Plasma Concentration Profiles Research Articles

Drug dissolution and transit in a heterogenous gastric chyme after fed administration: Semi-mechanistic modeling and simulations for an immediate-release and orodispersible tablets containing a poorly soluble drug

Mathematical models that treat the fed stomach content as a uniform entity emptied with a constant rate may not suffice to explain pharmacokinetic profiles recorded in clinical trials. In reality, phenomena such as the Magenstrasse or chyme areas of different pH and viscosity, play an important role in the intragastric drug dissolution and its transfer to the intestine. In this study, we investigated the data gathered in the bioequivalence trial between an immediate-release tablet (Reference) and an orally dispersible tablet (Test) with a poorly soluble weak base drug administered with or without water after a high-fat high-calorie breakfast. Maximum concentrations (Cmax) were significantly greater after administering the Reference product than the Test tablets, despite similar in vitro dissolution profiles. To explain this difference, we constructed a novel semi-mechanistic IVIVP model including a heterogeneous gastric chyme. The drug dissolution in vivo was modeled from the in vitro experiments in biorelevant media simulating gastric and intestinal fluids in the fed state (FEDGAS and FeSSIF). The key novelty of the model was separating the stomach contents into two compartments: isolated chyme (the viscous food content) that carries the drug slowly, and aq_chyme open for rapid Magenstrasse-like routes of drug transit. Drug distribution between these two compartments was both formulation- and administration-dependent, and recognized the respective drug fractions from the clinical pharmacokinetic data. The model’s assumption about the nonuniform mixing of the API with the chyme, influencing differential drug dissolution and transit kinetics, led to simulating plasma concentration profiles that reflected well the variability observed in the clinical trial. The model indicated that, after administration, the Reference product mixes to a greater extent with aq_chyme, where the released drug dissolves better and transfers faster to the intestine. In conclusion, this novel approach underlines that diverse gastric emptying of different oral dosage forms may significantly impact pharmacokinetics and affect the outcomes of bioequivalence trials.

Injectable testosterone PLGA microsphere with different characteristics: effect of preparation method (paddle mixing versus microfluidic device)

The purpose of this study was to compare the characteristics of testosterone polylactic-co-glycolic (PLGA) microspheres prepared by a paddle mixer or microfluidics device. The comparison was conducted by not only in vitro evaluation but also in vivo evaluation which has not been reported up to date. We discovered that, among the steps in microsphere preparation, the solvent removal process strongly impacted drug content, particle size and surface morphology. Spectroscopic measurements suggested that molecular interactions and crystallinity of the drug incorporated in the microspheres differed. For the drug release profile, although both mixer- and microfluidics-prepared samples showed similar sustained release of the incorporated drug for approximately one month in vitro, they exhibited different plasma concentration profiles in vivo. Together, our findings show that the preparation process, especially the solvent removal process, may affect the physicochemical characteristics of testosterone PLGA microspheres, leading to different in vivo performance.

In Vitro In Vivo Extrapolation and Bioequivalence Prediction for Immediate-Release Capsules of Cefadroxil Based on a Physiologically-Based Pharmacokinetic ACAT Model.

Physiologically based pharmacokinetic (PBPK) modeling is a mechanistic concept, which helps to judge the effects of biopharmceutical properties of drug product such as in vitro dissolution on its pharmacokinetic and in vivo performance. With the application of virtual bioequivalence (VBE) study, the drug product development using model-based approach can help in evaluating the possibility of extending BCS-based biowaiver. Therefore, the current study was intended to develop PBPK model as well as in vitro in vivo extrapolation (IVIVE) for BCS class III drug i.e. cefadroxil.A PBPK model was created in GastroPlus™ 9.8.3 utilizing clinical data of immediate-release cefadroxil formulations. By the examination of simulated and observed plasma drug concentration profiles, the predictability of the proposed model was assessed for the prediction errors. Furthermore, mechanistic deconvolution was used to create IVIVE, and the plasma drug concentration profiles and pharmacokinetic parameters were predicted for different virtual formulations with variable cefadroxil in vitro release. Virtual bioequivalence study was also executed to assess the bioequivalence of the generic verses the reference drug product (Duricef®).The developed PBPK model satisfactorily predicted Cmax and AUC0-t after cefadroxil single and multiple oral dose administrations, with all individual prediction errors within the limits except in a few cases. Second order polynomial correlation function obtained accurately predict in vivo drug release and plasma concentration profile of cefadroxil test and reference (Duricef®) formulation. The VBE study also proved test formulation bioequivalent to reference formulation and the statistical analysis on pharmacokinetic parameters reported 90% confidence interval for Cmax and AUC0-t in the FDA acceptable limits.The analysis found that a validated and verified PBPK model with a mechanistic background is as a suitable approach to accelerate generic drug development.

Review of the pharmacokinetics of French maritime pine bark extract (Pycnogenol®) in humans.

The French maritime pine bark extract Pycnogenol® is a proprietary product from Pinus pinaster Aiton. It complies with the quality specifications in the United States Pharmacopeia monograph "Pine extract" in the section of dietary supplements. Pycnogenol® is standardized to contain 65-75% procyanidins which are a variety of biopolymers consisting of catechin and epicatechin monomeric units. The effects of Pycnogenol® have been researched in a multitude of human studies. The basis for any in vivo activity is the bioavailability of constituents and metabolites of the extract. General principles of compound absorption, distribution, metabolism and elimination as well as specific data from studies with Pycnogenol® are summarized and discussed in this review. Based on plasma concentration profiles it can be concluded that low molecular weight constituents of the extract, such as catechin, caffeic and ferulic acid, taxifolin are readily absorbed from the small intestine into systemic circulation. Procyanidin oligomers and polymers are subjected to gut microbial degradation in the large intestine yielding small bioavailable metabolites such as 5-(3',4'-dihydroxyphenyl)-γ-valerolactone. After intake of Pycnogenol®, constituents and metabolites have been also detected in blood cells, synovial fluid and saliva indicating a substantial distribution in compartments other than serum. In studies simultaneously investigating concentrations in different specimen, a preferential distribution of individual compounds has been observed, e.g., of ferulic acid and 5-(3',4'-dihydroxyphenyl)-γ-valerolactone into synovial fluid compared to serum. The main route of elimination of constituents and metabolites of the French pine bark extract is the renal excretion. The broad knowledge accumulated regarding the pharmacokinetics of compounds and metabolites of Pycnogenol® constitute a rational basis for effects characterized on a cellular level and observed in human clinical studies.

Physiologically-based pharmacokinetic modelling guided dose evaluations of nirmatrelvir/ritonavir in renal impairment for the management of COVID-19.

We aimed to address factors contributing to the pharmacokinetic changes of nirmatrelvir/ritonavir in renal impaired (RI) patients and recommend dosing adjustment via a physiologically-based pharmacokinetic (PBPK) modelling approach. A PBPK model of nirmatrelvir/ritonavir was developed via Simcyp® Simulator. Sensitivity analysis of the influence of hepatic CYP3A4 intrinsic clearance and abundance, as well as hepatic non-CYP3A4 metabolism (other human liver microsomes [HLM] CLint) was performed to evaluate the effects of RI on oral clearance of nirmatrelvir. Other HLM CLint, the most sensitive parameter, was adjusted, and the simulated plasma concentration profiles of nirmatrelvir in severe RI subjects were within the therapeutic index of 292-10 000 ng/mL for dosing regimens of loading doses of 300/100 mg followed by 150/100 mg or 75/100 mg twice daily of nirmatrelvir/ritonavir. Considering that nirmatrelvir is available as a 150 mg tablet, we recommend 300/100 mg followed by 150/100 mg twice daily as the dosing regimen to be investigated in severe RI.

CORRELATION BETWEEN PLASMA CONCENTRATION OF VILOCCI, A CEFTIOFUR FORMULATION, AND MINIMUM INHIBITORY CONCENTRATION VALUES OF ZOOTECHNICAL INTEREST MICROORGANISMS IN CATTLE AND PIGS

Ceftiofur is a third-generation cephalosporin widely used in cattle and swine farming to treat respiratory and reproductive conditions. The veterinary pharma industry consistently develops new formulations with this molecule to bring highly effective products to market with short withdrawal periods, ensuring consumer safety for products derived from treated animals.
 This study aimed to evaluate the plasma concentration profile of Vilocci, a new formulation of ceftiofur, in comparison to the minimum inhibitory concentrations (MIC) of various pathogens commonly found in bovine and swine farming. Ten animals from each species were used, and a single dose of 1 mg/kg was given to bovines and 5 mg/kg to swine. Blood samples were collected at 12 time points to construct the pharmacokinetic profile.
 In addition, the minimum inhibitory concentration (MIC) of growth for the pathogens of interest isolated from the target species was determined. The effectiveness of Vilocci (Ceftiofur hydrochloride 50mg/mL) against each of the evaluated pathogens was also assessed.

Population pharmacokinetic modeling of oral brepocitinib in healthy volunteers and patients with immuno-inflammatory diseases.

The objective of this population pharmacokinetic (PK) analysis was to characterize the concentration-time profile of brepocitinib plasma concentration after single- and multiple-oral administration in healthy volunteers (HVs) and patients with immuno-inflammatory diseases. Blood samples from phase I HV and phase II clinical studies of patients with alopecia areata, psoriasis, psoriatic arthritis, ulcerative colitis (UC), vitiligo, and hidradenitis suppurativa were analyzed using a nonlinear mixed-effects modeling approach. Effects of patients' characteristics on brepocitinib exposure were investigated. Overall, 8552 brepocitinib plasma concentrations from 775 individuals were included in the analysis. The PKs of brepocitinib were adequately described by a two-compartment model with first-order absorption and a lag time for tablet formulation, dose-dependent bioavailability, and Box-Cox transformed interindividual variabilities on apparent clearance (CL/F) and apparent central volume of distribution (Vc/F). For a typical 70-kg non-Asian female patient with baseline aspartate aminotransferase of 22 unit/liter, CL/F and Vc/F estimates were 17.5 L/h and 88.5 L, respectively. Asians had a higher exposure (independent of body weight), caused by a 10% lower CL/F when compared to other individuals. Independent of baseline body weight, the male population showed 13% higher Vc/F compared to the female population. Patients with UC were predicted to have 46% slower absorption rate compared to other individuals. The PKs of brepocitinib were well-characterized by a two-compartment model with first-order absorption and dose-dependent bioavailability. Several covariates, such as race and sex, were identified to have statistically significant, but not clinically meaningful, effects on the estimated PK parameters.

Laser-machined two-stage nozzle optimised for laser wakefield acceleration

In this paper, the modelling and manufacturing of a two-stage supersonic gas jet nozzle enabling the formation of adaptive plasma concentration profiles for injection and acceleration of electrons using few-cycle laser beams are presented. The stages are modelled using the rhoSimpleFoam algorithm of the OpenFOAM computational fluid dynamics software. The first 200–300 ${\rm \mu}$ m diameter nozzle stage is dedicated to 1 % N2 + He gas jet formation and electron injection. By varying the pressure between the first and second stages of the injectors, the electron injection location could be adjusted, and the maximum acceleration distance could be ensured. By changing the concentration of the nitrogen in the gas mixture, the charge of the accelerated electrons could be controlled. The second nozzle stage is designed for acceleration in fully ionised He or hydrogen gas and forms the optimal plasma concentration for bubble formation depending on the laser pulse energy, duration and focused beam diameter. In order to reduce the diameter of the plasma profile formed by the first nozzle and the concentration drop gap between the two nozzles, a one-side straight section was introduced in the first nozzle. The shock wave reflected from the straight section of the wall propagates parallel to the shock wave of the intersecting supersonic jets and ensures a minimal gap between the jets. The second-stage longitudinal plasma concentration profile could have an increasing gas density gradient to compensate for dephasing between the electron bunch and the plasma wave due to wave shortening with increasing plasma concentration.

Population pharmacokinetics and humanized dosage regimens matching the peak, area, trough, and range of amikacin plasma concentrations in immune-competent murine bloodstream and lung infection models.

Amikacin is an FDA-approved aminoglycoside antibiotic that is commonly used. However, validated dosage regimens that achieve clinically relevant exposure profiles in mice are lacking. We aimed to design and validate humanized dosage regimens for amikacin in immune-competent murine bloodstream and lung infection models of Acinetobacter baumannii. Plasma and lung epithelial lining fluid (ELF) concentrations after single subcutaneous doses of 1.37, 13.7, and 137 mg/kg of body weight were simultaneously modeled via population pharmacokinetics. Then, humanized amikacin dosage regimens in mice were designed and prospectively validated to match the peak, area, trough, and range of plasma concentration profiles in critically ill patients (clinical dose: 25-30 mg/kg of body weight). The pharmacokinetics of amikacin were linear, with a clearance of 9.93 mL/h in both infection models after a single dose. However, the volume of distribution differed between models, resulting in an elimination half-life of 48 min for the bloodstream and 36 min for the lung model. The drug exposure in ELF was 72.7% compared to that in plasma. After multiple q6h dosing, clearance decreased by ~80% from the first (7.35 mL/h) to the last two dosing intervals (~1.50 mL/h) in the bloodstream model. Likewise, clearance decreased by 41% from 7.44 to 4.39 mL/h in the lung model. The humanized dosage regimens were 117 mg/kg of body weight/day in mice [administered in four fractions 6 h apart (q6h): 61.9%, 18.6%, 11.3%, and 8.21% of total dose] for the bloodstream and 96.7 mg/kg of body weight/day (given q6h as 65.1%, 16.9%, 10.5%, and 7.41%) for the lung model. These validated humanized dosage regimens and population pharmacokinetic models support translational studies with clinically relevant amikacin exposure profiles.

A preliminary study on plasma concentration, short-term efficacy, and safety profile of dolutegravir in Chinese people with HIV

ABSTRACT Background This study examined the plasma concentration, clinical efficacy, and safety of dolutegravir (DTG) in Chinese people with HIV(PWH). Methods In this observational study, HIV-positive individuals on DTG-based regimens for at least six months were included. Plasma DTG concentrations were measured one month after initiating treatment. Viral loads (VL) and CD4+ T cell counts were evaluated at baseline and after one and six months of therapy. High-performance liquid chromatography was used for measuring DTG concentrations, polymerase chain reaction for VL, and flow cytometry for CD4+ T cell counts. Safety assessments included monitoring liver enzymes, serum creatinine estimated glomerular filtration rate and adverse reactions. Results Eighty-two Chinese PWH were enrolled. Average VL decreased significantly from baseline by 3.1 log at one month and 3.5 log at six months. CD4+ T cell counts increased from 273 cells/mm3 at baseline to 378 cells/mm3 and 446 cells/mm3 after one and six months, respectively. 75% achieved undetectable VLs (<20 copies/mL) by six months. Cmax and Cτ were 4.63 and 1.98 μg/mL, respectively. Safety profile was favorable with only 4.88% experiencing transient dizziness. Conclusion Preliminary findings suggest higher DTG plasma concentrations in Chinese PWH compared to Western populations, with promising short-term efficacy and safety.

Evaluation of in vitro dissolution profiles of modified-release metoprolol succinate tablets crushed using mortar and pestle technique

PurposeClinical practice guidelines advise against crushing modified-release dosage forms. Metoprolol succinate modified-release (MS-MR) tablets are commonly crushed in clinical practice to facilitate administration to patients with swallowing difficulties or using feeding tubes. To date, the effect of this practice remains unexplored. The in vitro effects of crushing commercially available MS-MR tablets were explored using a holistic approach. MethodsDissolution profiles of crushed versus whole MS-MR tablets were compared. Tablets were crushed to powder state using pragmatic method mimicking hospital practices. For standardization purposes, the same operator, duration (60 seconds), hand, and mortar-pestle apparatus were used. Dissolution studies were conducted per U.S. Pharmacopeia at pH 1.2, pH 4.5, and pH 6.8 with USP apparatus 2 (paddle) at rotation speed of 50 rpm at 37±0.5 °C in 500 mL dissolution media. Samples were withdrawn at predetermined time points. Percent drug dissolved was measured by validated UV–vis Spectrophotometry. Comprehensive analysis of the dissolution data was conducted using model-independent, model-dependent, and ANOVA-based approaches (SPSS v.23 at α=0.05). Similarity (f2) and difference (f1) factors were calculated to compare the dissolution profiles between crushed (CT) and whole tablets (WT). Goodness of fit (GOF) analysis examined the compliance between in vitro dissolution behaviors and several drug release models. Model selection was based on GOF plots, Akaike criteria and adjusted coefficient of determination (R2adj). Imaging and particle size distribution analysis were conducted to examine associated surface and morphologic changes. ResultsThe dissolution profiles were not similar at pH 4.5 (f2=45.43, f1=18.97) and pH 6.8 (f2=31.47, f1=32.94). CT best fitted with Higuchi (pH 1.2: R2adj=0.9990), Weibull (pH 4.5: R2adj=0.9884), and Korsmeyer-Peppas (pH 6.8: R2adj=0.9719). Contrastingly, WT best fitted with Hopfenberg (pH 1.2: R2adj=0.9986), logistic (pH 4.5: R2adj=0.9839) and first-order (pH 6.8: R2adj=0.9979) models. A significant difference in the dissolution profiles was found between CT and WT using multivariate analysis of variance per time points and between the tablet forms (p=0.004). This was confirmed by unparalleled dissolution profiles. Crushing resulted in variations in particle size and surface morphological changes to the micropellets. ConclusionCrushing practices change the dissolution profile of MS-MR tablets by deforming the surface morphology of embedded micropellets. Amounts of drug dissolved between CT and WT were not the same at the compared time points across gastrointestinal pH ranges. This suggests potential clinical impact on plasma-concentration profiles of critically ill patients using feeding tube.

Mixing energy as an adjustment tool for aerodynamic behaviour of an inhaled product: In-vitro and in-vivo effects

This paper describes the development of a fixed dose dry powder combination of indacaterol maleate (Inda) and glycopyrronium bromide (Glyco) in Easyhaler® inhaler for a comparative pharmacokinetic (PK) study, as well as the outcome of such a study. The development aim was to produce formulations with three different in vitro dispersibility profiles for both Inda and Glyco. This so-called ‘rake’ approach allows for quantitation of the candidate formulations relative to the reference product Ultibro® Breezhaler® in terms of the key PK parameters.Three formulations (A, B and C) were produced based on the mixing energy concept. For both APIs, formulation A (lowest mixing energy) displayed the highest fine particle fractions and formulation C (highest mixing energy) the lowest. GMP manufacturing confirmed the performance of the three formulations.The candidate formulations were tested against the reference product in a single dose PK study in healthy volunteers. Clear differences in Inda plasma concentration profiles were observed between the treatments when administered concomitantly with charcoal, with Easyhaler A showing the highest Cmax value and Easyhaler C the lowest. Easyhaler B was bioequivalent to Ultibro Breezhaler with regard to the primary PK parameters of Inda, Cmax and AUC72h. For Glyco, Easyhaler formulations A, B and C provided lower peak concentrations than Ultibro Breezhaler. For AUC72h of Glyco, Easyhaler B was bioequivalent to the reference product. Additional measures for adjustment of formulation performance can be foreseen, whose effects can be predicted based on mixing energy theory.

Therapeutic drug monitoring of perampanel: Clinical utility and impact of co-medication on pharmacokinetic variability

BackgroundPerampanel (PER) is a newly developed antiseizure medication (ASM). This study aimed to determine the utilization of therapeutic drug monitoring (TDM) for PER in a real-world clinical setting and investigate the influence of concomitant use of ASMs on the plasma concentration profile of PER. MethodWe analyzed data from the Chang Gung Research Database, which is the largest multi-institutional electronic medical records database in Taiwan. The main outcomes were the comparisons of PER plasma concentration and the ratio of concentration to the weight-adjusted dose (C/D; [ng/mL]/[mg/kg/d]) among patients received TDM of different clinical indication and among different ASM co-medication subgroups. ResultsOverall, 88 plasma samples were collected from 66 epilepsy patients treated with PER. The majority of patients (77.3 %) underwent PER TDM owing to poorly controlled seizures. There was a trend toward a higher plasma concentration and C/D ratio in those suspected of having PER toxicity owing to adverse events than of other indications. The PER concentration exhibited dose linearity. The mean PER plasma concentrations in patients co-medicated with enzyme-inducing ASMs were significantly lower than those in the patients who were not prescribed enzyme-inducing or enzyme-inhibiting ASMs, and co-medication with carbamazepine (CBZ) resulted in a significant reduction in the PER concentration. ConclusionPER concentration exhibited a linear regression relationship with PER dose, and the plasma concentration of the drug was highly susceptible to the drug's interactions with enzyme-inducing ASMs. TDM with clear indication could help determine the influence of ASMs used concomitantly on PER concentrations and guide clinical adjustments.

Population pharmacokinetic modeling of levodropropizine: extended application to comparative analysis between commercial formulations and exploration of pharmacokinetic effects of diet.

Levodropropizine, a nonopioid antitussive agent, is being increasingly used in clinical practice with the development of several formulations for symptomatic relief of acute and chronic bronchitis. However, scientific and quantitative population pharmacokinetic analyses of levodropropizine are lacking. Moreover, no integrated quantitative comparison has been performed between formulations. This study quantitatively evaluated and predicted pharmacokinetic properties of formulations through population pharmacokinetic model-based comparisons of commercially available formulations. Plasma concentration profile results from bioequivalence studies of 60-mg immediate release (IR) levodropropizine tablets in 40 healthy Korean males were used as population pharmacokinetic modeling data. For interindividual variability in levodropropizine pharmacokinetics, body surface area was identified as an effective covariate that was positively correlated with peripheral compartment distribution volume. Population pharmacokinetic model for IR tablets well-described the levodropropizine syrup and capsule datasets, suggesting no significant differences in pharmacokinetics among IR tablets, syrups, and capsules of levodropropizine. In contrast, pharmacokinetic profiles differed between 90-mg controlled release (CR) and IR levodropropizine tablets; however, separate parameter estimation was possible by applying the same model structure. In terms of pharmacokinetics, twice-daily regimen of 90-mg CR tablets was equivalent to thrice-daily regimen of 60-mg IR tablets. However, at steady-state, interindividual plasma concentration variability within population was reduced by approximately 36.71-83.18%. For levodropropizine CR tablets, a high-fat diet significantly delayed gastrointestinal absorption but maintained overall plasma exposure equivalent. This study provides useful quantitative judgment data for precision medicine of levodropropizine and can be helpful in predicting the pharmacokinetics of levodropropizine based on commercialized formulation switching.

The Pharmacokinetics of CPZEN-45, a Novel Anti-Tuberculosis Drug, in Guinea Pigs.

CPZEN-45 is a novel compound with activity against drug-susceptible and drug-resistant tuberculosis (TB). The present study was undertaken to determine the best dose and dosing regimen of inhalable CPZEN-45 powders to use in efficacy studies with TB-infected guinea pigs. The disposition of CPZEN-45 after intravenous, subcutaneous (SC), and direct pulmonary administration (INS) was first determined to obtain their basal pharmacokinetic (PK) parameters. Then, the disposition of CPZEN-45 powders after passive inhalation using consecutive and sequential doses was evaluated. Plasma concentration versus time curves and PK parameters indicated that the absorption of CPZEN-45 after INS was faster than after SC administration (Ka = 12.94 ± 5.66 h-1 and 1.23 ± 0.55 h-1, respectively), had a longer half-life (2.06 ± 1.01 h versus 0.76 ± 0.22 h) and had higher bioavailability (67.78% and 47.73%, respectively). The plasma concentration versus time profiles and the lung tissue concentration at the end of the study period were not proportional to the dose size after one, two, and three consecutive passive inhalation doses. Three sequential passive inhalation doses maintained therapeutic concentration levels in plasma and lung tissue for a longer time than three consecutive doses (10 h vs. 3 h, respectively). Future studies to evaluate the efficacy of inhaled CPZEN-45 powders should employ sequential doses of the powder, with one nominal dose administered to animals three times per day.

Phys-DAT: A physiologically-based pharmacokinetic model for unraveling the dissolution, transit and absorption processes using PhysPK®

In silico methods have become the key for efficiently testing and qualifying drug properties. Due to the complexity of the LADME processes and drug characteristics associated to oral drug absorption, there is a growing demand in the development of Physiologically-based Pharmacokinetic (PBPK) software with greater flexibility. Thus, the aims of this work are (i) to develop a mechanistic-based modeling framework of dissolution, transit and absorption (Phys-DAT) processes in the PhysPK platform and (ii) to assess the predictive power of the acausal MOOM methodology embedded in Phys-DAT versus reference ODE-based PBPK software. A PBPK model was developed including unreleased, undissolved and dissolved thermodynamic states of the drug. The gastrointestinal tract (GI) was represented by nine compartments and first-order transit kinetics was assumed for the drug fractions. Dissolution processes were described using solubility-independent or solubility-dependent mechanisms and pH effects. Linear transit and linear absorption mechanisms including gradual decrease absorption rate were considered to represent the passive diffusion process. Internal validation of the Phys-DAT model was performed through simulation-based analysis, considering different theoretical scenarios. External validation was carried out using in silico and in vivo data of GI segments and plasma concentrations. Both BCS I and II class drugs were included. The model predicts plasma-concentration profiles of each compartment for undissolved, dissolved, and absorbed fractions using PhysPK® v.2.4.1. Internal and external validations demonstrate that the model aligned with the theoretical assumptions and accurately predicted Cmax, Tmax, and AUC 0-t for both BCS I and II drugs. Average Fold Error (AFE), Absolute Average Fold Error (AAFE), and Percent Prediction Error (PPE) calculations indicate good predictive performance, with predicted/observed ratios falling within the acceptable range. Phys-DAT represents a mechanistic model for predicting oral absorption, including the dissolution, pH effect, transit, and absorption processes. PhysPK has shown to be a tool with strong prediction accuracy, similar to the obtained by ODE-based PBPK reference software, and the results obtained with the Phys-DAT model for oral administered drugs showed predictive reliability in healthy volunteers, setting the basis to determine the interchangeability of the acausal MOOM methodology with other modeling approaches.

The Pharmacokinetics of Inhaled Drugs.

The pharmacokinetic (PK) profile of a drug after inhalation may differ quite markedly from that seen after dosing by other routes of administration. Drugs may be administered to the lung to elicit a local action or as a portal for systemic delivery of the drug to its site of action elsewhere in the body. Some knowledge of PK is important for both locally- and systemically-acting drugs. For a systemically-acting drug, the plasma concentration-time profile shares some similarities with drug given by the oral or intravenous routes, since the plasma concentrations (after the distribution phase) will be in equilibrium with concentrations at the site of action. For a locally-acting drug, however, the plasma concentrations reflect its fate after it has been absorbed and removed from the airways, and not what is available to its site of action in the lung. Consequently, those typical PK parameters which are determined from plasma concentration measurements, e.g., area under the curve (AUC), Cmax, tmax and post-peak t1/2 may provide information on the deposition and absorption of drugs from the lung; however, the information from these parameters becomes more complicated to decipher for those drugs which are locally-acting in the lung. Additionally, the plasma concentration profile for both locally- and systemically-acting drugs will not only reflect drug absorbed from the lung but also that absorbed from the gastrointestinal (GI) tract from the portion of the dose which is swallowed. This absorption from the GI tract adds a further complication to the interpretation of plasma concentrations, particularly for locally-acting drugs. The influence of physiological and pathological factors needs to be considered in the absorption of some inhaled drugs. The absorption of some hydrophilic drugs is influenced by the inspiratory maneuver used during initial inhalation of the drug, and at later times after deposition. Similarly, the effects of smoking have been shown to increase lung permeability and increase the absorption of certain hydrophilic drugs. The effects of different disease states of the lung have less defined influences on absorption into the systemic circulation.

The Development of Dermal Self-Double-Emulsifying Drug Delivery Systems: Preformulation Studies as the Keys to Success.

Self-emulsifying drug delivery systems (SEDDSs) are lipid-based systems that are superior to other lipid-based oral drug delivery systems in terms of providing drug protection against the gastrointestinal (GI) environment, inhibition of drug efflux as mediated by P-glycoprotein, enhanced lymphatic drug uptake, improved control over plasma concentration profiles of drugs, enhanced stability, and drug loading efficiency. Interest in dermal spontaneous emulsions has increased, given that systems have been reported to deliver drugs across mucus membranes, as well as the outermost layer of the skin into the underlying layers. The background and development of a double spontaneous emulsion incorporating four anti-tubercular drugs, clofazimine (CFZ), isoniazid (INH), pyrazinamide (PZY), and rifampicin (RIF), are described here. Our methods involved examination of oil miscibility, the construction of pseudoternary phase diagrams, the determination of self-emulsification performance and the emulsion stability index of primary emulsions (PEs), solubility, and isothermal micro calorimetry compatibility and examination of emulsions via microscopy. Overall, the potential of self-double-emulsifying drug delivery systems (SDEDDSs) as a dermal drug delivery vehicle is now demonstrated. The key to success here is the conduct of preformulation studies to enable the development of dermal SDEDDSs. To our knowledge, this work represents the first successful example of the production of SDEDDSs capable of incorporating four individual drugs.

Novel modeling approach integrating population pharmacokinetics and interspecies scaling to predict human pharmacokinetics of the new anti-tuberculosis agent telacebec (Q203)

Telacebec is a new anti-tuberculosis agent with promising therapeutic activity and a favorable safety profile. This study aimed to characterize the pharmacokinetics of telacebec via interspecies scaling and population pharmacokinetic modeling for the prediction of human pharmacokinetics. Preclinical pharmacokinetic data were obtained from mice, rats, and dogs following intravenous and oral doses of telacebec. A population pharmacokinetic model was developed to describe the pharmacokinetic data from all three species. The disposition parameters were well correlated with the body weight for all species using an allometric equation. Thus, the allometric scaling was incorporated into the population pharmacokinetic model, which could simultaneously describe the plasma concentration vs. time data from all preclinical studies as well as the Phase 1A clinical study. The developed model was used to predict the pharmacokinetics of telacebec after IV injection, including the clearance (CL) of 168.58 [118.86 – 238.73] mL/min and volume of distribution (Vss) of 968.84 [396.87 – 2831.31] L for 80-kg human. The absolute bioavailability of telacebec in humans in the fed state was estimated as 70.34 ± 9.91%. Finally, the population pharmacokinetic model with allometric scaling was utilized to simulate the plasma concentration vs. time profiles of telacebec after multiple oral doses in humans. The model-predicted profiles well agreed with the observed data in Phase 1B clinical trial. The present pharmacokinetic model may help better understand the activity of telacebec, leading to the design of optimal dosing regimens and new formulation development.

ADME characterization and PBK model development of 3 highly protein-bound UV filters through topical application.

Estimating human exposure in the safety assessment of chemicals is crucial. Physiologically based kinetic (PBK) models which combine information on exposure, physiology, and chemical properties, describing the absorption, distribution, metabolism, and excretion (ADME) processes of a chemical, can be used to calculate internal exposure metrics such as maximum concentration and area under the concentration-time curve in plasma or tissues of a test chemical in next-generation risk assessment. This article demonstrates the development of PBK models for 3 UV filters, specifically octyl methoxycinnamate, octocrylene, and 4-methylbenzylidene camphor. The models were parameterized entirely based on data obtained from in vitro and/or in silico methods in a bottom-up modeling approach and then validated based on human dermal pharmacokinetic (PK) data. The 3 UV filters are "difficult to test" in in vitro test systems due to high lipophilicity, high binding affinity for proteins, and nonspecific binding, for example, toward plastic. This research work presents critical considerations in ADME data generation, interpretation, and parameterization to assure valid PBK model development to increase confidence in using PBK modeling to help make safety decisions in the absence of human PK data. The developed PBK models of the 3 chemicals successfully simulated the plasma concentration profiles of clinical PK data following dermal application, indicating the reliability of the ADME data generated and the parameters determined. The study also provides insights and lessons learned for characterizing ADME and developing PBK models for highly lipophilic and protein-bound chemicals in the future.