The Use of Global Sensitivity Analysis to Assess the Oral Absorption of Weakly Basic Compounds: A Case Example of Dipyridamole.

OBJECTIVE: To utilize the global system analysis (GSA) in oral absorption modeling to gain a deeper understanding of system behavior, improve model accuracy, and make informed decisions during drug development. METHODS: GSA was utilized to give insight into which drug substance (DS), drug product (DP), and/or physiological parameter would have an impact on peak plasma concentration (Cmax) and area under the curve (AUC) of dipyridamole as a model weakly basic compound. GSA guided the design of in vitro experiments and oral absorption risk assessment using FormulatedProducts v2202.1.0. The solubility and precipitation profiles of dipyridamole in different bile salt concentrations were measured. The results were then used to build a mechanistic oral absorption model. RESULTS: GSA warranted further investigation into the precipitation kinetics and its link to the levels of bile salt concentrations. Mechanistic modeling studies demonstrated that a precipitation-integrated modeling approach appropriately predicted the mean plasma profiles, Cmax, and AUC from the clinical studies. CONCLUSIONS: This work shows the value of GSA utilization in early development to guide in vitro experimentation and build more confidence in identifying the critical parameters for the mathematical models.

Study of controlled-release floating tablets of dipyridamole using the dry-coated method.

Dipyridamole (DIP), having a short biological half-life, has a narrow absorption window and is primarily absorbed in the stomach. So, the purpose of this study was to prepare controlled-release floating (CRF) tablets of dipyridamole by the dry-coated method. The influence of agents with different viscosity, hydroxypropylmethylcellulose (HPMC) and polyvinylpyrollidon K30 (PVP K30) in the core tablet and low-viscosity HPMC and PVP K30 in the coating layer on drug release, were investigated. Then, a study with a three-factor, three-level orthogonal experimental design was used to optimize the formulation of the CRF tablets. After data processing, the optimized formulation was found to be: 80 mg HPMC K4M in the core tablet, 80 mg HPMC E15 in core tablet and 40 mg PVP K30 in the coating layer. Moreover, an in vitro buoyancy study showed that the optimized formulation had an excellent floating ability and could immediately float without a lag time and this lasted more than 12 h. Furthermore, an in vivo gamma scintigraphic study showed that the gastric residence time of the CRF tablet was about 8 h.

Influence of Polymers on the Physical and Chemical Stability of Spray-dried Amorphous Solid Dispersion: Dipyridamole Degradation Induced by Enteric Polymers.

Amorphous solid dispersions (ASDs) are inherently unstable because of high internal energy. Evaluating physical and chemical stability during the process and storage is essential. Numerous researches have demonstrated how polymers influence the drug precipitation and physical stability of ASDs, while the influence of polymers on the chemical stability of ASDs is often overlooked. Therefore, this study aimed to investigate the effect of polymers on the physical and chemical stability of spray-dried ASDs using dipyridamole (DP) as a model drug. Proper polymers were selected by assessing their abilities to inhibit drug recrystallization in supersaturated solutions. HPMC E5, Soluplus®, HPMCP-55, and HPMCAS-LP were shown to be effective stabilizers. The optimized formulations were further stored at a high temperature (60 °C) and high humidity (40 °C, 75% RH) for 2 months, and their physical and chemical stability was evaluated using polarizing optical microscopy, FTIR, HPLC, and mass spectrometry (MS). In general, crystallization was observed in all samples, which indicated the physical instability under stressed storage conditions. Also, it was noted that the polymers in ASDs rather than physical mixtures, induced a dramatic drug degradation after being exposed to a high temperature (HPMCP-55 > 80% and HPMCAS-LP > 50%) and high humidity (HPMCP-55 > 40% and HPMCAS-LP > 10%). The MS analysis further confirmed the degradation products, which might be generated from the reaction between dipyridamole and phthalic anhydride decomposed from HPMCP-55 and HPMCAS-LP. Overall, the exposure of ASDs to stressed conditions resulted in recrystallization and even the chemical degradation induced by polymers.

Utilization of Gastrointestinal Simulator, an in Vivo Predictive Dissolution Methodology, Coupled with Computational Approach To Forecast Oral Absorption of Dipyridamole.

Weakly basic drugs exhibit a pH-dependent dissolution profile in the gastrointestinal (GI) tract, which makes it difficult to predict their oral absorption profile. The aim of this study was to investigate the utility of the gastrointestinal simulator (GIS), a novel in vivo predictive dissolution (iPD) methodology, in predicting the in vivo behavior of the weakly basic drug dipyridamole when coupled with in silico analysis. The GIS is a multicompartmental dissolution apparatus, which represents physiological gastric emptying in the fasted state. Kinetic parameters for drug dissolution and precipitation were optimized by fitting a curve to the dissolved drug amount-time profiles in the United States Pharmacopeia apparatus II and GIS. Optimized parameters were incorporated into mathematical equations to describe the mass transport kinetics of dipyridamole in the GI tract. By using this in silico model, intraluminal drug concentration-time profile was simulated. The predicted profile of dipyridamole in the duodenal compartment adequately captured observed data. In addition, the plasma concentration-time profile was also predicted using pharmacokinetic parameters following intravenous administration. On the basis of the comparison with observed data, the in silico approach coupled with the GIS successfully predicted in vivo pharmacokinetic profiles. Although further investigations are still required to generalize, these results indicated that incorporating GIS data into mathematical equations improves the predictability of in vivo behavior of weakly basic drugs like dipyridamole.

Formulation and evaluation of gastroretentive floating drug delivery system of dipyridamole.

A multiple-unit floating alginate bead drug delivery system with prolonged stomach retention time was developed in this study. The floating alginate beads were prepared by ionic cross-linking method, using CaCO3 as the gas-forming agent. Over 92% of the beads remained floating after 9 h. In order to prepare sustained-release dosage forms of dipyridamole, the solid dispersion technique was applied using a blend of Eudragit L100 and Eudragit RLPO. Afterwards, the solid dispersions of dipyridamole were incorporated into the floating alginate beads. The drug release was modified by changing the ratio of Eudragit RLPO and Eudragit L100 in the solid dispersions. The in vivo results showed that the relative bioavailability of alginate beads was enhanced by approximately 2.52-fold compared with that of the commercial tablet. Therefore, our study illustrated the potential use of floating alginate beads combined with the solid dispersion technique for the delivery of acid-soluble compounds, such as dipyridamole.

Dipyridamole in antithrombotic treatment.

The antithrombotic activity of dipyridamole was initially discovered in an in vivo experiment about half a century ago. At that time science had not appreciated the complexity of the regulation of local thrombus formation. Inhibition of platelets has been the main focus for the prevention of arterial thrombus formation. Unfortunately, established in vitro test systems have to take away several important components of the hemostatic system. Rather than directly inhibiting platelet aggregation, dipyridamole amplifies endogenous antithrombotic systems and modulates or downregulates prothrombotic processes. While for many years the main focus had been on preventing acute thrombus formation in the case of a rupture of an atherosclerotic plaque in large coronary arteries, it now has been appreciated that perfusion of tissue and patency of small vessels and capillaries is equally important for preventing further damage to the tissue. Here dipyridamole was experimentally shown to improve perfusion and function in chronic hypoperfused tissue unrelated to its vasodilatory properties. Recently, several clinical trials have shown the benefit of dipyridamole when given in a formulation that assures a sufficient plasma concentration. Its potential to scavenge particularly peroxy radicals, its direct reduction of innate inflammation, and a chronic elevation of interstitial adenosine seems to be of more importance for the prevention of vascular and tissue damage than its adenosine- and prostacyclin-mediated antithrombotic effect. In its extended-release preparation with the tartaric acid nucleus, not only does it not seem to add significantly to the risk of bleeding, but seems to hold potential for protecting tissue from oxidative and metabolic stress.

Simulation of Intraluminal Performance of Lipophilic Weak Bases in Fasted Healthy Adults Using DDDPlusTM.

The majority of drug candidates exhibit weakly basic characteristics with high lipophilicity. The risk of intraluminal compound precipitation has been studied in vivo and extensively in vitro using advanced dissolution transfer setups mimicking drug transfer from the stomach to the small intestine. The present investigation aims to evaluate the usefulness of the recently introduced Artificial Stomach-Duodenum in silico tool in the DDDPlusTM platform (ASD-D+) to simulate intraluminal drug behavior. The weakly basic drugs ketoconazole and dipyridamole were used as model drugs within the ASD-D+ model at two dose levels. The simulated amounts per volume were compared to intraluminal data collected from fasted healthy adults. Four different in silico transfer models running on a continuous or a stepwise mode were utilized for the simulations. Each transfer model exhibited different capabilities to simulate observed intraluminal drug presence. Three out of the four in silico models overestimated the total drug amount measured in vivo (dissolved and precipitated drug), while only two of the four models matched the intraluminal drug concentrations. The stepwise model enabled adequate simulations of both drug concentration and total drug amount. The present investigation highlighted the importance of simulating drug transfer appropriately within the applied methodology prior to estimating precipitation kinetics. As a future step, optimization of ASD-D+ model would enable evaluations of solid/semi-solid dosage form simulations. Lastly, prediction of drug precipitation kinetics following simulation of gastrointestinal transfer may provide mechanistic understanding of drug absorption and appropriate justification of drug-formulated parameters within physiologically based pharmacokinetic models.

Precipitation in and supersaturation of contents of the upper small intestine after administration of two weak bases to fasted adults.

PURPOSE: To evaluate precipitation in and supersaturation of intestinal contents after administration of pharmacologically relevant doses of dipyridamole and ketoconazole to 12 healthy adults. METHODS: On two separate days each subject was administered in stomach 240 ml aqueous solutions of two dipyridamole doses (30/90 mg) and two ketoconazole doses (100/300 mg). Physicochemical characteristics, total drug content, and drug concentration were measured in individual intestinal contents (≤7 ml) aspirated at specific times post-dosing. Drug concentration after incubation (37°C/48 h) and equilibrium solubility were measured. Precipitate crystallinity was evaluated by x-ray powder diffraction. RESULTS: Precipitated fraction was minimal (dipyridamole, ≤7%) or limited (ketoconazole, ≤16%). Ketoconazole precipitates were mostly amorphous. Depending on dose, intestinal contents with pH > 3.6 were supersaturated with dipyridamole up to 10 and 30 min and with ketoconazole up to 30 and 50 min post-administration. Intestinal contents with pH > 5 and concentration of micellar components <5 mM were supersaturated with ketoconazole or dipyridamole, but precipitated fraction was significant only for ketoconazole. After incubation, crystalline precipitates were found in almost all samples. Slow precipitation of base and/or precipitation of other phases account for this observation. CONCLUSIONS: Intralumenal precipitation of weakly alkaline, lipophilic, high permeability drugs may not be substantial. Estimating intestinal supersaturation in regard to free base is inadequate as other phases may precipitate.

A differential equation based modelling approach to predict supersaturation and in vivo absorption from in vitro dissolution-absorption system (idas2) data.

In vitro dissolution tests are widely used to monitor the quality and consistency of oral solid dosage forms, but to increase the physiological relevance of in vitro dissolution tests, newer systems combine dissolution and permeation measurements. Some of these use artificial membranes while others (e.g., in the in vitro dissolution absorption system 2; IDAS2), utilize cell monolayers to assess drug permeation. We determined the effect of the precipitation inhibitor Hypromellose Acetate Succinate (HPMCAS) on the supersaturation/permeation of Ketoconazole and Dipyridamole in IDAS2 and its effect on their absorption in rats. Thus the main objectives of this study were to determine: (1) whether dissolution and permeation data from IDAS2 could be used to predict rat plasma concentration using an absorption model and (2) whether the effect of the precipitation inhibitor HPMCAS on supersaturation and permeation in IDAS2 was correlated with its effect on systemic absorption in the rat. Predicted drug concentrations in rat plasma, generated using parameters estimated from IDAS2 dissolution/permeation data and a mathematical absorption model, showed good agreement with measured concentrations. While in IDAS2, the prolongation of Ketoconazole's supersaturation caused by HPMCAS led to higher permeation, which paralleled the higher systemic absorption in rats, Dipyridamole showed no supersaturation and, thus, no effect of HPMCAS in dissolution or permeation in IDAS2 and no effect on Dipyridamole absorption in rats. The ability of IDAS2 to detect supersaturation following a pH-shift supports the potential value of this system for studying approaches to enhance intestinal absorption through supersaturation and the accuracy of plasma concentration predictions in rats suggest the possibility of combining IDAS2 with absorption models to predict plasma concentration in different species.

Stomach pH before vs. after different bariatric surgery procedures: Clinical implications for drug delivery.

Stomach pH may vary following bariatric surgery, with implications for drug delivery/bioavailability. Yet, this parameter has not been studied. In this work, gastric content was aspirated from patients before, immediately after, and the day after different bariatric procedures, and pH was immediately measured. Compared to pre-surgery (1.8), pH was increased one day after one-anastomosis gastric bypass (OAGB) and sleeve gastrectomy (LSG) by 3-4 pH units; pH immediately after these procedures was in between the other 2 time points. Post-OAGB pH was significantly higher than post-LSG (6.4 and 4.9, respectively). Prior adjustable gastric band did not significantly alter baseline pH. We then performed drug dissolution studies of the antiplatelet drugs dipyridamole and aspirin, mimicking pre-surgery, post-LSG and post-OAGB conditions, implementing our pH results and other relevant physiological parameters. Dipyridamole, a weak base, completely dissolved (100% of dose) under pre-surgery conditions, while dissolution was hampered under post-LSG (5%) and post-OAGB (0.25%) conditions, due to solubility limit. Aspirin was not released from enteric-coated tablet under pre-surgery or post-LSG gastric conditions, however, >75% dissolved within 15 min under post-OAGB gastric conditions, indicating potential failure of enteric coating, depending on the bariatric procedure. In conclusion, special care should be taken when using pH-dependent drugs and drug products after bariatric surgery, and the use of pH-independent formulations should be preferred. Overall, this research revealed the interim gastric pH after different bariatric procedures, and potentially important effects on post-bariatric oral drug delivery and treatment.

Fused deposition modelling for the development of drug loaded cardiovascular prosthesis.

Cardiovascular diseases constitute a number of conditions which are the leading cause of death globally. To combat these diseases and improve the quality and duration of life, several cardiac implants have been developed, including stents, vascular grafts and valvular prostheses. The implantation of these vascular prosthesis has associated risks such as infection or blood clot formation. In order to overcome these limitations medicated vascular prosthesis have been previously used. The present paper describes a 3D printing method to develop medicated vascular prosthesis using fused deposition modelling (FDM) technology. For this purpose, rifampicin (RIF) was selected as a model molecule as it can be used to prevent vascular graft prosthesis infection. Thermoplastic polyurethane (TPU) and RIF were combined using hot melt extrusion (HME) to obtain filaments containing RIF concentrations ranging between 0 and 1% (w/w). These materials are capable of providing RIF release for periods ranging between 30 and 80 days. Moreover, TPU-based materials containing RIF were capable of inhibiting the growth of Staphylococcus aureus. This behaviour was observed even for TPU-based materials containing RIF concentrations of 0.1% (w/w). TPU containing 1% (w/w) of RIF showed antimicrobial properties even after 30 days of RIF release. Alternatively, these methods were used to prepare dipyridamole containing TPU filaments. Finally, using a dual extrusion 3D printer vascular grafts containing both drugs were prepared.

Poly(DL-lactide)-b-poly(N,N-dimethylamino-2-ethyl methacrylate): synthesis, characterization, micellization behavior in aqueous solutions, and encapsulation of the hydrophobic drug dipyridamole.

We synthesized a series of well-defined poly(dl-lactide)-b-poly(N,N-dimethylamino-2-ethyl methacrylate) (PDLLA-b-PDMAEMA) amphiphilic diblock copolymers by employing a three-step procedure: (a) ring-opening polymerization (ROP) of dl-lactide using n-decanol and stannous octoate, Sn(Oct)(2), as the initiating system, (b) reaction of the PDLLA hydroxyl end groups with bromoisobutyryl bromide, and (c) atom transfer radical polymerization, ATRP, of DMAEMA with the newly created bromoisobutyryl initiating site. The aggregation behavior of the prepared block copolymers was investigated by dynamic light scattering and zeta potential measurements at 25 degrees C in aqueous solutions of different pH values. The hydrophobic drug dipyridamole was efficiently incorporated into the copolymer aggregates in aqueous solutions of pH 7.40. High partition coefficient values were determined by fluorescence spectroscopy.

Pharmacokinetics of extended-release dipyridamole following administration through a gastrostomy tube: an open-label, case-control, two-centre study.

BACKGROUND: Many stroke survivors have severe dysphagia and are unable to take antithrombotic medications orally. OBJECTIVE: To evaluate whether dipyridamole concentrations achieved in the plasma of patients taking an extended-release formulation of the medication through a gastrostomy tube (G-tube) are therapeutic and similar to those achieved in the plasma of patients who receive the drug orally. METHODS: This was an open-label, case-control, two-centre study conducted in two academic centres in a metropolitan area. Patients included were those admitted following an acute cerebral infarction, with an indication for antiplatelet therapy for secondary prevention. Twelve patients with severe dysphagia requiring G-tube placement were cases, and 12 patients who were able to swallow safely served as controls. The components of Aggrenox (extended-release dipyridamole/aspirin [acetylsalicylic acid]), suspended in water, were administered twice daily for 5 days through the G-tube. The 12 control patients without dysphagia took the medication orally. Dipyridamole plasma concentrations were compared between the groups at three different timepoints on the fifth day: 2, 6 and 12 hours after administration. The main outcome measure was dipyridamole plasma concentrations on day 5 at all three timepoints. RESULTS: No significant difference in dipyridamole plasma concentrations between the groups was found at 2 hours (p = 0.18), 6 hours (p = 0.92) or 12 hours (p = 0.69). CONCLUSION: Dipyridamole plasma concentrations obtained following administration of extended-release dipyridamole through a G-tube in dysphagic patients achieved similar therapeutic levels to those obtained in patients taking the medication orally.

Dissolution/permeation with PermeaLoop™: Experience and IVIVC exemplified by dipyridamole enabling formulations.

It is our hypothesis that the presence of an absorptive sink for in-vitro dissolution experiments is decisive to predict extent and duration of super-saturation of low soluble drugs in formulations expected to increase oral absorption, often called enabling formulations. Combined dissolution-/permeation-testing may provide such absorptive sink. Commonly used in-vitro dissolution-/permeation tools have a limited interfacial area-to-donor-volume-ratio (A/V), far below the physiological one which is estimated for humans. In consequence, super-saturation is expected to be more pronounced and thus precipitation to occur more readily in these models as compared to the in-vivo situation. In the current study, a PermeaLoop™ prototype a of a novel in-vitro dissolution-/permeation-tool with a substantially larger A/V was employed to investigate the dissolution and permeation behaviour of model formulations of dipyridamole containing fumaric acid as modifier of the micro-environmental pH. After identifying the most suitable experimental conditions in terms of donor- and acceptor pH and composition, dose, flow-rate and sampling intervals, both the dissolution and the permeation were simultaneously assessed over time and the extent and duration of super-saturation monitored. The importance of biomimetic media in the donor was revealed not only in terms of increasing the dissolution but also the permeation. The formulations were ranked in terms of their performance (cumulative amount permeated). As a result the data generated by PermeaLoop experiments showed for the same formulations a superior correlation with in rat bioavailability data than obtained from a traditional side-by-side Dissolution-/Permeation-system with a Caco-2-cell membrane (D/P-system). The insights into the effects of solubilisers and pH conditions gained in the present study contribute to an improved mechanistic understanding of dynamic dissolution/permeation behaviour of weakly basic drugs and their enabling formulations. Challenges with the current PermeaLoop prototype are still to be solved, as dispersed drug still tends to get stuck inside the system, but gained experiences are helpful for the improvement of the design.

Comparison of the prognostic value of dipyridamole and dobutamine myocardial perfusion scintigraphy in hemodialysis patients.

Screening for coronary artery disease (CAD) in hemodialysis patients is hampered by contraindications and/or limitations of the available techniques in this population. Myocardial perfusion scintigraphy (MPS) using dipyridamole has been considered inaccurate due to abnormally high basal levels of adenosine in uremia that could blunt the vasodilatory response. Since dobutamine may be more reliable, we directly compared the two in patients on hemodialysis. We performed MPS at rest and after separate dipyridamole or dobutamine stress in 121 chronic hemodialysis patients. More numerous, larger, and more intense reversible lesions were induced with dobutamine than with dipyridamole, mainly in the anteroseptal segments. Reversibility with dipyridamole but not dobutamine MPS was independently and strongly related with mortality associated with CAD and with fatal and non-fatal CAD. We hypothesize that the chronotropic action of dobutamine induced alterations of wall motion, leading to spurious perfusion defects, not unlike artifacts seen with left bundle branch block. Our study shows that even though dobutamine induced more pronounced myocardial ischemia than dipyridamole in chronic hemodialysis patients, dipyridamole MPS more accurately identifies patients at high risk for subsequent cardiac death or non-fatal CAD than dobutamine.

Distribution of dipyridamole in blood components among post-stroke patients treated with extended release formulation.

Extended release dipyridamole (ERD) is widely used in patients after ischaemic stroke; however, the ability of this antithrombotic agent to be stored in different blood cells has never been explored in post-stroke patients. We hypothesised that since ERD is known to be highly lipophilic, the drug may be present not only in plasma, but also accumulated in platelets, leukocytes, and erythrocytes. Fifteen patients after documented ischaemic stroke were treated with Aggrenox (ERD and low-dose aspirin combination) BID for 30 days, and 12 of them completed the study. ERD concentrations in blood cells and platelet-poor plasma were measured by spectrofluorimetry at Baseline, Day 14, and Day 30 after the initiation of therapy. The background level of spectrofluorometry readings differs slightly among the blood components (132-211 ng/ml) due to the differences in the preparation of samples and cell isolation techniques. As expected, two weeks of ERD therapy produced steady-state plasma concentration of dipyridamole already at Day 14 (1,680 +/- 542 ng/ ml), followed by a slight not significant decrease at one month (1,619 +/- 408 ng/ml). Two weeks of therapy was sufficient to achieve a consistent dipyridamole accumulation in erythrocytes (361 +/- 43 ng/ml), but not in platelets (244 +/- 78 ng/ml), or leukocytes (275 +/- 49 ng/ml). In fact, white blood cells continued dipyridamole intake beyond 14 days period, and this increase (398 +/- 66 ng/ml) was significant (p = 0.02) at 30 days. Treatment with ERD in post-stroke patients resulted not only in achievement of therapeutic plasma dipyridamole concentrations, but also deposition of the drug in erythrocytes and leukocytes, but not in platelets. If confirmed, these data will affect our better understanding of dipyridamole pleiotropy, and may explain long-term benefit of ERD formulation.

Integration of Precipitation Kinetics From an In Vitro, Multicompartment Transfer System and Mechanistic Oral Absorption Modeling for Pharmacokinetic Prediction of Weakly Basic Drugs.

Solubility, dissolution, and precipitation in the gastrointestinal tract can be critical for the oral bioavailability of weakly basic drugs. To understand the dissolution and precipitation during the transfer out of the stomach into the intestine, a multicompartment transfer system was developed by modifying a conventional dissolution system. This transfer system included gastric, intestinal, sink and supersaturation, and reservoir compartments. Simulated gastric fluid and fasted state simulated intestinal fluid were used in the gastric and intestinal compartment, respectively, to mimic fasted condition. The new transfer system was evaluated based on 2 model weak bases, dipyridamole and ketoconazole. Traditional 2-stage dissolution using 250 mL of simulated gastric fluid media, followed by 250 mL of fasted state simulated intestinal fluid, was used as a reference methodology to compare dissolution and precipitation results. An in silico model was built using R software suite to simulate the in vitro time-dependent dissolution and precipitation process when formulations were tested using the transfer system. The precipitation rate estimated from the in vitro data was then used as the input for absorption and pharmacokinetic predictions using GastroPlus. The resultant simulated plasma concentration profiles were generally in good agreement with the observed clinical data, supporting the translatability of the transfer system in vitro precipitation kinetics to in vivo.

Predicting the Changes in Oral Absorption of Weak Base Drugs Under Elevated Gastric pH Using an In Vitro-In Silico-In Vivo Approach: Case Examples-Dipyridamole, Prasugrel, and Nelfinavir.

The aim of the current research was to develop an in silico oral absorption model coupled with an in vitro dissolution/precipitation testing to predict gastric pH-dependent drug-drug interactions for weakly basic drugs. The effects of elevated gastric pH on the plasma profiles of dipyridamole, prasugrel, and nelfinavir were simulated and compared with pharmacokinetic data reported in humans with or without use of proton pump inhibitors or histamine H2 receptor antagonists. The in vitro dissolution and precipitation data for the weakly basic drugs in biorelevant media were obtained using paddle apparatus. An in silico prediction model based on the STELLA software was designed and simulations were conducted to predict the oral pharmacokinetic profiles of the 3 drugs under both usual (low) and elevated gastric pH conditions. The changes in oral absorption of dipyridamole and prasugrel in subjects with elevated gastric pH compared with those with low stomach pH were predicted well using the in vitro-in silico-in vivo approach. The proposed approach could become a powerful tool in the formulation development of poorly soluble weak base drugs.

Biopharmaceutic IVIVE-Mechanistic Modeling of Single- and Two-Phase In Vitro Experiments to Obtain Drug-Specific Parameters for Incorporation Into PBPK Models.

The physiological relevance of single-phase (aqueous only) and 2-phase (aqueous and organic phase) in vitro dissolution experiments was compared by mechanistic modeling. For orally dosed dipyridamole, stepwise, sequential estimation/confirmation of biopharmaceutical parameters from in vitro solubility-dissolution data was followed, before applying them within a physiologically based pharmacokinetic (PBPK) model. The PBPK model predicted clinical dipyridamole luminal and plasma concentration profiles reasonably well for a range of doses only where the precipitation rate constant was derived from the 2-phase experiment. The population model predicted a distribution of maximal precipitated fractions from 0% to 45% of the 90 mg dose (mean 7.6%). Such population information cannot be obtained directly from a few in vitro experiments; however well they may represent an "average" and several extreme subjects (those with low-high luminal fluid volumes, pH, etc.) because there is no indication of outcome likelihood. For this purpose, direct input of in vitro dissolution/precipitation profiles to a PBPK model is insufficient-mechanistic modeling is required. Biopharmaceutical in vitro-in vivo extrapolation tools can also simulate the effect of key experimental parameters (dissolution volumes, pH, paddle speed, etc.) on dissolution/precipitation behavior, thereby helping to identify critical variables, which may impact the number or design of in vitro experiments.