Food effects in paediatric medicines development for products co-administered with food

A small amount of food is commonly used to aid administration of medicines to children to improve palatability and/or swallowability. However the impact of this co-administered food on the absorption and subsequent pharmacokinetic profile of the drug is unknown. Existing information on food effects is limited to standard protocols used to evaluate the impact of a high fat meal in an adult population using the adult medication. In the absence of a substantial body of data, there are no specific guidelines available during development of paediatric products relating to low volumes of potentially low calorie food. This paper brings together expertise to consider how the impact of co-administered food can be risk assessed during the development of a paediatric medicine. Two case studies were used to facilitate discussions and seek out commonalities in risk assessing paediatric products; these case studies used model drugs that differed in their solubility, a poorly soluble drug that demonstrated a positive food effect in adults and a highly soluble drug where a negative food effect was observed. For poorly soluble drugs risk assessments are centred upon understanding the impact of food on the in vivo solubility of the drug which requires knowledge of the composition of the food and the volumes present within the paediatric gastrointestinal tract. Further work is required to develop age appropriate in vitro and in silico models that are representative of paediatric populations. For soluble drugs it is more important to understand the mechanisms that may lead to a food effect, this may include interactions with transporters or the impact of the food composition on gastro-intestinal transit or even altered gastric motility. In silico models have the most promise for highly soluble drug products although it is essential that these models reflect the relevant mechanisms involved in potential food effects. The development of appropriate in vitro and in silico tools is limited by the lack of available clinical data that is critical to validate any tool. Further work is required to identify globally acceptable and available vehicles that should be the first option for co-administration with medicines to enable rapid and relevant risk assessment

Absorption Rate Limit Considerations for Oral Phosphate Prodrugs

Purpose . To evaluate the potential of phosphate ester prodrugs to significantly improve the absorptive flux of poorly soluble parent drugs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41498/1/11095_2004_Article_465513.pd

Oral phosphate prodrugs: Absorption rate limit considerations.

Objectives. Phosphate ester prodrugs substantially enhance the aqueous solubility of some poorly soluble parent drugs due to ionization of the phosphate group at physiological pH. While phosphate prodrugs have proven successful in parenteral formulations, few oral phosphate prodrugs have been marketed to date as they have generally failed to improve parent drug absorption. The objective of this research was to investigate the absorption rate determinants of phosphate prodrugs, namely, (a) solubility-dissolution, (b) permeability, (c) enzymatic bioconversion by alkaline phosphatase, and (d) parent drug precipitation from prodrug solutions of phosphorylated drugs. Methods. The prodrugs, miproxifene phosphate (TAT-59), entacapone phosphate and fosphenytoin were selected for experimental evaluation of the absorption rate limits. Caco-2 cells, in-situ rat intestinal perfusion, UV-vis spectrometry, HPLC and mass spectrometry were among the experimental techniques employed. Parent drug absorptive flux, permeability and supersaturation level were determined in Caco-2 cell monolayers. In vitro precipitation induction times of parent drugs from prodrug/intestinal alkaline phosphatase solutions were also determined. The role of solubility and dose in the selection of suitable oral prodrug candidates was investigated for more than ten prodrugs. A Prodrug Number (PN), analogous to the dose number, was defined as highest targeted oral parent equivalent Dose/250 mL/Csmin, where Csmin is the lowest solubility at intestinal pH. Results. Prodrugs were dephosphorylated in apical Caco-2 chambers. Absorptive fluxes of DP-TAT-59 and phenytoin increased up to 9.8 and 3.3-fold for TAT-59 and fosphenytoin, respectively, compared to their parent drugs while permeability/bioconversion limited parent drug absorption from entacapone-phosphate. Parent drug precipitation induction times from TAT-59, fosphenytoin, and estramustine phosphate, mediated by alkaline phosphatase, decreased with increased enzyme activity and supersaturation level. Estramustine solubilization in prodrug solutions is postulated to reduce enzyme-mediated precipitation potential. Conclusions. Ideal, functional oral phosphate prodrug candidates like DP-TAT-59 have high permeability, low aqueous solubility, and a high-targeted dose (high PN). Early PN assessment is recommended since no absorption advantage is gained for parent drugs administered at sufficiently low doses to permit complete dissolution during the intestinal residence time. Phosphate prodrugs are not likely to optimize oral absorption of parent drugs with low permeability/high solubility, such as entacapone.Ph.D.Health and Environmental SciencesPharmaceutical sciencesPharmacy sciencesPure SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/123400/2/3079459.pd

Case studies for practical food effect assessments across BCS/BDDCS class compounds using in silico, in vitro, and preclinical in vivo data

Practical food effect predictions and assessments were described using in silico, in vitro, and/or in vivo preclinical data to anticipate food effects and Biopharmaceutics Classification System (BCS)/Biopharmaceutics Drug Disposition Classification System (BDDCS) class across drug development stages depending on available data: (1) limited in silico and in vitro data in early discovery; (2) preclinical in vivo pharmacokinetic, absorption, and metabolism data at candidate selection; and (3) physiologically based absorption modeling using biorelevant solubility and precipitation data to quantitatively predict human food effects, oral absorption, and pharmacokinetic profiles for early clinical studies. Early food effect predictions used calculated or measured physicochemical properties to establish a preliminary BCS/BDDCS class. A rat-based preclinical BCS/BDDCS classification used rat in vivo fraction absorbed and metabolism data. Biorelevant solubility and precipitation kinetic data were generated via animal pharmacokinetic studies using advanced compartmental absorption and transit (ACAT) models or in vitro methods. Predicted human plasma concentration-time profiles and the magnitude of the food effects were compared with observed clinical data for assessment of simulation accuracy. Simulations and analyses successfully identified potential food effects across BCS/BDDCS classes 1-4 compounds with an average fold error less than 1.6 in most cases. ACAT physiological absorption models accurately predicted positive food effects in human for poorly soluble bases after oral dosage forms. Integration of solubility, precipitation time, and metabolism data allowed confident identification of a compound's BCS/BDDCS class, its likely food effects, along with prediction of human exposure profiles under fast and fed conditions. © 2012 American Association of Pharmaceutical Scientists

Physiologically Based Absorption Modeling to Impact Biopharmaceutics and Formulation Strategies in Drug Development—Industry Case Studies

In recent years, there has been a significant increase in use of physiologically based pharmacokinetic models in drug development and regulatory applications. Although most of the published examples have focused on aspects such as first-in-human (FIH) dose predictions or drug–drug interactions, several publications have highlighted the application of these models in the biopharmaceutics field and their use to inform formulation development. In this report, we present 5 case studies of use of such models in this biopharmaceutics/formulation space across different pharmaceutical companies. The case studies cover different aspects of biopharmaceutics or formulation questions including (1) prediction of absorption prior to FIH studies; (2) optimization of formulation and dissolution method post-FIH data; (3) early exploration of a modified-release formulation; (4) addressing bridging questions for late-stage formulation changes; and (5) prediction of pharmacokinetics in the fed state for a Biopharmaceutics Classification System class I drug with fasted state data. The discussion of the case studies focuses on how such models can facilitate decisions and biopharmaceutic understanding of drug candidates and the opportunities for increased use and acceptance of such models in drug development and regulatory interactions

Prospective Predictions of Human Pharmacokinetics for Eighteen Compounds

Quantitative predictions of pharmacokinetics (PKs) and concentration-time profiles using in vitro and in vivo preclinical data are critical to estimate systemic exposures for first-in-human studies. Prospective prediction accuracies of human PKs for 18 compounds across all Biopharmaceutics Classification System/Biopharmaceutics Drug Disposition Classification System classes were evaluated. The a priori predicted profiles were then compared with clinical profiles. Predictions were conducted using advanced compartmental absorption and transit (ACAT) physiology based PK models. Human intravenous profiles were predicted with in vivo preclinical intravenous data using Wajima formulas. Human oral profiles were generated by combining intravenous PKs together with either physiologically based oral ACAT models utilizing solubility and permeability data or by using the average bioavailability (F) and absorption rate constant (ka) from preclinical species. Key PK parameters evaluated were the maximum plasma concentration (Cmax), the area under the plasma concentration-time curve (AUC), CL/F, and Vdss/F. A decision tree was provided to guide human PK and ACAT predictions. Our prospective human PK prediction methods yielded good prediction results. The predictions were within a twofold error for 80% (Cmax), 65% (AUC), 65% (CL/F), and 80% (Vz/F) of the compounds. The methods described can be readily implemented with available in vitro and in vivo data during early drug development

Prospective Predictions of Human Pharmacokinetics for Eighteen Compounds

Quantitative predictions of pharmacokinetics (PKs) and concentration-time profiles using in vitro and in vivo preclinical data are critical to estimate systemic exposures for first-in-human studies. Prospective prediction accuracies of human PKs for 18 compounds across all Biopharmaceutics Classification System/Biopharmaceutics Drug Disposition Classification System classes were evaluated. The a priori predicted profiles were then compared with clinical profiles. Predictions were conducted using advanced compartmental absorption and transit (ACAT) physiology based PK models. Human intravenous profiles were predicted with in vivo preclinical intravenous data using Wajima formulas. Human oral profiles were generated by combining intravenous PKs together with either physiologically based oral ACAT models utilizing solubility and permeability data or by using the average bioavailability (F) and absorption rate constant (ka) from preclinical species. Key PK parameters evaluated were the maximum plasma concentration (Cmax), the area under the plasma concentration-time curve (AUC), CL/F, and Vdss/F. A decision tree was provided to guide human PK and ACAT predictions. Our prospective human PK prediction methods yielded good prediction results. The predictions were within a twofold error for 80% (Cmax), 65% (AUC), 65% (CL/F), and 80% (Vz/F) of the compounds. The methods described can be readily implemented with available in vitro and in vivo data during early drug development