Application of in vitro transmucosal permeability, dose number, and maximum absorbable dose for biopharmaceutics assessment during early drug development for intraoral delivery.

Intraoral (IO) administration is a unique route that takes advantage of transmucosal absorption in the oral cavity to deliver a drug substance locally or systemically. IO delivery can also enhance or enable oral administration, providing a better therapeutic benefit/safety risk profile for patient compliance. However, there are relatively few systematic biopharmaceutics assessments for IO delivery to date. Therefore, the goals of this study were to i) identify the most relevant in vitro permeability models as alternatives to porcine oral tissues (gold standard) for predicting human IO absorption and ii) establish guidelines for biopharmaceutics assessment during early drug development for IO delivery. Porcine kidney LLC-PK1 cells provided the strongest correlation of transmucosal permeability with porcine oral tissues followed by human Caco-2 cells. Furthermore, cultured human buccal tissues predicted high/low permeability classification and correlated well with porcine oral tissues, which are used for predicting clinical IO absorption. In the meantime, we introduced maximum absorbable dose and dose number in the oral cavity for IO delivery assessment as well as a decision tree to provide guidance for biopharmaceutics assessment during early drug development for IO delivery.

Utility of PBPK Absorption Modeling to Guide Modified Release Formulation Development of Gaboxadol, a Highly Soluble Compound With Region-Dependent Absorption.

Given the complexity of controlled release (CR) formulations, selecting the right preclinical tools is important to enable decision making on the in vivo performance of these formulations during development. In recent years, with the advancements of absorption/physiologically based pharmacokinetic (PBPK) modeling, such computational approaches play an increasing role in guiding formulation development. Development of PBPK models for CR formulations requires additional information compared with immediate release (IR) products. Perhaps the most important aspect is the need to simulate absorption in the lower intestine. Relatively few publications have investigated the use of PBPK models for compounds with region-dependent absorption. In this manuscript, we use gaboxadol as a model compound with region-dependent absorption. We first explored gaboxadol regional absorption in dogs to develop a PBPK model for absorption in the large intestine. Two matrix-based CR formulations were subsequently developed and tested in minipigs and demonstrated distinctly different pharmacokinetic profiles from the IR formulation. A minipig absorption PBPK model successfully predicted the observed plasma concentration data, with the predictions based on the in vitro dissolution being within the observed experimental variability. Finally, we demonstrate the development of an in vitro-in vivo correlation for the preclinical data using the same PBPK model.

Use of minipig skin biopsy model as an innovative tool to design topical formulation to achieve desired pharmacokinetics in humans.

In vitro cadaver skin permeation studies are often conducted to characterize the permeation profile of compounds for dermal delivery. However, its utility could be limited in the case of topical products because of lack of reliable prediction of in vivo skin kinetics. In this paper, the use of in vivo skin biopsy data to guide topical formulation development is described. A formulation was developed by compounding MK-0873, a phosphodiesterase 4 (PDE4) inhibitor, into a commercially available cream base. The cream was characterized by skin pharmacokinetic studies in minipigs, which demonstrated that MK-0873 concentrations in the epidermis and dermis were substantially higher than the IC80 for human whole blood PDE4 inhibition of ∼200 nM, suggesting that cream should provide sufficient skin exposure to assess clinical efficacy. In toxicological studies, after 1 month repeat application in minipigs minor dermal irritation and minimal systemic exposure were observed. Based on these preclinical data, the cream formulation was chosen for single rising dose clinical studies, where plasma levels of MK-0873 were mostly below the LOQ, whereas skin biopsy concentrations ranged from 6.5 to 25.1 µM. These data suggested that minipig skin biopsy model can be a valuable tool to assess performance of topical formulations and guide formulation development.

Discovery of MK-8970: an acetal carbonate prodrug of raltegravir with enhanced colonic absorption.

Developing new antiretroviral therapies for HIV-1 infection with potential for less frequent dosing represents an important goal within drug discovery. Herein, we present the discovery of ethyl (1-((4-((4-fluorobenzyl)carbamoyl)-1-methyl-2-(2-(5-methyl- 1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)ethyl) carbonate (MK-8970), a highly optimized prodrug of raltegravir (Isentress). Raltegravir is a small molecule HIV integrase strand-transfer inhibitor approved for the treatment of HIV infection with twice-daily administration. Two classes of prodrugs were designed to have enhanced colonic absorption, and derivatives were evaluated in pharmacokinetic studies, both in vitro and in vivo in different species, ultimately leading to the identification of MK-8970 as a suitable candidate for development as an HIV therapeutic with the potential to require less frequent administration while maintaining the favorable efficacy, tolerability, and minimal drug-drug interaction profile of raltegravir.

Analysis of the absorption kinetics of macromolecules following intradermal and subcutaneous administration.

Recent years have witnessed rapid growth in the area of microneedle-assisted intradermal drug delivery. Several publications involving in vivo studies in humans and minipigs have demonstrated distinct change in pharmacokinetics of peptides and proteins following intradermal (ID) administration as compared to subcutaneous (SC) injections. Specifically, ID administration produced a "left-shift" in pharmacokinetic profiles i.e. shorter time to achieve maximum plasma concentrations (shorter Tmax), and often higher maximum plasma concentrations (higher Cmax), as compared to the SC route. In the present work differences in the kinetics of drug absorption after ID and SC administration were explored for eight peptides and proteins with the focus on obtaining quantitative information about the absorption process and identifying similarities and differences in the absorption behavior across compounds. We confirmed that systemic uptake, as judged by apparent absorption rate constants, was 2- to 20-fold higher from the dermis as compared to the subcutis. Additionally, shapes of time-resolved absorption rate profiles demonstrated notable differences in absorption kinetics between ID and SC routes. For both administration routes evaluated herein there was a general trend of small macromolecules absorbing at higher rates as compared to the large macromolecules.

Physicochemical properties, form, and formulation selection strategy for a biopharmaceutical classification system class II preclinical drug candidate.

This work summarizes the pharmaceutical evaluation of a preclinical drug candidate with poor physicochemical properties. Compound 1 is a weakly basic, GPR-119 agonist designated to Biopharmaceutics Classification System Class II because of good permeability in a Caco-2 cell line model and poor solubility. Compound 1 showed good oral bioavailability from a solution formulation at low doses and oral exposure sufficient for toxicological evaluation at high doses from a nanosuspension of Form A-the only known polymorph of 1 during drug discovery. The identification of the thermodynamically stable polymorph, Form B, during early development adversely affected the bioperformance of the nanosuspension. The poor solubility of Form B resulted in a significant reduction in the oral exposure from a nanosuspension to a level that was insufficient for toxicological evaluation of compound 1. Subsequent to the discovery of Form B, multiple form and formulation engineering strategies were evaluated for their ability to enhance the oral exposure of 1. Formulations based on cocrystals and amorphous solid dispersions showed a statistically significant increase in exposure, sixfold and sevenfold, respectively, over the benchmark formulation, a suspension of Form B. The physicochemical characterization of 1, and the solid form and formulation engineering approaches explored to address the insufficient oral exposure of Form B are discussed along with insights on improving the physicochemical properties of the follow-on drug candidates in discovery.

Design of prodrugs to enhance colonic absorption by increasing lipophilicity and blocking ionization.

Prodrugs are chemistry-enabled drug delivery modifications of active molecules designed to enhance their pharmacokinetic, pharmacodynamic and/or biopharmaceutical properties. Ideally, prodrugs are efficiently converted in vivo, through chemical or enzymatic transformations, to the active parent molecule. The goal of this work is to enhance the colonic absorption of a drug molecule with a short half-life via a prodrug approach to deliver sustained plasma exposure and enable once daily (QD) dosing. The compound has poor absorption in the colon and by the addition of a promoiety to block the ionization of the molecule as well as increase lipophilicity, the relative colonic absorption increased from 9% to 40% in the retrograde dog colonic model. A combination of acceptable solubility and stability in the gastrointestinal tract (GI) as well as permeability was used to select suitable prodrugs to optimize colonic absorption.

Suitability of a minipig model in assessing clinical bioperformance of matrix and multiparticulate extended-release formulations for a BCS class III Drug development candidate.

Preclinical studies in dogs are often employed as part of formulation screening process. However, the shorter transit time and colonic length in dogs may result in underestimation of absorption, especially for extended-release (ER) formulations. In the recent years, minipigs have attracted attention as an alternative animal model. However reports on studies with ER formulations are limited. In this manuscript, we report the first comprehensive comparison of minipig and clinical data for two types of ER formulations. Matrix tablets and multiparticulates in capsules of a BCS Class III compound were tested in the Yucatan minipig model. The relative performance of the formulations in minipigs in the fasted state was reasonably aligned with the clinical observations. The minipig model was able to rank order the formulations, reflecting the targeted release rate, in a manner consistent with the clinical data. Minipigs also reflected the loss of bioavailability relative to the immediate-release formulation. A level C in vitro/in vivo correlation was demonstrated for both the minipig and clinical data. However, an assessment of food effect in the minipig model appeared challenging, especially for the matrix formulation for which a negative food effect was observed in minipigs compared with the positive food effect in the clinic.

Model-based decision making in early clinical development: minimizing the impact of a blood pressure adverse event.

We describe how modeling and simulation guided program decisions following a randomized placebo-controlled single-rising oral dose first-in-man trial of compound A where an undesired transient blood pressure (BP) elevation occurred in fasted healthy young adult males. We proposed a lumped-parameter pharmacokinetic-pharmacodynamic (PK/PD) model that captured important aspects of the BP homeostasis mechanism. Four conceptual units characterized the feedback PD model: a sinusoidal BP set point, an effect compartment, a linear effect model, and a system response. To explore approaches for minimizing the BP increase, we coupled the PD model to a modified PK model to guide oral controlled-release (CR) development. The proposed PK/PD model captured the central tendency of the observed data. The simulated BP response obtained with theoretical release rate profiles suggested some amelioration of the peak BP response with CR. This triggered subsequent CR formulation development; we used actual dissolution data from these candidate CR formulations in the PK/PD model to confirm a potential benefit in the peak BP response. Though this paradigm has yet to be tested in the clinic, our model-based approach provided a common rational framework to more fully utilize the limited available information for advancing the program.

Synthesis and study of alendronate derivatives as potential prodrugs of alendronate sodium for the treatment of low bone density and osteoporosis.

Alendronate derivatives were evaluated as potential prodrugs for the osteoporosis drug alendronate sodium in an attempt to enhance the systemic exposure after oral administration. An investigation of the chemical behavior of alendronate derivatives led to development of practical synthetic strategies and prediction of each structural class's prodrug potential. Pharmacokinetic studies of N-myristoylalendronic acid revealed that 25% have been converted in vivo after i.v. administration in rat, providing an important proof-of-concept for this strategy.