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To explore the application of the parameters of the physiologically based finite time pharmacokinetic (PBFTPK) models subdivided in first-order (PBFTPK)1 and zero-order (PBFTPK)0 models to bioavailability and bioequivalence. To develop a methodology for the estimation of absolute bioavailability, F, from oral data exclusively. Simulated concentration time data were generated from the Bateman equation and compared with data generated from the (PBFTPK)1 and (PBFTPK)0 models. The blood concentration Cb(τ) at the end of the absorption process τ, was compared to Cmax; the utility of $$ {(AUC)}_0^{\tau } $$ and $$ {(AUC)}_t^{\infty } $$ in bioequivalence assessment was also explored. Equations for the calculation of F from oral data were derived for the (PBFTPK)1 and (PBFTPK)0 models. An estimate for F was also derived from an areas proportionality using oral data exclusively. The simulated data of the (PBFTPK)0 models exhibit rich dynamics encountered in complex drug absorption phenomena. Both (PBFTPK)1 and (PBFTPK)0 models result either in Cmax = Cb(τ) or Cmax > Cb(τ) for rapidly- and not rapidly-absorbed drugs, respectively; in the latter case, Cb(τ) and τ are meaningful parameters for drug’s rate of exposure. For both (PBFTPK)1 and (PBFTPK)0 models, $$ {(AUC)}_0^{\tau } $$ or portions of it cannot be used as early exposure rate indicators. $$ {(AUC)}_{\tau}^{\infty } $$ is a useful parameter for the assessment of extent of absorption for very rapidly absorbed drugs. An estimate for F for theophylline formulations was found close to unity. The (PBFTPK)1 and (PBFTPK)0 models are more akin to in vivo conditions. Estimates for F can be derived from oral data exclusively.

Cyclodextrin (CD) is commonly used to enhance the solubility of oral drugs. However, with the increase of CD concentrations, the fraction of free drug molecules decreases, which may potentially impede drug absorption. This study aims to predict the optimal ratio between drug and CD to achieve the best absorption efficiency by computational simulation. First, a physiologically based pharmacokinetic (PBPK) model was developed. This model can continuously adjust absorption according to free drug fraction and was validated against two model drugs, progesterone (PG) and andrographolide (AG). The further analysis involves 3-D surface graphs to investigate the relationship between free drug amount, theoretically absorbable concentration, and contents of drug and CD in the formulation. The PBPK model predicted the PK behavior of two drugs well. The concentration ratio of drug to CD, leading to maximal free drug amount and the best absorption efficiency, is nearly the same as the slope determined in the phase solubility test. The new modified PBPK model and 3-D surface graph can easily predict the absorption difference of formulations with various drug/CD ratios. This PBPK model and 3-D surface graph can predict the absorption and determine the optimal concentration ratio of CD formulation, which could accelerate the R&D of CD formulation.

PURPOSE: The involvement of the intestinally expressed xenobiotic transporters P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) have been implicated in apixaban disposition based on in vitro studies. Recommendations against co-administration of apixaban with inhibitors of these efflux transporters can be found throughout the literature as well as in the apixaban FDA label. However, the clinical relevance of such findings is questionable due to the high permeability and high solubility characteristics of apixaban. METHODS: Using recently published methodologies to discern metabolic- from transporter- mediated drug-drug interactions, a critical evaluation of all published apixaban drug-drug interaction studies was conducted to investigate the purported clinical significance of efflux transporters in apixaban disposition. RESULTS: Rational examination of these clinical studies using basic pharmacokinetic theory does not support the clinical significance of intestinal efflux transporters in apixaban disposition. Further, there is little evidence that efflux transporters are clinically significant determinants of systemic clearance. CONCLUSIONS: Inhibition or induction of intestinal CYP3A4 can account for exposure changes of apixaban in all clinically significant drug-drug interactions, and lack of intestinal CYP3A4 inhibition can explain all studies with no exposure changes, regardless of the potential for these perpetrators to inhibit intestinal or systemic efflux transporters.

To provide a comprehensive and up-to-date overview focusing on the extent of lymphatic transport of drugs following intestinal absorption and to summarize available data on the impact of molecular weight, lipophilicity, formulation and prandial state. Literature was searched for in vivo studies quantifying extent of lymphatic transport of drugs after enteral dosing. Pharmacokinetic data were extracted and summarized. Influence of molecular weight, log P, formulation and prandial state was analyzed using relative bioavailability via lymph (FRL) as the parameter for comparison. The methods and animal models used in the studies were also summarized. Pharmacokinetic data on lymphatic transport were available for 103 drugs. Significantly higher FRL [median (IQR)] was observed in advanced lipid based formulations [54.4% (52.0)] and oil solutions [38.9% (60.8)] compared to simple formulations [2.0% (27.1)], p

PURPOSE: To demonstrate that oral drug absorption is terminated in finite time. To develop models based on biopharmaceutical/physiological and finite absorption time concepts.The models are based on i) the passive drug diffusion mechanism under the sink conditions principle ii) the rate limiting role of the drug's properties solubility and permeability and iii) the relevant restrictions associated with the gastrointestinal transit times of drug in the stomach, the small intestines and the colon. Two input functions of constant rate are considered for the absorption of drug from i) the stomach/small intestines with an upper limit of 5 h and ii) the colon with an upper limit of 30 h. Branched differential equations were written for the time course of drug in the body.Simulations were performed using different scenarios, assuming a variety of drug properties and limited or non-existent absorption from the colon. Literature oral data of cephradine, ibuprofen, flurbiprofen and itraconazole were analyzed. For all drugs examined, nice fittings of the branched differential equations to the experimental data were observed.For all drugs the absorption process was terminated in the small intestine. The meaning of partial AUCs, Cmax, tmax are questioned. Applications of these models to IVIVC are anticipated.

During non-clinical and clinical development of a new molecular entity (NME), modeling and simulation (M&S) are routinely used to predict the exposure and pharmacokinetics (PK) of the drug compound in humans. The basic methodology and output are generally understood across all functional disciplines. However, this understanding is mostly restricted to traditional methods such as those in simplified kinetic models and void of adequate mechanistic foundation to address questions beyond the observed clinical data. In the past two decades, alternative and more mechanistic methods, particularly for describing absorption, distribution, excretion and metabolism (ADME) of drugs have been developed and applied under the general umbrella of physiologically-based pharmacokinetic (PBPK) methods. Their mechanistic nature gives the ability to ask many other questions which were not traditionally asked and provide some logically and evidenced-based potential answers. Whilst traditional PK methods are mainstream and understood by most scientists, mechanistic absorption models alongside other PBPK approaches are still deemed eclectic, despite making significant strides in the fundamental science as well as regulatory acceptance. On November 3rd, a short course was held at the annual American Association of Pharmaceutical Scientists (AAPS) meeting in San Antonio, Texas. The different talks were tailored to provide a basis or rationale for the subject, introduction to fundamental principles with historical perspective, a critique of the state-of-the-art, examples of successful application of the methods across different phases of the drug development process and the specific standards these mechanistic models should meet to be fully reliable from a regulatory perspective.

Gabapentin displays non-linear drug disposition, which complicates dosing for optimal therapeutic effect. Thus, the current study was performed to elucidate the pharmacokinetic/pharmacodynamic (PKPD) relationship of gabapentin’s effect on mechanical hypersensitivity in a rat model of CFA-induced inflammatory hyperalgesia. A semi-mechanistic population-based PKPD model was developed using nonlinear mixed-effects modelling, based on gabapentin plasma and brain extracellular fluid (ECF) time-concentration data and measurements of CFA-evoked mechanical hyperalgesia following administration of a range of gabapentin doses (oral and intravenous). The plasma/brain ECF concentration-time profiles of gabapentin were adequately described with a two-compartment plasma model with saturable intestinal absorption rate (K m = 44.1 mg/kg, V max = 41.9 mg/h∙kg) and dose-dependent oral bioavailability linked to brain ECF concentration through a transit compartment. Brain ECF concentration was directly linked to a sigmoid E max function describing reversal of hyperalgesia (EC 50, plasma = 16.7 μg/mL, EC 50, brain = 3.3 μg/mL). The proposed semi-mechanistic population-based PKPD model provides further knowledge into the understanding of gabapentin’s non-linear pharmacokinetics and the link between plasma/brain disposition and anti-hyperalgesic effects. The model suggests that intestinal absorption is the primary source of non-linearity and that the investigated rat model provides reasonable predictions of clinically effective plasma concentrations for gabapentin.

Purpose To examine the utility of human plasma as an assay medium in Caco-2 permeability studies to overcome poor mass balance and inadequate sink conditions frequently encountered with lipophilic compounds. Methods Caco-2 permeability was assessed for reference compounds with known transport mechanisms using either pH 7.4 buffer or human plasma as the assay medium in both the apical and basolateral chambers. When using plasma, Papp values were corrected for the unbound fraction in the donor chamber. The utility of the approach was assessed by measuring the permeability of selected antimalarial compounds using the two assay media. Results Caco-2 cell monolayer integrity and P-gp transporter function were unaffected by the presence of human plasma in the donor and acceptor chambers. For many of the reference compounds having good mass balance with buffer as the medium, higher Papp values were observed with plasma, likely due to improved acceptor sink conditions. The lipophilic antimalarial compounds exhibited low mass balance with buffer, however the use of plasma markedly improved mass balance allowing the determination of more reliable Papp values. Conclusions The results support the utility of human plasma as an alternate Caco-2 assay medium to improve mass balance and permeability measurements for lipophilic compounds. Electronic supplementary material The online version of this article (10.1007/s11095-018-2493-3) contains supplementary material, which is available to authorized users.

The effective rat intestinal permeability (P eff ) was deconvolved using a biophysical model based on parameterized paracellular, aqueous boundary layer, transcellular permeabilities, and the villus-fold surface area expansion factor. Four types of rat intestinal perfusion data were considered: single-pass intestinal perfusion (SPIP) in the jejunum (n = 40), and colon (n = 15), closed-loop (Doluisio type) in the small intestine (n = 78), and colon (n = 74). Moreover, in vitro Caco-2 permeability values were used to predict rat in vivo values in the rat data studied. Comparable number of molecules permeate via paracellular water channels as by the lipoidal transcellular route in the SPIP method, although in the closed-loop method, the paracellular route appears dominant in the colon. The aqueous boundary layer thickness in the small intestine is comparable to that found in unstirred in vitro monolayer assays; it is thinner in the colon. The mucosal surface area in anaesthetized rats is 0.96–1.4 times the smooth cylinder calculated value in the colon, and it is 3.1–3.6 times in the small intestine. The paracellular permeability of the intestine appeared to be greater in rat than human, with the colon showing more leakiness (higher P para ) than the small intestine. Based on log intrinsic permeability values, the correlations between the in vitro and in vivo models ranged from r2 0.82 to 0.92. The SPIP-Doluisio method comparison indicated identical log permeability selectivity trend with negligible bias.

To evaluate whether the impact of functional modulation of the breast cancer resistance protein (BCRP, ABCG2 421CA) on human pharmacokinetics after oral administration is predictable using Bcrp knockout mice and cynomolgus monkeys pretreated with a BCRP inhibitor, elacridar.The correlation of the changes of the area under the plasma concentration-time curve (AUC) caused by ABCG2 421CA with those caused by the Bcrp knockout in mice, or BCRP inhibition in monkeys, was investigated using well-known BCRP substrates (rosuvastatin, pitavastatin, fluvastatin, and sulfasalazine).In mice, the bioavailability changes, which corrected the effect of systemic clearance by Bcrp knockout, correlated well with the AUC changes in humans, whereas the correlation was weak when AUC changes were directly compared. In monkeys, the AUC changes pretreated with elacridar resulted in a good estimation of those in humans within approximately 2-fold ranges.This study suggests that pharmacokinetics studies that use the correction of the bioavailability changes in Bcrp knockout mice are effective for estimating clinical AUC changes in ABCG2 421CA variants for BCRP substrate drugs and those studies in monkeys that use a BCRP inhibitor serve for the assessment of BCRP impact on the gastrointestinal absorption in a non-rodent model.

We developed simulation and modeling methods to predict the in vivo pharmacokinetic profiles of acyclovir, following escalating oral doses of valacyclovir, in wildtype and Pept1 knockout mice. We also quantitated the contribution of specific intestinal segments in the absorption of valacyclovir in these mice. Simulations were conducted using a mechanistic advanced compartmental absorption and transit (ACAT) model implemented in GastroPlus™. Simulations were performed for 3 h post-dose in wildtype and Pept1 knockout mice following single oral doses of 10, 25, 50 and 100 nmol/g valacyclovir, and compared to experimentally observed plasma concentration-time profiles of acyclovir. Good fits were obtained in wildtype and Pept1 knockout mice. Valacyclovir was primarily absorbed from duodenum (42%) and jejunum (24%) of wildtype mice, with reduced uptake from ileum (3%) and caecum/colon (1%), for a total of 70% absorption. In contrast, the absorption of valacyclovir in Pept1 knockout mice was slow and sustained throughout the entire intestinal tract in which duodenum (4%), jejunum (14%), ileum (10%) and caecum/colon (12%) accounted for a total of 40% absorption. The ACAT model bridged the gap between in situ and in vivo experimental findings, and facilitated our understanding of the complicated intestinal absorption processes of valacyclovir.

Gabapentin exhibits saturable absorption kinetics, however, it remains unclear which transporters that are involved in the intestinal transport of gabapentin. Thus, the aim of the current study was to explore the mechanistic influence of transporters on the intestinal absorption of gabapentin by both in vivo and in vitro investigations Pharmacokinetic parameters were determined following a range of intravenous (5–100 mg/kg) and oral doses (10–200 mg/kg) in rats. Transepithelial transport (50 μM–50 mM) and apical uptake of gabapentin (0.01–50 mM) were investigated in Caco-2 cells. The effect of co-application of the LAT-inhibitor, BCH, and the b0,+-substrate, L-lysine, on intestinal transport of gabapentin was evaluated in vivo and in vitro. Gabapentin showed dose-dependent oral absorption kinetics and dose-independent disposition kinetics. Co-application of BCH inhibited intestinal absorption in vivo and apical uptake in vitro, whereas no effect was observed following co-application of L-lysine. The present study shows for the first time that BCH was capable of inhibiting intestinal absorption of gabapentin in vivo. Furthermore, in Caco-2 cell experiments BCH inhibited apical uptake of gabapentin. These findings may imply that a BCH-sensitive transport-system was involved in the apical and possibly the basolateral transport of gabapentin across the intestinal wall.