9, &6 Day 2, up to day 23

2 AUC (ng h/ml) /27/23 Inclusion Criteria 8 years of age Diagnosed with adult RA and treated with MTX for 3 months Concomitant medications stable for 3 months before screening and continued throughout treatment No other serious medical conditions and not taking medication that was restricted or would interfere with outcome measurements Willing and able to give written informed consent, comply with the protocol, adhere to the study visit schedule and follow instructions Key Exclusion Criteria Pregnant or lactating females Aspartate aminotransferase, alanine aminotransferase, or bilirubin >3x the upper limit of normal at the first visit Chronic or acute renal disease History of malignancy or neoplastic disease Other clinically significant disease Acute illness within 7 days or major illness/hospitalization within month of study drug administration History or current evidence of alcohol abuse, chronic alcohol-induced disease, drug abuse, or use of substances known to affect MTX PK Statistical Analyses Patient Demographics Dose-normalized, logarithmically transformed C max and AUC values were compared with a mixed-model analysis Relative bioavailability (BA) comparisons were based on route and/or location of administration at each dose level with analysis of variance (ANOVA) Mean (SD) age at informed consent, y Women, n (%) mg (n=3) 62.9 (2.) (84.6) Methotrexate mg 63.4 (7.49) (4.7) 2 mg 6. (.4) 8 (66.7) 2 mg 9. (.3) 7 (8.3) Overall (N=49) 6.4 (.3) 3 (63.3) White, n (%) 2 (92.3) (9.7) (83.3) (9.7) 44 (89.9) Black, n (%) (7.7) (8.3) 2 (6.7) (8.3) (.2) Mean (SD) BMI, kg/m (7.64) 3. (.3) 3. (.4) 3.6 (7.43) 3.7 (6.39) BMI=body mass index Patient Baseline Disease Characteristics Mean (SD) duration of RA*, y ACR RA classification, n (%) mg (n=3) 3.9 (9.29) Methotrexate mg 4.4 (7.33) 2 mg.6 (8.76) 2 mg 3.4 (.32) Overall (N=49) 3.3 (8.78) Stage I 2 (.4) (.) (.) (8.3) 3 (6.) Stage II (38.) 6 (.) (9.7) 8 (66.7) 3 (6.2) Stage III 6 (46.2) (4.7) (8.3) 2 (6.7) 4 (28.6) Stage IV (.) (8.3) (.) (8.3) 2 (4.) Functional status, n (%) Class I (7.7) 2 (6.7) 2 (6.7) 2 (6.7) 7 (4.3) Class II 7 (3.8) 9 (7.) 9 (7.) 8 (66.7) 33 (67.3) Class III (38.) (8.3) (8.3) 2 (6.7) 9 (8.4) Class IV (.) (.) (.) (.) (.) *At informed consent. ACR=American College of Rheumatology; RA=rheumatoid arthritis Mean Exposure Plateaus at Doses mg (n=96, thigh + abdomen) MTX exposure with increases in a linear, dose-proportional manner Data shown are mean AUC -24 ± SE 2

3 /27/23 Ratio of Subcutaneous to Oral AUC inf by Dose Dose Ratio of LS Mean, % 9% CI, % Intrasubject CV, % MTX mg MTX mg MTX 2 mg MTX 2 mg AUC -inf =area under the concentration vs time curve from time to infinity; CV=coefficient of variation; LS=least squares Dose-Normalized Pharmacokinetic s Mean (SD) Mean (SD) AUC -inf, ng h/ml 9.47 (39.9) (46.477) C max, ng/ml (7.4967) (7.9) t max, h.388 (.8378).23 (.97) t /2, h 3.84 (.674) (.77) *Number of pharmacokinetic profiles analyzed. A total of 47 patients received all treatments and completed the study. AUC -inf =area under the concentration vs time curve from time to infinity; C max=maximum observed concentration; t /2=terminal half life; t max=time to maximum observed concentration provided consistently higher bioavailability vs oral administration C max, t max, and t /2 were similar regardless of route of administration ACR/ARHP Annual Meeting 3, San Diego, CA Safety Adverse events SAEs 2 N* Comments At least TEAE 3 Fatigue, nausea, RA Injection site reactions 2 Erythema, Grade fatal MI (study day 6): 79-year-old man with prior cardiac history ( 2 mg abdomen) Sick sinus syndrome (after trial concluded): 72-year-old man with history of CAD ( mg thigh) Conclusions SC administration at all dose levels achieved higher systemic exposure than the comparable oral dose SC MTX delivered with the auto-injector had a linear, doseproportional increase in exposure from -2 mg/week systemic exposure plateaued at doses mg The SC MTX auto-injector was generally safe and well tolerated *Number of patients. Excluding TEAEs classified as an SAE. Also led to discontinuation. CAD=coronary artery disease; MI=myocardial infarction; MTXAI=methotrexate auto-injector; SAE=serious adverse event; TEAE=treatment-emergent adverse event Acknowledgments Questions I would like to express my sincere thanks to the patients who participated in this study I would also like to thank the principal investigators who were involved in this study Principal investigators: Stephen A. Bookbinder, MD, Ocala, FL Alan J. Kivitz, MD, Duncansville, PA David A. McLain, MD, Birmingham, AL Joel C. Silverfield, MD, Tampa, FL ACR/ARHP Annual Meeting 3, San Diego, CA 3

4 AUC (ng h/ml) AUC (ng h/ml) AUC (ng h/ml) Concentration /27/23 Pharmacokinetic Data for Optimizing MTX Key pharmacokinetic (PK) parameters: Back-Up C max AUC t max Time C max = maximum concentration of drug in plasma t max = time required to reach C max AUC = area under the concentration-time curve Mean Exposure Plateaus at Doses mg (n=47, abdomen) (n=47, thigh) Mean Exposure Plateaus at Doses mg (n=47, abdomen) (n=47, thigh) MTX exposure with increases in a linear, dose-proportional manner Data shown are mean AUC -24 ± SE MTX exposure with increases in a linear, dose-proportional manner Data shown are mean AUC -24 ± SD Mean Exposure Plateaus at Doses mg Dose-Normalized Pharmacokinetic s Mean (SD) Mean (SD) CV% CV% (n=96, thigh + abdomen) AUC -inf, ng h/ml 9.47 (39.9) (46.477) C max, ng/ml (7.4967) (7.9) t max, h.388 (.8378).23 (.97) t /2, h 3.84 (.674) (.77) l z, L/h.88 (.333).84 (.33) MTX exposure with increases in a linear, dose-proportional manner Data shown are mean AUC -24 ± SD C max, t max, t /2 and l z were similar regardless of route of administration l z=apparent terminal rate constant; AUC -inf =area under the concentration vs time curve from time to infinity; auto-injector; SC=subcutaneous; t /2=terminal half life; t max=time to maximum observed concentration 4

5 AUC (mg/l hr) /27/23 Dose-Normalized Pharmacokinetic s AUC -inf, ng h/ml Mean Mean CV% CV% C max, ng/ml t max, h t /2, h l z, L/h l z=apparent terminal rate constant; AUC -inf =area under the concentration vs time curve from time to infinity; auto-injector; SC=subcutaneous; t /2=terminal half life; t max=time to maximum observed concentration Dose-Normalized Pharmacokinetic s Mean (SD) Mean (SD) CV% CV% AUC -inf, ng h/ml 9.47 (39.9) (46.477) C max, ng/ml (7.4967) (7.9) t max, h.388 (.8378).23 (.97) C max, t max, t /2 and l z were similar regardless of route of administration l z=apparent terminal rate constant; AUC -inf =area under the concentration vs time curve from time to infinity; auto-injector; SC=subcutaneous; t /2=terminal half life; t max=time to maximum observed concentration MTX Bioavailability Is Associated with Clinical Response in RA 4 RA patients Initiated on oral MTX monotherapy, initial dose mg/m 2, titrated on the basis of clinical response; followed for 2 weeks Steady-state area under the curve (AUC) was determined by linear trapezoidal rule (AUC TRAP ) and by best linear unbiased predictors (AUC BLUP ) Response to treatment was achievement of ACR2 P=.2 AUC BLUP P=.26 AUC TRAP Hornung N, et al. J Rheumatol. 28;3:79-7.