Physiologically based pharmacokinetic modeling and simulations to inform dissolution specifications and clinical relevance of release rates on elagolix exposure.

The aim of this analysis was to use a physiologically based pharmacokinetic (PBPK) model to predict the impact of changes in dissolution rates on elagolix exposures and define clinically relevant acceptance criteria for dissolution. Varying in vitro dissolution profiles were utilized in a PBPK model to describe the absorption profiles of elagolix formulations used in Phase 3 clinical trials and for the to be marketed commercial formulations. Single dose studies of 200 mg elagolix formulations were used for model verification under fasted conditions. Additional dissolution scenarios were evaluated to assess the impact of dissolution rates on elagolix exposures. Compared to the Phase 3 clinical trial formulation, sensitivity analysis on dissolution rates suggested that a hypothetical scenario of ∼75% slower dissolution rate would result in 14% lower predicted elagolix plasma exposures, however, the predicted exposures are still within the bioequivalence boundaries of 0.8-1.25 for both Cmax and AUC. A clinically verified PBPK model of elagolix was utilized to evaluate the impact of wider dissolution specifications on elagolix plasma exposures. The simulation results indicated that a slower in vitro dissolution profile, would not have a clinically significant impact on elagolix exposures. These model results informed the setting of wider dissolution specifications without requiring in vivo studies.

In Vitro Characterization of Ritonavir Drug Products and Correlation to Human in Vivo Performance.

Ritonavir (RTV) is a weakly basic drug with a pH-dependent solubility. In vitro dissolution and supersatuation behaviors of three Norvir oral products including the tablet, powder, and solution were investigated by two biorelevant dissolution methods with pH alteration: a two-stage dissolution test and a biphasic dissolution-partition test. The two-stage dissolution test revealed a high degree of supersaturation of RTV from these products accompanied by the occurrence of liquid-liquid phase separation (LLPS) in biorelevant dissolution media. Higher, stable apparent RTV concentrations were observed in the FeSSIF-V2 as compared to those in the FaSSIF-V2, which suggested a food effect with higher exposure in the fed state. This is inconsistent with the evaluation in vivo. The biphasic test revealed significantly lower degrees of supersaturation of RTV in the aqueous media from these dosage forms as compared to results of the two-stage dissolution test. RTV concentrations in octanol at 6 h obtained from the tablet and powder with the use of the biorelevant media are consistent with corresponding in vivo AUC and Cmax under the fasting and moderate fat fed (MFF) states and predict the food effect. The underlying mechanisms responsible for the food effect are also proposed. Fractional partition profiles of RTV obtained in octanol from these three Norvir oral products are in agreement with the corresponding fractional absorption profiles in vivo under both the fasting and MFF states. This study reveals a complex interplay among the dissolution, precipitation, and partition processes from these formulations that dictate the oral exposure of RTV.

Development of In Vitro-In Vivo Correlation for Potassium Chloride Extended Release Tablet Formulation Using Urinary Pharmacokinetic Data.

PURPOSE: To develop and validate a Level A in vitro-in vivo correlation (IVIVC) for potassium chloride extended-release (ER) formulations. METHODS: Three prototype ER formulations of potassium chloride with different in vitro release rates were developed and their urinary pharmacokinetic profiles were evaluated in healthy subjects. A mathematical model between in vitro dissolution and in vivo urinary excretion, a surrogate for measuring in vivo absorption, was developed using time-scale and time-shift parameters. The IVIVC model was then validated based on internal and external predictability. RESULTS: With the established IVIVC model, there was a good correlation between the observed fraction of dose excreted in urine and the time-scaled and time-shifted fraction of the drug dissolved, and between the in vitro dissolution time and the in vivo urinary excretion time for the ER formulations. The percent prediction error (%PE) on cumulative urinary excretion over the 24 h interval (Ae0-24h) and maximum urinary excretion rate (Rmax) was less than 15% for the individual formulations and less than 10% for the average of the two formulations used to develop the model. Further, the %PE values using external predictability were below 10%. CONCLUSIONS: A novel Level A IVIVC was successfully developed and validated for the new potassium chloride ER formulations using urinary pharmacokinetic data. This successful IVIVC may facilitate future development or manufacturing changes to the potassium chloride ER formulation.

Bioequivalence of Elagolix/Estradiol/Norethindrone Acetate Fixed-Dose Combination Product: Phase 1 Results in Healthy Pre- and Postmenopausal Women.

Fixed-dose combination (FDC) therapies can enhance patient convenience and adherence to prescribed treatment regimens. Elagolix is a novel oral gonadotropin-releasing hormone receptor antagonist approved for management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Hormonal add-back therapy can attenuate the reversible hypoestrogenic effects of elagolix. An FDC formulation containing elagolix/estradiol (E2)/norethindrone acetate (NETA) 300/1/0.5 mg as the morning dose and an elagolix 300 mg capsule as the evening dose, were evaluated in 2 bioequivalence studies including the effects of food. Study 1 in premenopausal women assessed the bioavailability of the elagolix 300-mg capsule relative to the commercially available elagolix 300-mg tablet. Study 2 in postmenopausal women, elagolix/E2/NETA (300 mg/1 mg/0.5 mg) FDC capsule was assessed relative to the elagolix 300-mg tablet coadministered with E2/NETA 1-mg/0.5-mg tablet, the regimen that was studied in Phase 3 uterine fibroid studies. Under fasting conditions, the test elagolix 300-mg capsule was bioequivalent to the reference elagolix 300-mg tablet. Under fasting conditions, the elagolix/E2/NETA FDC capsule was bioequivalent to the coadministered elagolix 300-mg tablet and E2/NETA 1/0.5-mg tablet. Following administration of elagolix/E2/NETA FDC capsule after a high-fat breakfast, elagolix mean maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) were 38% and 28% lower, relative to fasting conditions. NETA mean Cmax was 51% lower and AUC from time 0 to infinity was 20% higher, while baseline-adjusted total estrone mean Cmax and AUC were 46% and 14% lower, respectively. No safety concerns were identified. These results enabled bridging the elagolix/E2/NETA FDC capsule.

Venetoclax Clinical Pharmacokinetics After Administration of Crushed, Ground or Whole Tablets.

PURPOSE: Venetoclax is a potent, orally bioavailable BCL-2 inhibitor used in the treatment of some hematological malignancies. Crushing tablets may be necessary to help with the administration of venetoclax to patients with swallowing difficulties or patients requiring nasogastric tube feeding. The study was conducted to assess the bioavailability of crushed and finely ground venetoclax tablets relative to whole tablets. METHODS: An open-label, randomized, 3-way, crossover study in 15 healthy adult females was conducted. Venetoclax tablets were administered orally in a crushed, ground or intact form on Day 1 of each period with water following a high-fat breakfast. Pharmacokinetic samples were collected up to 72 hours postdosing. FINDINGS: The crushed and ground tablets met the bioequivalence criteria (0.80-1.25) relative to the intact tablets with respect to area under the concentration-time curve to time of the last measurable concentration (AUCt) and to infinite time (AUCinf) but exhibited a slightly lower maximum plasma concentration (Cmax). This was not considered clinically significant as only venetoclax overall exposure (AUC) has been shown to correlate with clinical efficacy. There was no change in the physical appearance and the evaluated physicochemical properties of crushed and ground venetoclax tablets after 72 hours of storage at 25°C/60% relative humidity. IMPLICATIONS: Crushing or grinding venetoclax tablets before administration could be considered as a viable alternative method of administration for patients who have difficulty swallowing whole venetoclax tablets or patients requiring nasogastric tube feeding. GOV IDENTIFIERS: NCT05909553, registered June 12, 2023.

Clinical Bridging From Prefilled Syringe to On-body Injector for Risankizumab in Crohn's Disease.

PURPOSE: This article describes the clinical development bridging strategy and key data to support the marketing application of the risankizumab on-body injection (OBI) system for the treatment of moderately to severely active Crohn's disease (CD), even though the OBI was not evaluated directly in the pivotal Phase III studies in CD. METHODS: Three studies were conducted as part of the clinical bridging strategy. The pilot pharmacokinetics (PK) study was a Phase I, single-dose, 4-arm, open-label, randomized, parallel-group exploratory PK and tolerability study that assessed the effect of rate and volume of administration on the bioavailability (BA) of risankizumab and the extent of injection site-related pain after subcutaneous (SC) administration in healthy subjects. The pivotal BA/bioequivalence (BE) study was a relative BA/BE bridging study in healthy subjects to assess the relative BA of the to-be-marketed risankizumab OBI compared with the prefilled syringe (PFS) used in the Phase III CD studies. The OBI adhesive study was a randomized, open-label, non-drug interventional study in healthy subjects to assess the OBI adhesive effectiveness and skin tolerability at 2 different locations (abdomen and upper thigh) over different periods of time (5 and 30 minutes). FINDINGS: The pilot PK study showed that risankizumab exposures were similar across different rates/volumes of SC administration in healthy subjects, thereby supporting further development of the OBI. Second, a pivotal BA/BE study showed comparability between the OBI and Phase III PFS with bioequivalent risankizumab AUCs and no clinically meaningful difference for Cmax based on the wide therapeutic window of risankizumab. In both studies, no new safety risks were identified. No impact of immunogenicity on PK profile or safety was observed for the OBI. Third, an adhesive OBI (without risankizumab) study showed that there were no differences in adhesion/skin tolerability observed over time (up to 30 minutes) or for location of adhesion, and the OBI device adhesion was well tolerated at both the abdomen and thigh locations. IMPLICATIONS: These results supported the risankizumab OBI presentation approval in CD.

Analysis of level A in vitro-in vivo correlations for an extended-release formulation with limited bioavailability.

A two-stage, numerical deconvolution approach was employed to develop level A in vitro-in vivo correlations using data for three formulations of an extended-release oral dosage form. The in vitro dissolution data for all formulations exhibited near-complete dissolution within the time frame of the test. The pharmacokinetic concentration-time profiles for 16 subjects in a cross-over study demonstrated notably limited bioavailability for the slowest formulation. These data were used as the basis for the IVIVC model development. Two models were identified that satisfied the nominal requirements for a conclusive internal predictability of the IVIVC, provided that all three formulations were used as internal datasets. These were a simple linear model with absorption cut-off and a piecewise-linear variable absorption scale model. A subsequent cross-validation of the models' robustness indicated that neither model predicted satisfactorily the pharmacokinetic characteristics of all formulations in a conclusive manner. The piecewise-linear variable absorption scale model provided the most accurate results, particularly with respect to the prediction of the slowest formulation's pharmacokinetic metrics. But this latter model also involved additional free parameters compared with the simple linear model with absorption cut-off. It is argued that more complex IVIVC models with extra parameterization require comprehensive validation to ascertain the accuracy and robustness of the model. In order to achieve this, it is necessary to ensure a complete suite of supporting datasets for internal and external validation, irrespective of the mathematical approach used subsequently to develop the IVIVC.

Virtual Bioequivalence Assessment of Elagolix Formulations Using Physiologically Based Pharmacokinetic Modeling.

In lieu of large bioequivalence studies and exposing healthy postmenopausal women to additional drug exposure for elagolix coadministered with hormonal add-back therapy, physiologically based pharmacokinetic (PBPK) modeling was used with in vitro dissolution data to test for virtual bioequivalence. For endometriosis, elagolix is approved at doses of 150 mg once daily and 200 mg twice daily as a tablet. As a combination therapy, two individual tablets, consisting of an elagolix tablet and an estradiol/norethindrone acetate 1/0.5 mg (E2/NETA) tablet, were utilized in Phase 3 endometriosis trials. However, the commercial combination drug products consist of a morning capsule (containing an elagolix tablet and E2/NETA tablet as a fixed-dose combination capsule, AM capsule) and an evening capsule (consisting of an elagolix tablet, PM capsule). In vitro dissolution profiles were dissimilar for the tablet and capsule formulations; thus, in vivo bioequivalence studies or a bioequivalence waiver would have been required. To simulate virtual cross-over, bioequivalence trials, in vitro dissolution data was incorporated into a previously verified PBPK model. The updated PBPK model was externally validated using relevant bioequivalence study data. Based on results of the virtual bioequivalence simulations, the commercial drug product capsules met the bioequivalence criteria of 0.80-1.25 when compared to the reference tablets. This was a novel example where PBPK modeling was utilized along with in vitro dissolution data to demonstrate virtual bioequivalence in support of a regulatory bioequivalence waiver.

Relationships between in vitro drug dissolution and in vivo response.

In recent years there has been an effort to relate manufacturing variables to the performance of the dosage form from a clinical point of view (in terms of safety and efficacy). Consequently any control strategy or the establishment of meaningful specifications should take into consideration the clinical impact on the patient. Since plasma levels are considered to be one of the most useful surrogates for clinical safety (in that bioequivalent plasma levels are considered therapeutically equivalent) and dissolution is the best surrogate for bioavailability, it is a natural consequence that dissolution be used to establish the design space in which all the formulations would have similar safety and efficacy profiles.

Utility of Modeling and Simulation Approach to Support the Clinical Relevance of Dissolution Specifications: a Case Study from Upadacitinib Development.

Dissolution specifications are often essential in assuring the quality and consistency of therapeutic benefits of drug lots released to the market as in vitro dissolution is often considered to be a surrogate for bioavailability. Despite the importance of demonstrating the clinical relevance of the dissolution specifications, it is often challenging to achieve this goal. In this case study, a modeling and simulation approach was utilized to support the clinical relevance of the dissolution specifications for upadacitinib extended-release tablets. A level A in vitro in vivo correlation was developed and utilized in predicting upadacitinib plasma exposures for formulations which correspond to the upper and lower dissolution limits. Exposure-response models for upadacitinib efficacy and safety in patients with moderate to severe rheumatoid arthritis (RA) were utilized to conduct clinical trial simulations to evaluate the efficacy and safety of formulations at the upper and lower dissolution boundaries. Each simulated clinical trial consisted of three treatment arms: (1) upadacitinib 15 mg QD using the target formulation, (2) upadacitinib 15 mg QD using a formulation at the lower dissolution boundary, and (3) upadacitinib 15 mg QD using a formulation at the upper dissolution boundary. Each simulated trial included 300 patients per arm and simulations were replicated 200 times. Results demonstrated that formulations at the lower and upper dissolution boundaries are predicted to have noninferior efficacy and comparable safety to the target 15 mg extended-release formulation. This approach was successfully utilized in demonstrating the clinical relevance of upadacitinib extended-release tablet dissolution specifications. Graphical Abstract.

Evaluation of US Food and Drug Administration Drug Label Recommendations for Coadministration of Antivirals and Acid-Reducing Agents.

Coadministration with acid-reducing agents (ARAs), including proton pump inhibitors (PPIs), histamine H2 -receptor antagonists (H2 blockers), and antacids has been demonstrated to reduce antiviral exposure and efficacy. Therefore, it is essential that US Food and Drug Administration (FDA) drug labels include recommendations to manage these drug-drug interactions (DDIs). This investigation analyzed information in FDA drug labels to manage DDIs between ARAs and antivirals approved from 1998 to 2019. To ascertain clinical adoption, we assessed whether FDA label recommendations were incorporated into current antiviral clinical practice guidelines. We identified 82 label recommendations for 43 antiviral approvals. Overall, 56.1% of recommendations were deemed clinically actionable, with the most common actionable management strategies being dose adjustment during coadministration (40.2%) and coadministration not recommended (9.8%). The sources informing DDI recommendations were clinical DDI studies (59.8%) and predictions of altered exposure (40.2%). Antivirals with low aqueous solubility were more likely to have label recommendations and were more commonly investigated using clinical DDI studies (P < 0.01). For recommendations informed by clinical DDI studies, changes in drug exposure were associated with actionable label recommendations (P < 0.01). The frequency of exposure changes in clinical DDI studies was similar across antiviral indications, but exposure changes were numerically higher for antacids (71.4%) relative to PPIs (42.9%) and H2 blockers (28.6%). Of DDI pairs identified within drug labels, 76.8% were included in guidelines, and recommended management strategies were concordant in 90.5% of cases. Our findings demonstrate that current regulatory oversight mostly (but not completely) results in actionable label recommendations to manage DDIs for high-risk antivirals.

Bioavailability Evaluation of Venetoclax Lower-Strength Tablets and Oral Powder Formulations to Establish Interchangeability with the 100 mg Tablet.

BACKGROUND AND OBJECTIVE: Venetoclax is an approved BCL-2 inhibitor, currently under evaluation in different hematological malignancies in adult and pediatric populations. Venetoclax is available as 10, 50, and 100 mg tablets. To provide an alternative to patients who find taking the commonly prescribed 100 mg tablet a challenge, the interchangeability of lower-strength tablets with the 100 mg tablet was investigated. Additionally, newly developed oral suspension powder formulations to facilitate dosing in pediatrics were evaluated. METHODS: Pharmacokinetic data from 80 healthy female participants from three phase I studies were utilized to evaluate the bioavailability of (1) 10 and 50 mg tablets relative to a 100 mg tablet; (2) 0.72 and 7.2% (drug to total weight) oral powder formulations relative to the 100 mg tablet; and (3) oral powder formulations administered using different vehicles (apple juice, apple sauce, and yogurt) relative to water under fed conditions. RESULTS: Bioavailability assessments at a 100 mg dose of venetoclax demonstrated bioequivalence across the 10, 50, and 100 mg tablet strengths. Oral powder formulations met the bioequivalence criteria (0.80-1.25) with respect to area under the concentration-time curve to time of the last measurable concentration (AUCt) and to infinite time (AUC∞) but exhibited a slightly lower maximum plasma concentration (Cmax). Exposure-response analyses were utilized to demonstrate that the lower Cmax observed with the powder formulations is not clinically meaningful. The delivery vehicles tested did not affect the bioavailability of venetoclax oral powder formulations. CONCLUSIONS: The smaller-sized tablets (10 and 50 mg) and the newly developed oral powder formulations of venetoclax can be used interchangeably with the 100 mg tablets to improve the patients' experience, while maintaining adequate exposure. CLINICAL TRIALS IDENTIFIERS: NCT01682616, 11 September 2012; NCT02005471, 9 December 2013; NCT02242942, 17 September 2014; NCT02203773, 30 July 2014; NCT02287233, 10 November 2014; NCT02993523, 15 December 2016; NCT03069352, 3 March 2017.

In vivo bioequivalence and in vitro similarity factor (f2) for dissolution profile comparisons of extended release formulations: how and when do they match?

PURPOSE: To investigate how likely two extended release formulations are to be bioequivalent when they demonstrate f2 similarity. METHOD: Dissolution profiles were simulated using the Weibull model and varying model parameters around those of a reference profile. The f2 values were calculated for the comparisons of each simulation with the reference profile. The in vivo inputs obtained from an in vitro-in vivo correlation model were convolved with a unit impulse response function. The AUC, Cmax, and Tmax from each simulated in vivo concentration profile were compared to the reference profile. The AUCR (AUC ratio) and CmaxR (Cmax ratio) were determined. The consistency between f2 and bioequivalence was investigated. RESULTS: The relationships between AUCR, CmaxR, f2 and the Weibull model parameters demonstrate that the bioequivalence regions enclosed by the contour lines of 80% and 125% of AUCR and CmaxR were generally close to the regions enclosed by the f2 = 50 contour line, but did not exactly match, especially when Dmax and B deviated from the reference values. CONCLUSIONS: When f2 is used for in vitro dissolution profile comparison, the completeness of the dissolution profiles should not differ more than 10%, and the shapes of the dissolution profiles should not be significantly different.

Pharmacokinetics of Upadacitinib With the Clinical Regimens of the Extended-Release Formulation Utilized in Rheumatoid Arthritis Phase 3 Trials.

Upadacitinib is a Janus kinase 1 inhibitor under development for the treatment of several inflammatory disorders including rheumatoid arthritis (RA). Upadacitinib was administered in the phase 2 RA trials primarily as twice-daily regimens of an immediate-release (IR) formulation. The upadacitinib extended-release (ER) formulation was developed to enable once-daily dosing. In the present study, upadacitinib pharmacokinetics were characterized after the administration of single and multiple once-daily doses of the ER formulation in healthy subjects relative to single and multiple twice-daily doses of the IR formulation. Increase in upadacitinib exposure was dose-proportional over the evaluated 15- to 30-mg ER dose range. Single 15- and 30-mg ER doses provided equivalent AUC0-inf compared with single 12- and 24-mg IR doses, respectively. A high-fat breakfast increased upadacitinib ER Cmax and AUC0-inf by only 20% and 17%, respectively, relative to fasting conditions. The median time to peak plasma concentrations was 2 to 4 hours for the ER formulation, and steady state was achieved by day 4 of once-daily dosing. Doses of 15 and 30 mg once daily using the ER formulation provided equivalent AUC0-24 , comparable Cmax and Cmin , and a fluctuation index over a 24-hour period at steady state similar to 6 and 12 mg twice daily, respectively, using the IR formulation. These results supported the use of upadacitinib 15- and 30-mg doses of the ER formulation in the phase 3 trials in RA.

Accelerating Drug Development in Pediatric Oncology With the Clinical Pharmacology Storehouse.

Pediatric drug development is a challenging process due to the rarity of the population, the need to meet regulatory requirements across the globe, the associated uncertainty in extrapolating data from adults, the paucity of validated biomarkers, and the lack of systematic testing of drugs in pediatric patients. In oncology, pediatric drug development has additional challenges that have historically delayed availability of safe and effective medicines for children. In particular, the traditional approach to pediatric oncology drug development involves conducting phase 1 studies in children once the drug has been characterized and in some cases approved for use in adults. The objective of this article is to describe clinical pharmacology factors that influence pediatric oncology trial design and execution and to highlight efficient approaches for designing and expediting oncology drug development in children. The topics highlighted in this article include (1) study design considerations, (2) updated dosing approaches, (3) ways to overcome the significant biopharmaceutical challenges unique to the oncology pediatric population, and (4) use of data analysis strategies for extrapolating data from adults, with case studies. Finally, suggestions for ways to use clinical pharmacology approaches to accelerate pediatric oncology drug development are provided.

Development of In Vitro-In Vivo Correlation for Upadacitinib Extended-Release Tablet Formulation.

Upadacitinib is a selective Janus Kinase 1 inhibitor which is being developed for the treatment of several inflammatory diseases including rheumatoid arthritis. Upadacitinib was evaluated in Phase 3 studies as an oral extended-release (ER) formulation administered once daily. The purpose of this study was to develop a level A in vitro-in vivo correlation (IVIVC) for upadacitinib ER formulation. The pharmacokinetics of four upadacitinib extended-release formulations with different in vitro release characteristics and an immediate-release capsule formulation of upadacitinib were evaluated in 20 healthy subjects in a single-dose, randomized, crossover study. In vivo pharmacokinetic data and in vitro dissolution data (USP Dissolution Apparatus 1; pH 6.8; 100 rpm) were used to establish a level A IVIVC. Three formulations were used to establish the IVIVC, and the fourth formulation was used for external validation. A non-linear IVIVC best described the relationship between upadacitinib in vitro dissolution and in vivo absorption profiles. The absolute percent prediction errors (%PE) for upadacitinib Cmax and AUC were less than 10% for all three formulations used to establish the IVIVC, as well as for the %PE for the external validation formulation and the overall mean internal validation. Model was cross-validated using the leave-one-out approach; all evaluated cross-validation runs met the regulatory acceptance criteria. A level A IVIVC was successfully developed and validated for upadacitinib ER formulation, which meets the FDA and EMA regulatory validation criteria and can be used as surrogate for in vivo bioequivalence.

New era in drug interaction evaluation: US Food and Drug Administration update on CYP enzymes, transporters, and the guidance process.

Predicting clinically significant drug interactions during drug development is a challenge for the pharmaceutical industry and regulatory agencies. Since the publication of the US Food and Drug Administration's (FDA's) first in vitro and in vivo drug interaction guidance documents in 1997 and 1999, researchers and clinicians have gained a better understanding of drug interactions. This knowledge has enabled the FDA and the industry to progress and begin to overcome these challenges. The FDA has continued its efforts to evaluate methodologies to study drug interactions and communicate recommendations regarding the conduct of drug interaction studies, particularly for CYP-based and transporter-based drug interactions, to the pharmaceutical industry. A drug interaction Web site was established to document the FDA's current understanding of drug interactions (http://www.fda.gov/cder/drug/drugInteractions/default.htm). This report provides an overview of the evolution of the drug interaction guidances, includes a synopsis of the steps taken by the FDA to revise the original drug interaction guidance documents, and summarizes and highlights updated sections in the current guidance document, Drug Interaction Studies-Study Design, Data Analysis, and Implications for Dosing and Labeling.

Developing Quantitative In Vitro-In Vivo Correlation for Fenofibrate Immediate-Release Formulations With the Biphasic Dissolution-Partition Test Method.

This study is to evaluate 3 fenofibrate (FEN) formulations including Fournier® 200 mg capsule, Lipidil® 145 mg tablet, and a clinical HME 160 mg tablet by an in vitro biphasic method. Key experimental parameters were evaluated including the selection of biorelevant media, the United States Pharmacopeia IV flow rate, and the United States Pharmacopeia paddle speed. Varying the hydrodynamic condition resulted in a significant impact on FEN concentration time profiles in both aqueous and octanol phases for these formulations. In vivo pharmacokinetic profiles of the HME tablet, the Lipidil tablet, and Fournier capsule under the fasting and low-fat fed states are reported. Their corresponding absorption-time profiles were obtained through deconvolution by the Wagner-Nelson method. When fed state simulated intestinal fluid version 2 was used, the partitioned FEN amount-time profiles in octanol from the 3 formulations under an appropriate hydrodynamic condition exhibited a good agreement with their in vivo absorbed amount-time profiles, permitting a quantitative in vitro-in vivo correlation. When fasted state simulated intestinal fluid version 2 was used, partitioned FEN amounts into octanol from these formulations are significantly lower than those from in vivo data. Although no food effect was observed for both HME and Lipidil tablets, the positive food effect of the Fournier capsules significantly overestimated by the biphasic test.

Industry Perspective on Standardizing Food-Effect Studies for New Drug Development.

Investigating the effect of food on bioavailability during the development of an oral drug product is of prime importance because it has major implications on the study design of the clinical trials and dosing and administration recommendations. For modified-release formulations that exhibit dose dumping when administered with food, this may result in clinical concerns around safety and efficacy. In this article, we provide an overview of the various considerations in our opinion that impact the design and conduct of food-effect studies. We summarize the various recommendations from the different regulatory agencies and provide specific suggestions on study conduct in terms of statistical design, timing of studies, subject selection, and type and caloric content of the meal. We also discuss the role of modeling and simulation. Finally, we present an interpretation of the results of food-effect studies in addition to dosing and labeling recommendations in relation to regulatory guidance documents.

Applications of Clinically Relevant Dissolution Testing: Workshop Summary Report.

This publication summarizes the proceedings of day 3 of a 3-day workshop on "Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development." Specifically, this publication discusses the current approaches in building clinical relevance into drug product development for solid oral dosage forms, along with challenges that both industry and regulatory agencies are facing in setting clinically relevant drug product specifications (CRDPS) as presented at the workshop. The concept of clinical relevance is a multidisciplinary effort which implies an understanding of the relationship between the critical quality attributes (CQAs) and their impact on predetermined clinical outcomes. Developing this level of understanding, in many cases, requires introducing deliberate but meaningful variations into the critical material attributes (CMAs) and critical process parameters (CPPs) to establish a relationship between the resulting in vitro dissolution/release profiles and in vivo PK performance, a surrogate for clinical outcomes. Alternatively, with the intention of improving the efficiency of the drug product development process by limiting the burden of conducting in vivo studies, this understanding can be either built, or at least enhanced, through in silico efforts, such as IVIVC and physiologically based pharmacokinetic (PBPK) absorption modeling and simulation (M&S). These approaches enable dissolution testing to establish safe boundaries and reject drug product batches falling outside of the established safe range (e.g., due to inadequate in vivo performance) enabling the method to become clinically relevant. Ultimately, these efforts contribute towards patient-centric drug product development and allow regulatory flexibility throughout the lifecycle of the drug product.