Example for an early drug-device development plan

Transcription

1 Example for an early drug-device development plan Dr. Barbara Schug SocraTec R&D, Oberursel Joint Conference of European Human Pharmacological Societies and 20 th Anniversary of AGAH Berlin, Germany, March 31 April 01, 2011

2 Why early drug-device combinations? Potential reasons for early drug-device combinations intended local application for locally acting drugs intended drug targeting due to improved therapeutic effect when the site of action is difficult to reach improved tolerability when the side-effect pattern constrains regular use necessity to overcome drug substance limitations high first pass metabolism poor absorption due to solubility problems or molecule size

3 Locally acting / applied: ciclesonide Metered dose inhaler for treatment of asthma R-epimer Structural formula of ciclesonide A. Weinbrenner: J Clin Endo 87(5): , 2002

4 Locally acting / applied: ciclesonide Metered dose inhaler for treatment of asthma B Esterase B (M1) B (16-hydroxyprednislone) CYP3A4 CYP2D6 CYP3A4 CYP2D6 CYP3A4 CYP2C8 M2 M3 family anidentified metabolites Proposed metabolic pathway of ciclesonide R-epimer CYP3A4 CYP2C8 RM1 has approximately 100-fold greater affinity for glucocorticoid receptor CDER Document: Application Number:

5 Questions answered for ciclesonide (1) Pharmacokinetic development program of ciclesonide with assessment of absolute oral bioavailability absolute inhaled bioavailability single dose (inhaled) dose proportionality ( µg) in healthy subjects and asthmatics steady state (inhaled) dose proportionality ( µg)

6 Absolute oral bioavailability Contribution of swallowed ciclesonide to be assessed primarily for safety reasons single dose administrations 6.9mg (oral) vs 0.64mg (i.v.) [ 14 c] ciclesonide separated by wash-out phase of 14 days 6 healthy male subjects aged 19 to 40 years assessment of total radioactivity and of ciclesonide and RM1 in whole blood, plasma, urine and faeces

7 Study results Absolute oral bioavailability after oral administration the parent compound was not detectable in plasma only traces of RM1 were determined resulting oral bioavailability below 1% for the parent compound conclusion: swallowed ciclesonide of minor importance ciclesonide < 1% budesonide 10.7% fluticasone 1%

8 Absolute oral bioavailability Due to poor systemic availability evaluation focuses on urine and faeces data Fig 2. Cumulative excretion of radioactivity in urine and faeces after administration of 0.64mg of [ 14 C]ciclesonide as a 10-minute intravenous infusion (IV) or 6.9mg of [ 14 C]ciclesonide as an oral capsule (PO). Values are means ± standard error. Nave R. et al: Int J Clin Pharm (2006), 1-7

9 Oral systemic availability Conclusions from study results in contrast to orally administered drugs with intended systemic availability, exposure after administration of such a drug-device combination for locally acting / locally applied drugs is only of relevance for the swallowed fraction thus, absolute bioavailability after oral administration in this case is assessed for safety reasons only absolute bioavailability after inhaled administration is also determined for safety reasons

10 Questions answered for ciclesonide (2) Clinical pharmacology development program of ciclesonide with assessment of absolute oral bioavailability (safety) absolute inhaled bioavailability (safety) single dose (inhaled) dose proportionality ( µg) steady state (inhaled) dose proportionality ( µg) PK in asthmatics and healthy subjects PK in adults, children, male, female, whites, Japanese, black, elderly, patients with renal or hepatic impairment

11 PK after inhalation patients? Comparison healthy vs. asthmatics underlying disease influences site of absorption (obstruction and inflammation) PK may be different in patient population Target population is a special PK population per definition Parallel group study performed for ciclesonide 12 patients with persistent asthma were matched with 12 healthy subjects (sex, age, BMI) single inhaled dose of 1280µg (8 puffs)

12 PK after inhalation Primary parameter: AUC of des-cic ( ) R. Nave: Clin Pharm 43 (7): , 2004 Fig 1. Mean ± standard error of the mean serum concentrations of ciclesonide and desisobutyril ciclesonide in healthy subjects and patients with asthma after receiving a single inhaled dose of ciclesonide 1,280 µg.

13 Questions answered for ciclesonide (3) Clinical pharmacology development program of ciclesonide with assessment of classical drug-drug interaction studies with erythromycin, ketoconazole and formoterol single dose lung deposition with 99m Tc-labeled ciclesonide in adults with moderate asthma single dose lung deposition with 99m Tc-labeled ciclesonide in healthy volunteers

14 Lung-deposition Local Pharmacokinetics to be assessed in addition 99m Tc-labeled ciclesonide administered to healthy subjects and asthmatics assessment of percent deposition in mouth and pharynx assessment of percent deposition in the lung characterisation of deposition pattern for peripheral and lower central regions of lung

15 Lung-deposition: efficacy Deposition in healthy subjects mouth/ pharynx: 38% ± 14% lung: 52% ± 11% central: 17% / 30% peripheral: 47% / 34% 2Dimaging 3D- SPECT Fig 3. Representative two-dimensional lung deposition pattern of 99m Tc ciclesonide-hydrofluoroalkane (HFA) in a healthy male volunteer. C. Leach: J Aero Medi 19(2): , 2006

16 Questions answered for ciclesonide (4) Cortisol suppression as safety marker HPA-axis suppression determined in adults 12 healthy male volunteers 4-period-changeover design over 7 days each 800 µg morning administration 800 µg evening administration 400 µg BID comparison with placebo Hypothalamic-Pituitary-Adrenocortical-axis suppression also assessed in asthmatic children

17 Influence on HPA-axis Cortisol suppression as safety marker primary endpoints (cortisol in serum) 24h mesor (AUC (0-24h) / 24h) 24h amplitude (1/2 Δ max / min) acceptance criterion: % assay: fluorescence polarisation immunoassay study results (PE in comparison to placebo) Dose Ratio / Confidence interval morning dose 800µg 0.94 / evening dose 800µg 0.98 / BID 400µg 0.93 / A. Weinbrenner: J Clin Endo 87(5): , 2002

18 Cortisol suppression: safety Fig 2. Mean 24-h profiles of serum cortisol of 12 healthy volunteers treated for 7 d with (A) placebo twice daily, (B) 800 µg ciclesonide in the morning and placebo in the evening, (C) 800 µg ciclesonide in evening and placebo in the morning, and (D) 400 µg ciclesonide in the morning and 400 µg ciclesonide in the evening in a randomized, double-blind, changeover, equivalence study with at least 7 d wash-out. A. Weinbrenner: J Clin Endo 87(5): , 2002

19 Deficiency letter for HPA-axis in children Comments to sponsor referring to study in children with mild persistent asthma more than 40% of the subjects included had a 24hurine volume < 250ml analytical method for cortisol in urine showed no adequate validation patient compliance could not be a assured new study requested with children aged 4-11 y 24h urine cortisol and 24h serum cortisol CDER Document: Application Number:

20 Summary ciclesonide (1) Early development plan major steps classical pharmacokinetic program, but primarily for safety reasons underlying disease interferes with site of absorption bridging study healthy vs. patients necessary characterisation of site-of-action deposition in addition to systemic availability needed 99m Tc-marker lung deposition study needed established PD-model for safety assessment commonly required HPA-axis study regulatory requirement CDER Document: Application Number: Deficiency letter refers to basic methodological issues

21 Summary ciclesonide (2) Development plan strongly influenced by site of action ciclesonide has also been developed as nasal formulation ( seasonal allergic rhinitis ) with (different) study package necessary systemic availability (safety reasons) influence of underlying disease not characterised deposition at site of action commonly not assessed but local tolerability metabolism in human epithelial cells for activation of the pro-drug needed (and assessed in cell cultures) SMPC Nycomed: Interactions with food have not been assessed and are unlikely with nasal corticosteroids Product monograph Omnaris, Nycomed Canada

22 rhbmp-2 for bone tissue induction Recombinant human bone morphogenetic protein treatment of acute, open tibial shaft fractures stabilized with intramedullary nail fixation after appropriate wound management within 14 days after the initial fracture patients must be skeletally mature above 18 years radiographic evidence of epiphyseal closure no active infection at the operative site INFUSE bone graft induces new bone tissue at the site of implantation Summary of safety and efficacy data, INFUSE bone graft, Whyeth Pharmaceutical Inc., Pennsylvania

23 rhbmp 2: therapeutic principle rhbmp-2 as active moiety disulfide linked dimeric protein two major subunit species of 114 and 131 amino acids each subunit glycosylated with high mannose type glycans produced by genetically engineered Chinese hamster ovary cell line lyophilised drug + excipients for reconstitution solution applied to absorbable collagen sponge placed to bone within 15min after preparation Need for local, but not systemic availability

24 rhbmp 2: absorbable collagen sponge

25 rhbmp-2 / ACS pre-clinical tests Animal studies no mortality / no systemic toxicity no evidence for carcinogenicity / genotoxicity no intracutanous toxicity / no dermal irritation no delayed skin sensitization no cell lysis (cytotoxicity tests) no hemolysis / no cellular mutagenicity hard, granular formation in muscle irritation test single/ multiple dose general toxicity studies after intravenous administration no treatment related toxicity no disseminated bone formation when systemically applied potent bone inducing activity only at implantation site

26 rh BMP-2: PK in animals Studies with iv-administration and implantation rapid uptake in highly perfused tissues extensive metabolism rapid renal excretion rapid elimination from systemic circulation f ½ (rat) : 16 min f ½ (primates) : 6.7 min local retention of rh BMP-2 / ACS Several / comprehensive pre-clinical trials conducted

27 rh BMP-2: PK in animals Retention and clearance from systemic circulation: iv administration (left) and after implantation (right) Presentation Gerard Riedel, Wyeth-Genetics Institute

28 rhbmp-2: clinical trials Summary of clinical trials safety / effectiveness in patient population 150 subjects per treatment group ( 2 doses of rhbmp-2 vs. control) follow-up: 12 months after wound closure clinical endpoint: fracture healing testing for antibodies (9 / 149) antibody formation depends on location of implantation No further studies in human for initial submission

29 rhbmp-2: deficiency letter Additional investigations requested Centre for Devices and radiological health at FDA in-vitro investigations tumor promotion rabbit studies - embryonic development better in-vitro release characterisation training plan for surgeons requested No further prospective clinical trials requested!

30 Summary: rhbmp-2 (Pre-)Clinical development plan comprehensive in vitro tests comprehensive animal tests 1 clinical trial with a total of 2*150 patients with efficacy and safety assessments Additional post-approval studies to be performed for characterisation of immunological response

31 Rotigotine: dopamine receptor agonist structural similarity with dopamine (also) high first-pass metabolism oral administration not meaningful Initial development as transdermal therapeutic system Pfeiffer RF, Neurology 2005,

32 Rotigotine development program Summary of study designs sequential repeated measurement design with increasing i.v. doses in PK/PD trial (patients) dose finding done with i.v. administration titration against the L-dopa dose needed ADME with i.v. administration in healthy subjects early characterisation of absorption site abdomen flank upper arm shoulder thigh hip CDER Document: Application Number: All absorption sites demonstrate adequate systemic availability

33 PK characterisation of rotigotine Classical PK-program due to systemic action after patch administration single dose multiple dose drug-drug interactions special populations different patches: bioavailability / bioequivalence

34 Summary: rotigotine Relevant aspects of the clinical development program systemic availability is prerequisite for efficacy i.v. administration for proof-of-concept study and early dose finding transdermal administration to overcome first-pass metabolism classical PK program classical PD program characterisation of route of administration incl. influence of body area used for application

35 Conclusion: early drug-device Development program strongly depends on necessity of systemic availability Systemic availability means high similarity to classical development programs with additional assessment of specific influence of device Locally acting means comprehensive evaluation of application site and systemic exposure Program also depends on classification drug-device-combination vs medical device No cookery book approach playing field for human pharmacology instead

36 Many thanks to Dr. Ramón Villalobos Hernández, SocraTec R&D Katrin Jäger, SocraTec R&D