Altered GI absorption in special populations: An industry perspective

Transcription

1 Altered GI absorption in special populations: An industry perspective Cordula Stillhart and Neil J. Parrott F. Hoffmann La Roche Ltd, Basel (CH) UNGAP WG meeting, Leuven (B) 8 March 2018

2 Current challenges Roche approach Case example: Development in pediatric patients Case example: Development in oncology patients Concluding remarks

3 Current trends in the pharmaceutical industry Where do we come from... Blockbusters have been developed over decades (e.g., painkillers, penicillin, benzodiazepines, insulin,...) Drug development was focusing on broad applicability in large patient populations, regulatory acceptance and manufacturing costs Where are we going... Focus towards personalized medicine Smaller patient populations Accelerated development programs for promising compounds and indications with high unmet medical need New regulations introduced in US/EU in the last decade requesting clinical trials in specific populations (e.g. pediatrics) to ensure safety/efficacy 3

4 Biopharmaceutics in drug development Solubility logp Ionization Solid state Stability Dissolution rate Healthy adults vs. special patient populations? Permeability Physicochemical properties Supersaturation/precipitation Biorelevant dissolution testing Nonstandard in vitro assays IVIVC/ IVIVR PBPK models Physiology and anatomy of the GI tract Oral drug absorption Formulation properties Compatibility Disintegration Stability Release rate Influence of excipients Patient-centric administration 4

5 Drug development in special populations Current challenges Limited knowledge about specific GI tract physiology among different age groups and disease state Lack of in vitro and in silico models to simulate the anatomy and physiology of special populations Limited availability of clinical data Heterogenous populations (age-groups, co-medications, severity of disease, etc.) Particularly sensitive populations (pediatrics, geriatrics, critically ill patients) Prospective prediction of oral drug absorption is becoming increasingly important to ensure product safety/efficacy, de-risk and guide clinical strategy and formulation development. New methods and approaches are required. 5

6 Current challenges Roche approach Case example: Development in pediatric patients Case example: Development in oncology patients Concluding remarks

7 Drug development in special populations The Roche approach Mechanistic understanding of drug and formulation behavior in the GI tract based on standard/non-standard in vitro testing and oral absorption modelling (stageappropriate approach) Understanding differences in GI tract physiology between healthy adults and the targeted patient population based on current knowledge Predict potential differences in oral absorption behavior using PBPK modelling and in vitro testing (sensitivity analyses) Cross-functional approach (formulation, M&S, clinical pharmacology, pharmacometrics, DMPK, preclinical PK ) Retrospective analysis of clinical pharmacokinetics Increase confidence in new biopharmaceutics tools (e.g., pediatric PBPK models) 7

8 Drug development in special populations Use of PBPK modelling to study oral absorption in paediatric subjects 8

9 Current challenges Roche approach Case example: Development in pediatric patients Case example: Development in oncology patients Concluding remarks

10 Drug development in pediatric patients Case example Compound A Target population: children (>1M) and adults Molecular weight: <500 Formulation (development & market): Oral solution Ionization: weakly basic compound Solubility: ph-dependent logd: 2 ph 1.2: >15 mg/ml ph 6.5: <0.013 mg/ml Permeability: medium to high BCS: class 2 Stomach (ph ~2 ) High solubility Intestine (ph ~6.5) Solubility Supersaturation drug properties excipients drug concentration bile fluids permeability... Potential precipitation Low solubility / Slow re-dissolution Absorption

11 Drug development in pediatric patients Case example Compound A Phase 1 studies were conducted in healthy adult volunteers Pivotal Phase 2/3 studies included pediatric patients Ph 1 oral solution Oral solution used in pediatric studies (Ph 2/3) Is the absorption behavior in children expected to be different compared to adults? Do potential changes in the formulation affect the oral absorption of Compound A in adults and in children? 11

12 Mechanistic absorption model in adults Case example Compound A Development of a mechanistic absorption model in GastroPlus Verification against observed clinical in healthy adults (single ascending dose and food effect studies): PBPK model captures the rate and extent of absorption in healthy adults 12

13 Drug concentration profiles in adult GI tract Case example Compound A Evaluation of simulated concentration profiles in GI lumen in adults (highest dose): GastroPlus predicted complete solubilization of Compound A during GI transit (assuming 900 s precipitation time, default value) Permeation across the membrane appeared to be absorption-rate limiting Drug concentrations in the upper intestine significantly exceeded FaSSIF solubility (high level of supersaturation) Very stable supersaturation behavior of Compound A confirmed under simulated fasted state conditions (in vitro) model assumption is reasonable 13

14 Absorption behavior in children? Case example Compound A Adult vs. pediatric GI tract physiology [1]: - Gastric ph close to neutral in newborns, followed by a decrease to acidic values comparable to adults at 2 years - Reduced bile secretion in newborns (lower luminal concentrations) - Reduced volumes of GI fluids Do we expect a different absorption behavior in pediatric patients? [1] Batchelor et al. Eur J Pharm Biopharm 2013, 85,

15 Parameter sensitivity analysis in newborns Case example Compound A No significant impact of individual paramaters (precipitation time, permeability, dose volume, BS solubilization ratio, stomach/duodenum ph) on the total fraction absorbed 15

16 Simulated absorption in newborns Case example Compound A Default GastroPlus scaling with reduced bile salts concentration (newborn): GastroPlus model predicts some precipitation in the newborn intestine (using default precipitation time) Is Compound A expected to precipitate in the absence of bile salt micelles? 16

17 Impact of excipients Case example Compound A Oral solution containing poorly absorbed sugar alcohols as inactive ingredients Such excipients may reduce the small intestinal transit time (osmotic gradient) [1] The likelihood of changes in the oral absorption of Compound A due to the variation in the amount of sugar alcohols was therefore assessed via parameter sensitivity analysis [1] Adkin DA et al., Br J Clin Pharm 1995, 39(4), 381-7; Adkin DA et al. Pharm Res 1995, 12(3),

18 Clinical data in pediatric patients Case example Compound A Prospective prediction of the oral absorption behavior of Compound A based on in vitro data and PBPK modelling suggested that The risk of intraluminal drug precipitation in intestine in adults and children is very low Potential differences in GI tract physiology between adults and children are unlikely to affect oral exposure Formulation changes are unlikely to affect the rate and extent of absorption 7 months old infant Observed individual PK profile in clinical study 18

19 Current challenges Roche approach Case example: Development in pediatric patients Case example: Development in oncology patients Concluding remarks

20 Oral absorption in oncology patients Case example Alectinib Targert population: Adult oncology patients Molecular weight: <500 Formulation: Hard-gelatin capsule, 150 mg Ionization: Weakly basic compound (pka 7) Solubility: ph-dependent Buffer ph 2: 4.5 mg/ml FaSSIF ph 6.5: mg/ml FeSSIF ph 5: mg/ml logd: 1.96 at ph 3.6 Permeability: Medium to high (2.5 x 10-4 cm/s) BCS: Class 2 Parrott NJ et al., Physiologically based absorption modeling to explore the impact of food and gastric ph changes on the pharmacokinetics of Alectinib. The AAPS Journal 2016, 18(6). 20

21 Oral absorption in oncology patients Generally large pharmacokinetic variability across oncology patients Estimated intrasubject variability in absorption: 40 to >100% [1] Common sources of variability in absorption: Surgery, radiation, chemotherapy Nausea/vomiting Diet Genetic differences in intestinal drug metabolizing enzymes and drug transport systems Concomitant medications Patients undergoing cancer treatment frequently use acid-reducing agents (20-55%) [2] Understanding if acid suppression therapy leads to clinically significant decreases in drug exposure, and thus potential failure of the therapy, is particularly important for weakly basic oncology compounds [1] Undevia SD et al. Nat Rev Cancer, 2005, 5(6), ; [2] Budha NR et al. Clin Pharmacol Ther, 2012, 92(2),

22 Oral absorption in oncology patients Case example Alectinib Development of a PBPK model in GastroPlus based on physicochemical in vitro input data (ph-dependent solubility, FaSSIF/FeSSIF solubility, etc) Refinement of model based on clinical food effect PK data Prospective prediction of the effect of gastric ph elevation on Alectinib absorption Literature values used in GI physiology model [1,2]: Gastic ph Gastric emptying time (h) Fasted Fed Fasted Fed Without PPI With PPI [1] Tolman KG et al. J Clin Gastroenterol, 1997, 24(2):65-70 [2] Rasmussen L et al. Scand J Gastroenterol, 1999; 7:

23 Oral absorption in oncology patients Case example Alectinib Prospective simulations predicted no reduction of Alectinib exposures with PPI coadministration in either fasted or fed states Prediction was confirmed by clinical study results showing no clinically relevant effect of Esomeprazole co-administration on Alectinib exposure Slight increase in exposures (~20% for Cmax and AUC) is well matched by simulations when the gastric emptying time is increase to 1.8 h (default fed state value: 1 h) Absorption modelling was included in NDA submission to FDA. Reviewers concluded that no dose modification is recommended for patients taking Alectinib with an acidreducing agent 23

24 PBPK modelling in oncology patients PBPK information in product labels or US FDA review documents for drugs approved by the FDA between Jan 2013 and Aug 2016: Yoshida K et al. Impact of physiologically based pharmacokinetic models on regulatory reviews and product labels: Frequent utilization in the field of oncology. Clin Pharm Therap, 2017, 101(5) 24

25 PBPK modelling in oncology patients Establishment of a custom population profile representative for patients with cancer in SimCyp Demographic data from ~2500 patients with cancer Significant differences in age, hematocrit, albumin and AAG levels Higher Saquinavir exposure predicted in cancer patients compared to healthy subjects explained by altered drug binding due to elevated AAG levels 25

26 Current challenges Roche approach Case study 1: Development in pediatric patients Case study 2: Development in oncology patients Concluding remarks

27 Concluding remarks Considering specific GI tract physiology and absorption behavior in the targeted patient population is a key element of patient-centric drug development Providing well-described and optimized absorption models illustrating the mechanistic absorption behavior of new development compounds helps reviewers to reach decisions and reduce the need for «tick box» clinical studies in the future Development and verification of novel in vitro and in silico tools mimicking the biochemistry and physiology in the GI tract of special populations is required Need to generate more confidence in prospective prediction of oral absorption Collaboration between industry, academia, and regulatory bodies to address challenges in drug development in special populations Cross-functional collaboration (pharmaceutical, clinical, M&S, formulation scientists) Publication of case examples to increase knowledge and confidence in oral absorption and biopharmaceutical tools for special populations 27

28 Acknowledgements Neil J. Parrott Yumi Cleary Roche pred Biopharmaceutics Working Group Peter Kühl Heidemarie Kletzl Li J. Yu Ryusuke Takano Mikiko Nakamura Peter N. Morcos 28

29 Doing now what patients need next