Usefulness of the Beagle Model in the Evaluation of Paracetamol and Ibuprofen Exposure after Oral Administration to Pediatric Populations:An Exploratory Study

The present study aimed to explore the usefulness of beagle dogs in combination with physiologically based pharmacokinetic (PBPK) modeling in the evaluation of drug exposure after oral administration to pediatric populations at an early stage of pharmaceutical product development. An exploratory, single-dose, crossover bioavailability study in six beagles was performed. A paracetamol suspension and an ibuprofen suspension were coadministered in the fasted-state conditions, under reference-meal fed-state conditions, and under infant-formula fed-state conditions. PBPK models developed with GastroPlus v9.7 were used to inform the extrapolation of beagle data to human infants and children. Beagle-based simulation outcomes were compared with published human-adult-based simulations. For paracetamol, fasted-state conditions and reference-meal fed-state conditions in beagles appeared to provide adequate information for the applied scaling approach. Fasted-state and/or reference-meal fed-state conditions in beagles appeared suitable to simulate the performance of ibuprofen suspension in pediatric populations. Contrary to human-adult-based translations, extrapolations based on beagle data collected under infant-formula fed-state conditions appeared less useful for informing simulations of plasma levels in pediatric populations. Beagle data collected under fasted and/or reference-meal fed-state conditions appeared to be useful in the investigation of pediatric product performance of the two investigated highly permeable and highly soluble drugs in the upper small intestine. The suitability of the beagle as a preclinical model to understand pediatric drug product performance under different dosing conditions deserves further evaluation with a broader spectrum of drugs and drug products and comparisons with pediatric in vivo data.</p

On the Design of Food Effect Studies in Adults for Extrapolating Oral Drug Absorption Data to Infants:an Exploratory Study Highlighting the Importance of Infant Food

In the present investigation, it was explored whether food effect on drug absorption in adults is similar with the food effect after administration of an infant meal with the drug product to adults. After confirming lack of pharmaceutical and pharmacokinetic interaction, a paracetamol suspension and an ibuprofen suspension were co-administered to eight healthy adults on a crossover basis in three different occasions, i.e. in the fasted state (as defined by regulatory agencies, fasted conditions), in the fed state (as defined by regulatory agencies, fed conditions) and under conditions simulating the fed state in infants (infant fed conditions). Unlike under fed conditions, under infant fed conditions early exposure was significantly lower than under fasted conditions for both paracetamol and ibuprofen. Also, for ibuprofen, Cmax values under infant fed conditions were significantly higher than under fed conditions. These data suggest that, even for drugs with non-problematic absorption administered in simple dosage forms, food effects in infants may not be adequately evaluated if the protocol suggested by regulatory agencies is applied. The usefulness of the methodology employed in the present investigation for simulating the fed state in infants deserves further evaluation. Until then, food effects in infants should be considered cautiously or be evaluated in infants.</p

Factors affecting successful extrapolation of ibuprofen exposure from adults to paediatric populations after oral administration of a paediatric aqueous suspension

The importance of physiologically based pharmacokinetic (PBPK) model refinement for adults with data acquired in adults using a paediatric formulation under age-relevant dosing conditions in order to extrapolate drug exposure to infants was recently demonstrated for paracetamol. In the present investigation the aim was to expand the use of PBPK modeling informed by bioavailability data collected in healthy adults under different dosing conditions for a low solubility weak acid, ibuprofen, to simulate exposure across paediatric populations, i.e., infants, pre-school children, and schoolchildren. After developing and evaluating an adult disposition and oral absorption model for the aqueous suspension of ibuprofen, ibuprofen performance was extrapolated to paediatrics simulating exposure as a function of different prandial and dosing conditions: fasted conditions, reference-meal-fed conditions (solid-liquid meal), and infant-formula-fed conditions (homogeneous liquid). Successful predictions were achieved when employing the refined model for fasted or by applying appropriate fed conditions for different age groups, i.e., infant formula for infants and reference meal for children. The present study suggested that ibuprofen performance was primarily guided by gastric emptying events and showed sensitivity towards formulation characteristics and pH changes in the small intestine. Better understanding of luminal conditions’ changes in paediatrics and age-dependent ibuprofen post-absorptive processes could improve modeling confidence for ibuprofen, as well as other drugs with similar properties

On the design of food effect studies in adults for extrapolating oral drug absorption data to infants: An exploratory study highlighting the importance of infant food

In the present investigation, it was explored whether food effect on drug absorption in adults is similar with the food effect after administration of an infant meal with the drug product to adults. After confirming lack of pharmaceutical and pharmacokinetic interaction, a paracetamol suspension and an ibuprofen suspension were co-administered to eight healthy adults on a crossover basis in three different occasions, i.e. in the fasted state (as defined by regulatory agencies, fasted conditions), in the fed state (as defined by regulatory agencies, fed conditions) and under conditions simulating the fed state in infants (infant fed conditions). Unlike under fed conditions, under infant fed conditions early exposure was significantly lower than under fasted conditions for both paracetamol and ibuprofen. For ibuprofen, Cmax values under infant fed conditions were also significantly higher than under fed conditions. These data suggest that, even for drugs with non-problematic absorption administered in simple dosage forms, food effects in infants may not be adequately evaluated if the protocol suggested by regulatory agencies is applied. The usefulness of the methodology employed in the present investigation for simulating the fed state in infants deserves further evaluation. Until then, food effects in infants should be considered cautiously or be evaluated in infants

Biopharmaceutical considerations in paediatrics with a view to the evaluation of orally administered drug products – a PEARRL review

Objective In this review, the current biopharmaceutical approaches for evaluation of oral formulation performance in paediatrics are discussed. Key findings The paediatric gastrointestinal (GI) tract undergoes numerous morphological and physiological changes throughout its development and growth. Some physiological parameters are yet to be investigated, limiting the use of the existing in vitro biopharmaceutical tools to predict the in vivo performance of paediatric formulations. Meals and frequencies of their administration evolve during childhood and affect oral drug absorption. Furthermore, the establishment of a paediatric Biopharmaceutics Classification System (pBCS), based on the adult Biopharmaceutics Classification System (BCS), requires criteria adjustments. The usefulness of computational simulation and modeling for extrapolation of adult data to paediatrics has been confirmed as a tool for predicting drug formulation performance. Despite the great number of successful physiologically based pharmacokinetic models to simulate drug disposition, the simulation of drug absorption from the GI tract is a complicating issue in paediatric populations. Summary The biopharmaceutics tools for investigation of oral drug absorption in paediatrics need further development, refinement and validation. A combination of in vitro and in silico methods could compensate for the uncertainties accompanying each method on its own

The mechanisms of pharmacokinetic food-drug interactions - A perspective from the UNGAP group

The simultaneous intake of food and drugs can have a strong impact on drug release, absorption, distribution, metabolism and/or elimination and consequently, on the efficacy and safety of pharmacotherapy. As such, food-drug interactions are one of the main challenges in oral drug administration. Whereas pharmacokinetic (PK) food-drug interactions can have a variety of causes, pharmacodynamic (PD) food-drug interactions occur due to specific pharmacological interactions between a drug and particular drinks or food. In recent years, extensive efforts were made to elucidate the mechanisms that drive pharmacokinetic food-drug interactions. Their occurrence depends mainly on the properties of the drug substance, the formulation and a multitude of physiological factors. Every intake of food or drink changes the physiological conditions in the human gastrointestinal tract. Therefore, a precise understanding of how different foods and drinks affect the processes of drug absorption, distribution, metabolism and/or elimination as well as formulation performance is important in order to be able to predict and avoid such interactions. Furthermore, it must be considered that beverages such as milk, grapefruit juice and alcohol can also lead to specific food-drug interactions. In this regard, the growing use of food supplements and functional food requires urgent attention in oral pharmacotherapy. Recently, a new consortium in Understanding Gastrointestinal Absorption-related Processes (UNGAP) was established through COST, a funding organisation of the European Union supporting translational research across Europe. In this review of the UNGAP Working group "Food-Drug Interface", the different mechanisms that can lead to pharmacokinetic food-drug interactions are discussed and summarised from different expert perspectives

The mechanisms of pharmacokinetic food-drug interactions: A perspective from the UNGAP group

The simultaneous intake of food and drugs can have a strong impact on drug release, absorption, distribution, metabolism and/or elimination and consequently, on the efficacy and safety of pharmacotherapy. As such, food-drug interactions are one of the main challenges in oral drug administration. Whereas pharmacokinetic (PK) food-drug interactions can have a variety of causes, pharmacodynamic (PD) food-drug interactions occur due to specific pharmacological interactions between a drug and particular drinks or food. In recent years, extensive efforts were made to elucidate the mechanisms that drive pharmacokinetic food-drug interactions. Their occurrence depends mainly on the properties of the drug substance, the formulation and a multitude of physiological factors. Every intake of food or drink changes the physiological conditions in the human gastrointestinal tract. Therefore, a precise understanding of how different foods and drinks affect the processes of drug absorption, distribution, metabolism and/or elimination as well as formulation performance is important in order to be able to predict and avoid such interactions. Furthermore, it must be considered that beverages such as milk, grapefruit juice and alcohol can also lead to specific food-drug interactions. In this regard, the growing use of food supplements and functional food requires urgent attention in oral pharmacotherapy. Recently, a new consortium in Understanding Gastrointestinal Absorption-related Processes (UNGAP) was established through COST, a funding organisation of the European Union supporting translational research across Europe. In this review of the UNGAP Working group "Food-Drug Interface", the different mechanisms that can lead to pharmacokinetic food-drug interactions are discussed and summarised from different expert perspective

Biopharmaceutical considerations in paediatrics with a view to the evaluation of orally administered drug products – a PEARRL review.

Objectives: In this review, the current biopharmaceutical approaches for evaluation of oral formulation performance in paediatrics are discussed. Key findings: The paediatric gastrointestinal (GI) tract undergoes numerous morphological and physiological changes throughout its development and growth. Some physiological parameters are yet to be investigated, limiting the use of the existing in vitro biopharmaceutical tools to predict the in vivo performance of paediatric formulations. Meals and frequencies of their administration evolve during childhood and affect oral drug absorption. Furthermore, the establishment of a paediatric Biopharmaceutics Classification System (pBCS), based on the adult Biopharmaceutics Classification System (BCS), requires criteria adjustments. The usefulness of computational simulation and modeling for extrapolation of adult data to paediatrics has been confirmed as a tool for predicting drug formulation performance. Despite the great number of successful physiologically based pharmacokinetic models to simulate drug disposition, the simulation of drug absorption from the GI tract is a complicating issue in paediatric populations. Summary: The biopharmaceutics tools for investigation of oral drug absorption in paediatrics need further development, refinement and validation. A combination of in vitro and in silico methods could compensate for the uncertainties accompanying each method on its own

Developing new in vivo and in silico methodologies to predict performance of paediatric formulations

Η επέκταση της άδειας κυκλοφορίας φαρμάκων για παιδικούς ασθενείς αποτελεί σημαντικό στάδιο κατά τη διαδικασία ανάπτυξης φαρμακευτικών προϊόντων. Θέματα βιοηθικής περιορίζουν τις κλινικές δοκιμές σε παιδιά και τα δεδομένα που συλλέγονται από μελέτες βιοδιαθεσιμότητας και μελέτες επίδρασης τροφής σε ενήλικες συχνά χρησιμοποιούνται ως προέκταση για τους παιδικούς (υπο)πληθυσμούς. Τα ζωικά μοντέλα θα μπορούσαν να προσφέρουν μια εναλλακτική προσέγγιση για την αξιολόγηση φαρμακευτικών προϊόντων που προορίζονται για παιδικούς ασθενείς. Πρόσφατα, μία οδηγία που εκδόθηκε από τον Αμερικάνικο Οργανισμό Τροφίμων και Φαρμάκων προτείνει τη χρήση γευμάτων ανάλογα με την παιδική ηλικιακή ομάδα που στοχεύει το υπό ανάπτυξη προϊόν, π.χ. βρεφικό γάλα για ηλικιακές ομάδες που διατρέφονται κυρίως με γάλα όπως τα βρέφη και τα προνήπια, χωρίς όμως να προσδιορίζει τους ακριβείς όγκους και τις συνθήκες χορήγησης. Οι στόχοι της παρούσας μελέτης ήταν: • Ο σχεδιασμός μιας διερευνητικής κλινικής μελέτης για την εκτίμηση της επίδρασης της τροφής στην απορρόφηση φαρμάκων σε ενήλικες μετά από τη χορήγηση του γεύματος που χρησιμοποιείται για να επάγει την περίοδο πέψης στις μελέτες βιοδιαθεσιμότητας/βιοϊσοδυναμίας (πρότυπο γεύμα) σε σχέση με τη χορήγηση βρεφικού γάλακτος. • Η ανάπτυξη και η αξιολόγηση φυσιολογικών φαρμακοκινητικών μοντέλων για την περιγραφή της συμπεριφοράς των φαρμάκων σε ενήλικες και η προέκταση αυτών των μοντέλων στην πρόβλεψη της συμπεριφοράς των φαρμάκων σε βρέφη και παιδιά λαμβάνοντας υπόψη τις διαφορές στις συνθήκες χορήγησης. • Ο σχεδιασμός μιας μελέτης σε σκύλους για τη διερεύνηση της χρησιμότητας του μοντέλου του σκύλου σε συνδυασμό με φυσιολογικά φαρμακοκινητικά μοντέλα στην αξιολόγηση per os χορηγούμενων παιδικών φαρμακευτικών προϊόντων και σύγκριση της χρησιμότητας αυτών των δεδομένων σε σχέση με τα δεδομένα από την κλινική μελέτη. Οκτώ υγιείς ενήλικοι άνδρες εθελοντές συμμετείχαν σε μια τυχαιοποιημένη, απλής δόσης, τριών φάσεων, διασταυρωτή μελέτη. Εναιώρημα παρακεταμόλης και εναιώρημα ιβουπροφαίνης συγχορηγήθηκαν σε τρεις διαφορετικές συνθήκες: στη διαπεπτική περίοδο και στην περίοδο πέψης, όπως ορίζονται από τις κανονιστικές αρχές και υπό συνθήκες που προσομοιώνουν την περίοδο πέψης σε βρέφη (συγχορήγηση των φαρμάκων με βρεφικό γάλα). Παρόμοιες συνθήκες εφαρμόστηκαν στο σχεδιασμό μιας διερευνητικής μελέτης βιοδιαθεσιμότητας σε έξι Beagle σκύλους. Για τη μοντελοποίηση των φαρμακοκινητικών δεδομένων που συλλέχθηκαν από ενήλικες και σκύλους αναπτύχθηκαν φυσιολογικά φαρμακοκινητικά μοντέλα και διερευνήθηκε η χρησιμότητά τους στην πρόβλεψη της συμπεριφοράς των φαρμάκων σε βρέφη και παιδιά χρησιμοποιώντας τα δεδομένα από τις διαφορετικές συνθήκες χορήγησης κάθε μελέτης. Η ανάπτυξη των μοντέλων πραγματοποιήθηκε χρησιμοποιώντας το λογισμικό GastroPlus ™ V9.7. Η χρησιμότητα των μοντέλων που αναπτύχθηκαν για την πρόβλεψη των συγκεντρώσεων στο αίμα σε βρέφη και παιδιά αξιολογήθηκε χρησιμοποιώντας δεδομένα από τη βιβλιογραφία μετά από per os χορήγηση της παρακεταμόλης και της ιβουπροφαίνης σε ηλικιακές ομάδες των 2 μηνών έως 12 ετών. Στους ενήλικες, τόσο για την παρακεταμόλη όσο και για την ιβουπροφαίνη, η απορρόφηση ήταν σημαντικά χαμηλότερη στις συνθήκες πέψης μετά από τη χορήγηση του φαρμάκου με βρεφικό γάλα από ότι στη διαπεπτική περίοδο για τουλάχιστον 3 ώρες μετά τη χορήγηση του φαρμάκου, σε αντίθεση με τις συνθήκες πέψης με πρότυπο γεύμα. Για την παρακεταμόλη, επιτυχείς προσομοιώσεις των επιπέδων συγκέντρωσης στο πλάσμα στα βρέφη επιτεύχθηκαν μετά την προέκταση των δεδομένων της διαπεπτικής περιόδου και των συνθηκών πέψης με βρεφικό γάλα σε υγιείς ενήλικες. Για την ιβουπροφαίνη, επιτυχείς προβλέψεις επιτεύχθηκαν με τη χρήση του μοντέλου που βασίζεται σε δεδομένα που συλλέχθηκαν από ενήλικες κατά τη διαπεπτική περίοδο ή χρησιμοποιώντας δεδομένα από τις συνθήκες πέψης ανάλογα με τις υπό εξέταση ηλικιακές ομάδες, δηλαδή, βρεφικό γάλα για βρέφη και πρότυπο γεύμα για παιδιά. Για την παρακεταμόλη και για την ιβουπροφαίνη, τα δεδομένα που συλλέχθηκαν από τους σκύλους κατά τη διαπεπτική περίοδο και την περίοδο πέψης μετά τη χορήγηση βρεφικού γάλακτος χρησιμοποιήθηκαν με επιτυχία στην ανάπτυξη των φυσιολογικών φαρμακοκινητικών μοντέλων και στην προέκτασή τους στην πρόβλεψη των επιπέδων στο αίμα για τις ηλικιακές ομάδες των βρεφών και των παιδιών. Παρά τις διαφορές που παρατηρούνται στα αποτελέσματα με τη χρήση των μοντέλων που βασίζονται σε δεδομένα που έχουν συλλεγεί από υγιείς ενήλικες και από σκύλους, το μοντέλο που βασίζεται στους σκύλους φαίνεται κατάλληλο για την αρχική αξιολόγηση παιδικών φαρμακευτικών προϊόντων στα στάδια της ανάπτυξης φαρμάκων, όταν χρησιμοποιούνται δεδομένα από τη διαπεπτική περίοδο ή/και μετά τη χορήγηση του πρότυπου γεύματος. Τα δεδομένα από την παρούσα κλινική μελέτη υποδεικνύουν ότι, ακόμη και για φάρμακα με μη προβληματική απορρόφηση που χορηγούνται σε απλές μορφές, η αξιολόγηση της επίδραση της τροφής στα βρέφη μπορεί να μην είναι επαρκής όταν εφαρμόζεται το πρωτόκολλο που προτείνουν οι κανονιστικές αρχές για την επίδραση της τροφής σε ενήλικες. Η καλύτερη κατανόηση των αλλαγών στη φυσιολογία των παιδικών ηλικιακών ομάδων και οι εξαρτώμενες από την ηλικία διαδικασίες μετά την απορρόφηση θα μπορούσαν να βελτιώσουν τα in silico εργαλεία.Background Extending licensed drug use to paediatric population has become an essential part of the drug development process. Ethical concerns limit clinical testing in paediatric populations and data collected from oral bioavailability and food effect studies in adults are often extrapolated to the paediatric (sub)populations. Preclinical animal models could offer an alternative approach for paediatric products evaluation. Recently, a draft guidance by regulatory authorities suggested the consideration of age-appropriate meal types and quantities for the target paediatric populations, e.g., infant formula for age groups receiving mainly milk-based feeds, without specifying exact feeding volumes and dosing conditions. Aims To design an exploratory clinical study to understand whether food effect on drug absorption in adults is similar with the food effect after administration of an infant meal with the drug product to adults. To describe and evaluate a PBPK modeling approach for extrapolation of drug exposure from adults to infants and children with a view to the different dosing conditions that can be used to inform the modeling process. To explore the usefulness of the Beagle model in the evaluation of drug exposure after oral administration to paediatric populations and compare the usefulness of the Beagle data in evaluating drug exposure in paediatrics with the usefulness of human adult data. Methods An exploratory single-dose bioavailability study was performed in eight healthy adult male volunteers following a randomized, three-phase, crossover design. After confirming lack of pharmaceutical and pharmacokinetic interactions, a paracetamol suspension and an ibuprofen suspension were co-administered to healthy adults on three different occasions, i.e. in the fasted state (as defined by regulatory agencies, fasted conditions), in the fed state (as defined by regulatory agencies, reference-meal fed conditions) and under conditions simulating the fed state in infants (infant-formula fed conditions). Similar oral dosing conditions were applied to an exploratory single-dose bioavailability study in six Beagle dogs following a blocked, crossover design. Physiologically based pharmacokinetic (PBPK) approaches for modeling paracetamol and ibuprofen suspension data collected in adults and in Beagles were developed in order to investigate whether extrapolation to infants and children is affected by the dosing conditions applied in each study. Extrapolation of these dosing conditions was performed by using the mechanical understanding gained from the collected data and after scaling to infants and children considering physiological, anatomical, and drug clearance changes. The development of the PBPK models was performed using GastroPlus™ V9.7. The usefulness of the developed models in adults and in Beagles to predict drug exposure in infants and in children was evaluated using literature clinical data sets in infants and in children following oral administration of paracetamol and ibuprofen. Results In adults, under infant-formula fed conditions early exposure was significantly lower than under fasted conditions for both paracetamol and ibuprofen, unlike under reference-meal fed conditions. Also, for ibuprofen, Cmax values under infant-formula fed conditions were significantly higher than under reference-meal fed conditions. For paracetamol, successful simulations of previously observed plasma concentration levels in infants were achieved when extrapolating from fasted and infant formula–fed conditions data in healthy adults, whereas data collected following the reference meal appeared less useful for simulating paracetamol suspension performance in infants. For ibuprofen, successful predictions were achieved when employing the adult-based model for fasted conditions or by applying appropriate fed conditions for different age groups, i.e., infant formula for infants and reference meal for children. For paracetamol, fasted dosing conditions and reference-meal fed conditions in Beagle dogs appeared useful to inform modeling for infant formulations. Extrapolation of paracetamol performance during infant formula administration in Beagles appeared less successful to predict plasma levels in infants. Fasted conditions in Beagles appeared useful for predicting ibuprofen performance in a mixed paediatric population while reference-meal fed conditions appeared to lead to adequate predictions for the children dataset. Despite the differences observed between the Beagle-based model and human adult-based model predictions, the Beagle-based model appears suitable for investigating paediatric products at early development stages, when applying fasted and/or reference-meal fed conditions. Concluding remarks Clinical data from this study suggest that, even for drugs with non-problematic absorption administered in simple dosage forms, food effects in infants may not be adequately evaluated if the protocol suggested by regulatory agencies is applied in adults. Preclinical data coupled with PBPK modeling could be a useful tool for paediatric product evaluation at the early stage pharmaceutical development. Better understanding of luminal conditions’ changes in paediatrics and age-dependent post-absorptive processes could improve modeling confidence. The two proposed methodologies to predict performance of paediatric formulations deserve further evaluation using high-quality preclinical data and clinical data both in adults and in infants.

Factors Affecting Successful Extrapolation of Ibuprofen Exposure from Adults to Pediatric Populations After Oral Administration of a Pediatric Aqueous Suspension

The importance of physiologically based pharmacokinetic (PBPK) model refinement with data acquired in adults using a pediatric formulation under age-relevant dosing conditions in order to extrapolate drug exposure to infants was recently demonstrated for paracetamol. In the present investigation, the aim was to evaluate the importance of similar PBPK model refinement for a low-solubility weak acid, ibuprofen, to simulate exposure across pediatric populations, i.e., infants, young children, and schoolchildren. After developing and evaluating adult disposition and oral absorption models for the aqueous suspension of ibuprofen, ibuprofen performance was extrapolated to pediatrics simulating exposure as a function of different prandial and dosing conditions: fasted conditions, reference-meal fed conditions (solid-liquid meal), and infant-formula fed conditions (homogeneous liquid). Successful predictions were achieved when employing the refined model for fasted state conditions or for fed state conditions relevant to specific age groups, i.e., infant formula for infants and reference meal for children. The present study suggested that ibuprofen performance was primarily guided by gastric emptying and showed sensitivity towards formulation characteristics and pH changes in the small intestine. Better understanding of luminal conditions in pediatrics and age-dependent ibuprofen post-absorptive processes could improve modeling confidence for ibuprofen, as well as other drugs with similar characteristics.</p