Bioavailability trial design for products delivered via the inhalation route

Transcription

1 Bioavailability trial design for products delivered via the inhalation route Jianmeng Chen, Suresh Doddapaneni, Ping Ji, Chandrahas G Sahajwalla Division of Clinical Pharmacology 2 US FDA/CDER/OTS/OCP 1

2 Disclaimer The opinions and views expressed in this presentation are my own and do not reflect US Food and Drug Administration policy or official guidance. 2

3 Overview PK study for NME inhalation product PK study for 505b2/product changes PK study for generic inhalation product PK study for pediatric development 3

4 Locally acting, inhaled drug products Local delivery: efficacy Systemic exposure: systemic safety GI absorption Lung absorption 4

5 Overview PK study for NME inhalation product PK study for 505b2/product changes PK study for generic inhalation product PK study for pediatric development 5

6 General clinical pharmacology requirements for NMEs as inhalation products Clinical Pharmacology First-in-Human SAD and MAD PK Studies Healthy vs. Patient population ADME (Mass Balance) Specific Populations Renal Impairment Hepatic Impairment Age, gender, etc. Pediatrics Drug Interactions Population PK Biomarkers (optional) Pharmacogenomics (optional) Special Safety (e.g., TQTc study) Exposure-response (PK/PD) Safety Biopharmaceutics Bioavailability/Bioequivalence (BA/BE) Food Effect (not required if no significant GI absorption) In Vitro Studies Protein Binding Blood to Plasma Partitioning In vitro drug metabolism, transport and drug interactions Bioanalytical Methods Assay Validation & Performance Reports 6

7 Special concerns for inhalation products Assay sensitivity Supra-therapeutic Dose (specific population, DDI) Multiple dose Dosing technique Bridge for final device/formulation 7

8 Supra-therapeutic dose in DDI study: BREO ELLIPTA Therapeutic dose: FF/VI 100/25 and 200/25 mcg DDI study: FF/VI 800/100 Linear PK Reasonable safety Final formulation /device Kempsford R, et al. Clinical pharmacology in Drug Development 2015, 4(1) 8

9 Inhalation PK with charcoal block: not a regulatory requirement Administration of activated charcoal with some inhaled drugs can block the absorption from GIT Systemic drug concentrations with charcoal block represent absorption via respiratory tract Useful in comparing relative dose delivery to lung from different formulations Does not discriminate potentially important product differences Regional lung deposition (delivery to relevant biospace) Oropharyngeal deposition 9

10 Inhalation PK with charcoal block: Potential label language.., primarily due to absorption of the inhaled portion of the dose delivered to the lung. 10

11 Exposure response analysis for inhalation products Efficacy Topical vs. systemic effect studies, where applicable and specific topical claim is sought Safety HPA axis QT, HR 11

12 Exposure response for efficacy Drug X has the following PK profile [C] 0 24h Time (h) Inhalation IV Clinical study is still required to establish dose frequency before phase 3 Half life may be listed in the label as PK facts, but not speculations on efficacy The terminal half life is 20 hours. x.,indicating slow release from the lung 12

13 Exposure response for efficacy Drug X (an ICS) has the following PK profile [C] 0 24h Time (h) Inhalation oral Proposed to use in asthma as inhalation drug Should prove the efficacy is not due to the systemic exposure to corticosteroid 13

14 Overview PK study for NME inhalation product PK study for 505b2/product changes PK study for generic inhalation product PK study for pediatric development 14

15 Bridge different product based on systemic PK studies for locally acting, orally inhaled drug products For locally acting inhalation drugs, PK bridging trials can only be used to extrapolate systemic safety. Local safety, efficacy, and dose selection cannot be established using a PK bridging trial(s) alone, although a bridging approach may be useful in establishing a starting point for further dose ranging trials. 15

16 PK study design for bridging purpose Healthy subjects or patients Single dose, cross-over Adequate assay sensitivity and PK sampling (supra-therapeutic dose if necessary) Comparable or less systemic exposure 16

17 Overview PK study for NME inhalation product PK study for 505b2/product changes PK study for generic inhalation product PK study for pediatric development 17

18 Generic drug for inhalation products In vitro studies PK BE Study Clinical Endpoint Study Fasting Single-dose, two-way cross over Dose: sufficient to characterize PK Subjects: healthy Equivalence: % 18

19 Overview PK study for NME inhalation product PK study for 505b2/product changes PK study for generic inhalation product PK study for pediatric development 19

20 PK study for pediatric patients Efficacy cannot be extrapolated based on systemic PK Safety cannot be extrapolated from adult data No extrapolation from adult based on PK 20

21 PK study for pediatric patients Systemic exposure may help to define a start dose in the dose ranging study Safety can be extrapolated from pediatric safety data of another product, based on systemic exposure Systemic safety information Extrapolation based on systemic PK 21

22 Pediatric PK study design Not in Healthy subjects If the study is for systemic safety bridging, use the highest dose Instruction on inhalation technique 22

23 Questions? 23