In vitro and in vivo correlation for lipid-based formulations: Current status and future perspectives

Lipid-based formulations (LBFs) have demonstrated a great potential in enhancing the oral absorption of poorly water-soluble drugs. However, construction of in vitro and in vivo correlations (IVIVCs) for LBFs is quite challenging, owing to a complex in vivo processing of these formulations. In this paper, we start with a brief introduction on the gastrointestinal digestion of lipid/LBFs and its relation to enhanced oral drug absorption; based on the concept of IVIVCs, the current status of in vitro models to establish IVIVCs for LBFs is reviewed, while future perspectives in this field are discussed. In vitro tests, which facilitate the understanding and prediction of the in vivo performance of solid dosage forms, frequently fail to mimic the in vivo processing of LBFs, leading to inconsistent results. In vitro digestion models, which more closely simulate gastrointestinal physiology, are a more promising option. Despite some successes in IVIVC modeling, the accuracy and consistency of these models are yet to be validated, particularly for human data. A reliable IVIVC model can not only reduce the risk, time, and cost of formulation development but can also contribute to the formulation design and optimization, thus promoting the clinical translation of LBFs.KEY WORDS: Lipid-based formulation, In vitro and in vivo correlations, Lipolysis, Absorption, Oral delivery, Model, In silico prediction, Perspectives     

Development and validation of an in vitro–in vivo correlation (IVIVC) model for propranolol hydrochloride extended-release matrix formulations

The objective of this study was to develop an in vitro–in vivo correlation (IVIVC) model for hydrophilic matrix extended-release (ER) propranolol dosage formulations. The in vitro release characteristics of the drug were determined using USP apparatus I at 100 rpm, in a medium of varying pH (from pH 1.2 to pH 6.8). In vivo plasma concentrations and pharmacokinetic parameters in male beagle dogs were obtained after administering oral, ER formulations and immediate-release (IR) commercial products. The similarity factor f₂ was used to compare the dissolution data. The IVIVC model was developed using pooled fraction dissolved and fraction absorbed of propranolol ER formulations, ER-F and ER-S, with different release rates. An additional formulation ER-V, with a different release rate of propranolol, was prepared for evaluating the external predictability. The results showed that the percentage prediction error (%PE) values of C_max and AUC_0–∞ were 0.86% and 5.95%, respectively, for the external validation study. The observed low prediction errors for C_max and AUC_0–∞ demonstrated that the propranolol IVIVC model was valid.     

Investigating a Modified Apparatus to Discriminate the Dissolution Capacity In Vitro and Establish an IVIVC of Mycophenolate Mofetil Tablets in the Fed State

In this study, a modified dissolution apparatus was developed by equipping a USP apparatus Ⅰ with an open-loop system to discriminate the dissolution capacity in vitro and establish an in vitro and in vivo correlation (IVIVC) for mycophenolate mofetil (MMF) tablets. MMF had strong pH-dependent solubility that could influence the dissolution rate in vivo after the meal. Dissolution tests involving reference (Cellcept®) and test formulations (F1 and F2) were conducted using pH 4.5 acetate buffer to simulate gastric fluids in the fed state. The dissolution profiles of the reference and test formulations were distinguished by using the modified dissolution apparatus and compared with those determined using the USP apparatuses Ⅱ and Ⅳ, and the dissolution capacities of the formulations were discriminated at different sampling time-points. The results of human bioequivalence (BE) studies in the fed state were consistent with in vitro evaluations that the maximum concentrations (C_{max, in vivo}) of both F1 and F2 fell below the acceptable range (80.00%). A level A IVIVC between the absorption fraction in vivo and dissolution in vitro, and a level C correlation between C_{max, in vivo} and C_{max, in vitro}, were established to guide the optimization of the tablet formulation containing MMF.     

In vitro and in vivo correlation for lipid-based formulations: Current status and future perspectives

Lipid-based formulations (LBFs) have demonstrated a great potential in enhancing the oral absorption of poorly water-soluble drugs. However, construction of in vitro and in vivo correlations (IVIVCs) for LBFs is quite challenging, owing to a complex in vivo processing of these formulations. In this paper, we start with a brief introduction on the gastrointestinal digestion of lipid/LBFs and its relation to enhanced oral drug absorption; based on the concept of IVIVCs, the current status of in vitro models to establish IVIVCs for LBFs is reviewed, while future perspectives in this field are discussed. In vitro tests, which facilitate the understanding and prediction of the in vivo performance of solid dosage forms, frequently fail to mimic the in vivo processing of LBFs, leading to inconsistent results. In vitro digestion models, which more closely simulate gastrointestinal physiology, are a more promising option. Despite some successes in IVIVC modeling, the accuracy and consistency of these models are yet to be validated, particularly for human data. A reliable IVIVC model can not only reduce the risk, time, and cost of formulation development but can also contribute to the formulation design and optimization, thus promoting the clinical translation of LBFs.     

A novel dendritic mesoporous silica based sustained hydrogen sulfide donor for the alleviation of adjuvant-induced inflammation in rats

PurposeS-propargyl-cysteine (SPRC), an excellent endogenous hydrogen sulfide (H₂S) donor, could elevate H₂S levels via the cystathionine γ-lyase (CSE)/H₂S pathway both in vitro and in vivo. However, the immediate release of H₂S in vivo and daily administration of SPRC potentially limited its clinical use.MethodsTo solve the fore-mentioned problem, in this study, the dendritic mesoporous silica nanoparticles (DMSN) was firstly prepared, and a sustained H₂S delivery system consisted of SPRC and DMSN (SPRC@DMSN) was then constructed. Their release profiles, both in vitro and in vivo, were investigated, and their therapeutical effect toward adjuvant-induced arthritis (AIA) rats was also studied.ResultsThe spherical morphology of DMSN could be observed under scanning Electron Microscope (SEM), and the transmission electron microscope (TEM) images showed a central-radiational pore channel structure of DMSN. DMSN showed excellent SPRC loading capacity and attaining a sustained releasing ability than SPRC both in vitro and in vivo, and the prolonged SPRC releasing could further promote the release of H₂S in a sustained manner through CSE/H₂S pathway both in vitro and in vivo. Importantly, the SPRC@DMSN showed promising anti-inflammation effect against AIA in rats was also observed.ConclusionsA sustained H₂S releasing donor consisting of SPRC and DMSN was constructed in this study, and this sustained H₂S releasing donor might be of good use for the treatment of AIA.     

Comparison of Deconvolution-Based and Absorption Modeling IVIVC for Extended Release Formulations of a BCS III Drug Development Candidate

In vitro–in vivo correlations (IVIVC) are predictive mathematical models describing the relationship between dissolution and plasma concentration for a given drug compound. The traditional deconvolution/convolution-based approach is the most common methodology to establish a level A IVIVC that provides point to point relationship between the in vitro dissolution and the in vivo input rate. The increasing application of absorption physiologically based pharmacokinetic model (PBPK) has provided an alternative IVIVC approach. The current work established and compared two IVIVC models, via the traditional deconvolution/convolution method and via absorption PBPK modeling, for two types of modified release (MR) formulations (matrix and multi-particulate tablets) of MK-0941, a BCS III drug development candidate. Three batches with distinct release rates were studied for each formulation technology. A two-stage linear regression model was used for the deconvolution/convolution approach while optimization of the absorption scaling factors (a model parameter that relates permeability and input rate) in Gastroplus^TM Advanced Compartmental Absorption and Transit model was used for the absorption PBPK approach. For both types of IVIVC models established, and for either the matrix or the multiparticulate formulations, the average absolute prediction errors for AUC and C_max were below 10% and 15%, respectively. Both the traditional deconvolution/convolution-based and the absorption/PBPK-based level A IVIVC model adequately described the compound pharmacokinetics to guide future formulation development. This case study highlights the potential utility of absorption PBPK model to complement the traditional IVIVC approaches for MR products.KEY WORDS: absorption modeling, deconvolution, in vitro–in vivo correlation (IVIVC), modified release, physiologically based pharmacokinetic (PBPK) modeling     

Can semipermeable membranes coating materials influence in vivo performance for paliperidone tri-layer ascending release osmotic pump tablet: In vitro evaluation and in vivo pharmacokinetics study

One purpose of this study was to develop a paliperidone (PAL) tri-layer ascending release push–pull osmotic pump (TA-PPOP) tablet which could meet the needs of clinical applications. And another purpose was to investigate whether different coating materials influenced in vivo performance of TA-PPOP. The ascending release mechanism of this tri-layer delivery system on theory was elaborated. TA-PPOP was prepared by means of coating with cellulose acetate (CA) or ethyl cellulose (EC). Several important influence factors such as different core tablet compositions and different coating solution ingredients involved in the formulation procedure were investigated. The optimization of formulation and process was conducted by comparing different in vitro release behaviors of PAL. In vitro dissolution studies indicated that both the two formulations of different coating materials were able to deliver PAL at an ascending release rate during the whole 24 h test. The in vivo pharmacokinetics study showed that both self-made PPOP tablets with different coating had a good in vitro-in vivo correlation (IVIVC) and were bioequivalent with the brand product, which demonstrated no significant influence of the coating materials on the in vivo release acceleration of TA-PPOP.     

Quantitative Assessment of the in vivo Dissolution Rate to Establish a Modified IVIVC for Isosorbide Mononitrate Tablets

A modified in vitro-in vivo correlation (IVIVC) of the oral solid dosage forms has been proposed as a linear correlation between in vitro and in vivo dissolution. Nevertheless, the analysis of in vivo dissolution is limited by the lack of available methods. In this proof-of-concept study, a novel pharmacokinetic (PK) model containing the in vivo dissolution process and its quantification was presented to directly estimate the in vivo dissolution rate constant (k_d). The new model was validated with a hypothetical oral solution (k_d → +∞). The accuracy of the new method was clarified by comparing with the relatively true value of k_d from the literature. Isosorbide mononitrate (ISMN) was used as a model drug to explore the practicability of the novel method. The dissolution capacities of ISMN reference and test tablets were discriminated by an improved in vitro dissolution method. Following the human PK studies, the k_d values and corresponding in vivo dissolution profiles of two formulations were obtained using the novel method. Finally, a modified level A IVIVC between in vitro and in vivo dissolution of ISMN tablets was established, which is expected to guide the optimization of the tablet formulation containing ISMN.     

Development and validation of an in vitro–in vivo correlation (IVIVC) model for propranolol hydrochloride extended-release matrix formulations

The objective of this study was to develop an in vitro–in vivo correlation (IVIVC) model for hydrophilic matrix extended-release (ER) propranolol dosage formulations. The in vitro release characteristics of the drug were determined using USP apparatus I at 100 rpm, in a medium of varying pH (from pH 1.2 to pH 6.8). In vivo plasma concentrations and pharmacokinetic parameters in male beagle dogs were obtained after administering oral, ER formulations and immediate-release (IR) commercial products. The similarity factor f₂ was used to compare the dissolution data. The IVIVC model was developed using pooled fraction dissolved and fraction absorbed of propranolol ER formulations, ER-F and ER-S, with different release rates. An additional formulation ER-V, with a different release rate of propranolol, was prepared for evaluating the external predictability. The results showed that the percentage prediction error (%PE) values of C_max and AUC_0–∞ were 0.86% and 5.95%, respectively, for the external validation study. The observed low prediction errors for C_max and AUC_0–∞ demonstrated that the propranolol IVIVC model was valid.     

Intranasal administration of dauricine loaded on graphene oxide: multi-target therapy for Alzheimer's disease

Alzheimer''s disease (AD) is a degenerative disease of the central nervous system characterized by progressive cognitive and memory-related impairment. However, current therapeutic treatments have not proved sufficiently effective, mainly due to the complicated pathogenesis of the disease. In this study, a nano-formulation of graphene oxide (GO) loaded with dauricine (Dau) was investigated in terms of the combined anti-inflammatory and anti-oxidative stress effects of Dau and the inhibition of misfolding and aggregation of the amyloid-β (Aβ) protein by GO. Both in vivo and in vitro models were induced using Aβ_1-42, and the formulation was administered nasally in mice. The results showed that GO loaded with Dau greatly reduced oxidative stress through increasing superoxide dismutase levels and decreasing reactive oxygen species and malondialdehyde levels in vitro; it also alleviated the cognitive memory deficits and brain glial cell activation in mice with Aβ_1-42-induced AD. This proved that GO loaded with Dau could protect against Aβ_1-42-induced oxidative damage and apoptosis in both in vitro and in vivo AD models; therefore, GO loaded with Dau has the potential to be an effective and agent for the rapid treatment of AD.     

Controllable release of pirfenidone by polyvinyl alcohol film embedded soft contact lenses in vitro and in vivo

To increase the amount of pirfenidone (PFD) loaded in polyvinyl alcohol (PVA) film embedded soft contact lens (SCL), and evaluate its function of sustaining delivery of drug in vitro and in vivo. Drug loading efficiency within PVA film and SCLs, drug release from SCLs in vitro, and the effects of parameters of SCLs and external environment on drug release in vitro were evaluated by ultraviolet–visible spectrophotometer at 312 nm. Safety of SCLs was evaluated in vitro by transformed human corneal epithelial cell. Safety in vivo was determined by optical coherence tomography and histology of anterior segment of rabbits. Drug release study in tear fluid and aqueous humor were measured by ultra-performance liquid chromatography. SCLs had smooth surface and were fit for experimental rabbits. Amount of PFD in PVA film and SCLs were 153.515 μg ± 12.508 and 127.438 μg ± 19.674, respectively, PFD in PVA film was significantly higher than SCLs (p=.006) and closed to 150 μg (targeting amount of PFD to be loaded). Thickness of SCLs, molecular weight of PVA, and amount of PVA used in SCLs affected drug release in vitro significantly. Thickness of PVA film and amount of drug in SCLs had no effect on drug release rate in vitro. SCLs were safe in vitro and in vivo, PFD released from SCLs could be detected around 12 hours in tears and aqueous humor, and the concentration of drug was higher than eye drop at all detected time points while amount of PFD in SCLs was lower than eye drop. Drug loaded PVA film embedded SCLs may be a promising ocular drug delivery system.     

In vivo delivery of CRISPR-Cas9 therapeutics: Progress and challenges

Within less than a decade since its inception, CRISPR-Cas9-based genome editing has been rapidly advanced to human clinical trials in multiple disease areas. Although it is highly anticipated that this revolutionary technology will bring novel therapeutic modalities to many diseases by precisely manipulating cellular DNA sequences, the low efficiency of in vivo delivery must be enhanced before its therapeutic potential can be fully realized. Here we discuss the most recent progress of in vivo delivery of CRISPR-Cas9 systems, highlight innovative viral and non-viral delivery technologies, emphasize outstanding delivery challenges, and provide the most updated perspectives.KEY WORDS: CRISPR, Cas9, Genome editing therapy, LNP, Nanoparticle, AAV, Lentivirus, In vivo     

Gastrointestinal lipolysis and trans-epithelial transport of SMEDDS via oral route

Self-microemulsifying drug delivery systems (SMEDDSs) have recently returned to the limelight of academia and industry due to their enormous potential in oral delivery of biomacromolecules. However, information on gastrointestinal lipolysis and trans-epithelial transport of SMEDDS is rare. Aggregation-caused quenching (ACQ) fluorescent probes are utilized to visualize the in vivo behaviors of SMEDDSs, because the released probes during lipolysis are quenched upon contacting water. Two SMEDDSs composed of medium chain triglyceride and different ratios of Tween-80 and PEG-400 are set as models, meanwhile Neoral® was used as a control. The SMEDDS droplets reside in the digestive tract for as long as 24 h and obey first order kinetic law of lipolysis. The increased chain length of the triglyceride decreases the lipolysis of the SMEDDSs. Ex vivo imaging of main tissues and histological examination confirm the trans-epithelial transportation of the SMEDDS droplets. Approximately 2%–4% of the given SMEDDSs are transported via the lymph route following epithelial uptake, while liver is the main termination. Caco-2 cell lines confirm the cellular uptake and trans-epithelial transport. In conclusion, a fraction of SMEDDSs can survive the lipolysis in the gastrointestinal tract, permeate across the epithelia, translocate via the lymph, and accumulate mainly in the liver.KEY WORDS: SMEDDS, In vivo fate, Lipolysis, Trans-epithelial transport, Lymph, Aggregation-caused quenching, Caco-2, Absorption     

L-EGCG-Mn nanoparticles as a pH-sensitive MRI contrast agent

This study aimed to synthesize and characterize L-epigallocatechin gallate (EGCG) complexed Mn²⁺ nanoparticle (L-EGCG-Mn), a proof-of-concept pH-sensitive manganese core nanoparticle (NP), and compare its magnetic resonance (MR) properties with those of Gd-DTPA, both in vitro and in vivo. Reverse microemulsion was used to obtain the L-EGCG-Mn NPs. The physicochemical properties of L-EGCG-Mn were characterized using dynamic light scattering, transmission electron microscopy, and near-infrared fluorescence small animal live imaging. The in vitro relaxivity of L-EGCG-Mn incubated with different pH buffer solutions (pH = 7.4, 6.8, 5.5) was evaluated. The T1-weighted MR imaging (MRI) properties were evaluated in vitro using hypoxic H22 cells as well as in H22 tumor-bearing mice. Cytotoxicity tests and histological analysis were performed to evaluate the safety of L-EGCG-Mn. L-EGCG-Mn showed good biocompatibility, stability, pH sensitivity, and tumor-targeting ability. Moreover, when the pH was decreased from 7.4 to 5.5, the r₁ relaxivity of L-EGCG-Mn was shown to gradually increase from 1.79 to 6.43 mM⁻¹·s⁻¹. Furthermore, after incubation with L-EGCG-Mn for 4 h, the T1 relaxation time of hypoxic H22 cells was significantly lower than that of normoxic H22 cells (1788 ± 89 vs. 1982 ± 68 ms, p=.041). The in vivo analysis showed that after injection, L-EGCG-Mn exhibited a higher MRI signal compared to Gd-DTPA in H22 tumor-bearing mice (p < .05). Furthermore, L-EGCG-Mn was found to have a good safety profile via cytotoxicity tests and histological analysis. L-EGCG-Mn has a good safety profile and pH sensitivity and may thus serve as a potential MRI contrast agent.     

Combination of paeoniflorin and calycosin-7-glucoside alleviates ischaemic stroke injury via the PI3K/AKT signalling pathway

ContextPaeoniflorin (PF) and calycosin-7-glucoside (CG, Paeonia lactiflora Pall. extract) have demonstrated protective effects in ischaemic stroke.ObjectiveTo investigate the synergistic effects of PF + CG on ischaemia/reperfusion injury in vivo and in vitro.Materials and methodsMale Sprague-Dawley rats were subjected to the middle cerebral artery occlusion/reperfusion (MCAO/R). After MCAO/R for 24 h, rats were randomly subdivided into 5 groups: sham, model (MCAO/R), study treatment (PF + CG, 40 + 20 mg/kg), LY294002 (20 mg/kg), and study treatment + LY294002. Males were given via intragastric administration; the duration of the in vivo experiment was 8 days. Neurologic deficits, cerebral infarction, brain edoema, and protein levels were assessed in vivo. Hippocampal neurons (HT22) were refreshed with glucose-free DMEM and placed in an anaerobic chamber for 8 h. Subsequently, HT22 cells were reoxygenated in a 37 °C incubator with 5% CO₂ for 6 h. SOD, MDA, ROS, LDH and protein levels were measured in vitro.ResultsPF + CG significantly reduced neurobehavioral outcomes (21%), cerebral infarct volume (44%), brain edoema (1.6%) compared with the MCAO/R group. Moreover, PF + CG increased p-PI3K/PI3K (4.69%, 7.4%), p-AKT/AKT (6.25%, 60.6%) and Bcl-2/BAX (33%, 49%) expression in vivo and in vitro, and reduced GSK-3β (10.5%, 9.6%) expression. In vitro, PF + CG suppressed apoptosis in HT22 cells and decreased ROS and MDA levels (20%, 50%, respectively).ConclusionsPF + CG showed a synergistic protective effect against ischaemic brain injury, potentially being a future treatment for ischaemic stroke.     

Tumor-targeted Gd-doped mesoporous Fe3O4 nanoparticles for T1/T2 MR imaging guided synergistic cancer therapy

In this study, a novel intelligent nanoplatform to integrate multiple imaging and therapeutic functions for targeted cancer theranostics. The nanoplatform, DOX@Gd-MFe₃O₄ NPs, was constructed Gd-doped mesoporous Fe₃O₄ nanoparticles following with the doxorubicin (DOX) loading in the mesopores of the NPs. The DOX@Gd-MFe₃O₄ NPs exhibited good properties in colloidal dispersity, photothermal conversion, NIR triggered drug release, and high T₁/T₂ relaxicity rate (r₁=9.64 mM⁻¹s⁻¹, r₂= 177.71 mM⁻¹s⁻¹). Benefiting from the high MR contrast, DOX@Gd-MFe₃O₄ NPs enabled simultaneous T₁/T₂ dual-modal MR imagining on 4T1 bearing mice in vivo and the MR contrast effect was further strengthened by external magnetic field. In addition, the DOX@Gd-MFe₃O₄ NPs revealed the strongest inhibition to the growth of 4T1 in vitro and in vivo under NIR irradiation and guidance of external magnetic field. Moreover, biosafety was also validated by in vitro and in vivo tests. Thus, the prepared DOX@Gd-MFe₃O₄ NPs would provide a promising intelligent nanoplatform for dual-modal MR imagining guided synergistic therapy in cancer theranostics.     

Synergic fabrication of multifunctional liposomes nanocomposites for improved radiofrequency ablation combination for liver metastasis cancer therapy

The field of biomedical research has recently been interested in nanoplatforms with various functionalities, such as cancer drug carriers and MRI and optical imaging, as well as thermal treatment, among other things. As a result of the present investigation, a unique multifunctional liposome (MFL) was established in this investigation. Using radiofrequency-induced imaging and drug release based on magnetic field impact, a dual drug delivery targeted with tumor multi-mechanism treatment was made more effective. The C60 (fullerene) surface was coated with iron nanocomposites to establish the proposed nanosystems, and PEGylation was used (Fe₃O₄-C60-PEG₂₀₀₀). For fullerene radiofrequency-triggered drug release, thermosensitive DPPC liposomes with folate-DSPE-PEG₂₀₀₀ enveloped the binary nanosystems and doxorubicin (DOX). The in vitro cytotoxicity of the nanocomposites was confirmed by the liver metastasis in HT-29 colon cancer cells using radiofrequency. The flow cytometry analysis confirmed the apoptosis cell death mechanism. The thermal treatment combined chemotherapeutic MFL nano framework transformed radiofrequency radiation from thermoresponsive liposomes, which was noticed both in vivo and in vitro. Due to their superior active tumor targeting and magnetic targeting characteristics, the MFL could also selectively destroy cancerous liver cells in highly co-localized targets.     

Green synthesis of gold nanoparticles from Dendrobium officinale and its anticancer effect on liver cancer

A novel gold nanoparticle (Do-AuNP) was successfully synthesized from water extracts of traditional Chinese medicine Dendrobium officinale (DO) without using any extra chemicals regents. The physicochemical properties of Do-AuNPs were analyzed by transmission electron microscopy, dynamic light scattering, energy-dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, and atomic force microscopy. The amount of DO extract on the AuNPs was about 13%. In order to evaluate the anti-tumor efficiency and biosafety, the inhibitory rate of HepG2 cells and survival rate of L02 cells were performed in vitro, and the immunohistochemical analysis of H&E, Ki-67, and TUNEL staining were conducted in vivo. Our results demonstrated that Do-AuNP had better anti-tumor efficiency compared with DO extraction alone without increasing toxicity in vivo and in vitro. The present study provides useful information for Do-AuNP as a new nanomedicine for liver cancer.     

Development of <Emphasis Type="BoldItalic">In Vitro-In Vivo</Emphasis> Correlation for Potassium Chloride Extended Release Tablet Formulation Using Urinary Pharmacokinetic Data

Purpose

To develop and validate a Level A in vitro-in vivo correlation (IVIVC) for potassium chloride extended-release (ER) formulations.

Methods

Three prototype ER formulations of potassium chloride with different in vitro release rates were developed and their urinary pharmacokinetic profiles were evaluated in healthy subjects. A mathematical model between in vitro dissolution and in vivo urinary excretion, a surrogate for measuring in vivo absorption, was developed using time-scale and time-shift parameters. The IVIVC model was then validated based on internal and external predictability.

Results

With the established IVIVC model, there was a good correlation between the observed fraction of dose excreted in urine and the time-scaled and time-shifted fraction of the drug dissolved, and between the in vitro dissolution time and the in vivo urinary excretion time for the ER formulations. The percent prediction error (%PE) on cumulative urinary excretion over the 24 h interval (A_e0–24h) and maximum urinary excretion rate (R_max) was less than 15% for the individual formulations and less than 10% for the average of the two formulations used to develop the model. Further, the %PE values using external predictability were below 10%.

Conclusions

A novel Level A IVIVC was successfully developed and validated for the new potassium chloride ER formulations using urinary pharmacokinetic data. This successful IVIVC may facilitate future development or manufacturing changes to the potassium chloride ER formulation.