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Heimbach, T., Suarez-Sharp, S., Kakhi, M., Holmstock, N., Olivares-Morales, A., Pepin, X., . . . Kesisoglou, F. (2019). Dissolution and Translational Modeling Strategies Toward Establishing an In Vitro-In Vivo Link: a Workshop Summary Report. AAPS Journal, 21(2), Article ID 29.
Open this publication in new window or tab >>Dissolution and Translational Modeling Strategies Toward Establishing an In Vitro-In Vivo Link: a Workshop Summary Report
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2019 (English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 21, no 2, article id 29Article in journal (Refereed) Published
Abstract [en]

This publication summarizes the proceedings of day 2 of a 3-day workshop on Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development. Patient-centric drug product development from a drug product quality perspective necessitates the establishment of clinically relevant drug product specifications via an in vitro-in vivo link. Modeling and simulation offer a path to establish this link; in this regard, physiologically based modeling has been implemented successfully to support regulatory decision-making and drug product labeling. In this manuscript, case studies of physiologically based biopharmaceutics modeling (PBBM) applied to drug product quality are presented and summarized. These case studies exemplify a possible path to achieve an in vitro-in vivo link and encompass (a) development of biopredictive dissolution methods to support biowaivers, (b) model-informed formulation selection, (c) predicting clinical formulation performance, and (d) defining a safe space for regulatory flexibility via virtual bioequivalence (BE). Workflows for the development and verification of absorption models/PBBM and for the establishment of a safe space using dissolution as an input are described with examples. Breakout session discussions on topics, such as current challenges and some best practices in model development and verification, are included as part of the Supplementary material.

Place, publisher, year, edition, pages
SPRINGER, 2019
Keywords
clinically relevant dissolution specifications, IVIVC, IVIVR, physiologically based biopharmaceutics modeling (PBBM), safe space, virtual bioequivalence
National Category
Pharmacology and Toxicology Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-378626 (URN)10.1208/s12248-019-0298-x (DOI)000458466000001 ()30746576 (PubMedID)
Available from: 2019-03-11 Created: 2019-03-11 Last updated: 2019-03-11Bibliographically approved
Keemink, J., Sjögren, E., Holm, R. & Bergström, C. A. S. (2019). Does the Intake of Ethanol Affect Oral Absorption of Poorly Soluble Drugs?. Journal of Pharmaceutical Sciences, 108(5), 1765-1771
Open this publication in new window or tab >>Does the Intake of Ethanol Affect Oral Absorption of Poorly Soluble Drugs?
2019 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 108, no 5, p. 1765-1771Article in journal (Refereed) Published
Abstract [en]

The presence of ethanol in gastrointestinal (GI) fluids may increase the solubility of poorly water-soluble drugs. This suggests that intake of ethanol with such compounds could result in increased drug absorption in the stomach and duodenum because of the greater concentration gradient present. To test this hypothesis, in vitro dissolution of 2 poorly soluble compounds (indomethacin and felodipine) was studied in simulated GI rat fluids in the presence or absence of ethanol. Results were used to predict plasma exposure of the compounds using the software PK-Sim. Finally, in vivo plasma exposure in rats was investigated after oral dosing followed by immediate administration of water or ethanol. Despite increased solubility in GI fluids in the presence of ethanol, simulations predicted a negligible effect on absorption. This was confirmed in the rat study where oral intake of indomethacin or felodipine with ethanol did not increase in vivo plasma exposure. A possible explanation for the lack of an effect may be that dilution, absorption, and transfer of ethanol upon arrival in the stomach resulted in intragastric and intraduodenal ethanol concentrations that did not reach the levels required to affect local solubility.

Keywords
ethanol, solubility, drug absorption, poorly water-soluble compounds
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-392063 (URN)10.1016/j.xphs.2018.12.006 (DOI)000477746900012 ()30562491 (PubMedID)
Funder
Swedish Research Council, 2014-3309
Available from: 2019-09-10 Created: 2019-09-10 Last updated: 2019-09-10Bibliographically approved
Roos, C., Dahlgren, D., Sjögren, E., Sjöblom, M., Hedeland, M. & Lennernäs, H. (2019). Effects of absorption-modifying excipients on jejunal drug absorption in simulated fasted and fed luminal conditions. European journal of pharmaceutics and biopharmaceutics, 142, 387-395
Open this publication in new window or tab >>Effects of absorption-modifying excipients on jejunal drug absorption in simulated fasted and fed luminal conditions
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2019 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 142, p. 387-395Article in journal (Refereed) Published
Abstract [en]

Oral administration of drug products is the preferred administration route. In recent decades there has been an increase in drug candidates with low solubility and/or low permeability. To increase the possibility of oral administration for the poorly permeating drugs, the use of absorption modifying excipients (AMEs) has been proposed. These types of AMEs may also affect the regulatory assessment of a novel drug delivery system if they affect the absorption of a drug from any of the four BCS classes. The effects of AMEs have previously been investigated in various animal models, including the single-pass intestinal perfusion (SPIP) in rats. To further improve the biorelevance and the in vivo predictiveness of the SPIP model, four compounds (atenolol, enalaprilat, ketoprofen, metoprolol) were perfused in fasted or fed state simulated intestinal fluid (FaSSIF or FeSSIF) together with the AMEs N-acetyl-cysteine, caprate, or sodium dodecyl sulfate. For the highly soluble and poorly permeating compounds enalaprilat and atenolol (BCS class III), the flux was increased the most by the addition of SDS in both FaSSIF and FeSSIF. For ketoprofen (BCS class II), the flux decreased in the presence of all AMEs in at least one of the perfusion media. The flux of metoprolol (BCS class I) was not affected by any of the excipients in none of simulated prandial states. The changes in magnitude in the absorption of the compounds were in general smaller in FeSSIF than in FaSSIF. This may be explained by a reduced free concentration AMEs in FeSSIF. Further, the results in FeSSIF were similar to those from intrajejunal bolus administration in rat in a previous study. This suggests that the biorelevance of the SPIP method may be increased when investigating the effects of AMEs, by the addition of intraluminal constituents representative to fasted and/or fed state to the inlet perfusate.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-396543 (URN)10.1016/j.ejpb.2019.07.012 (DOI)000488654000040 ()31306752 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme
Available from: 2019-11-07 Created: 2019-11-07 Last updated: 2019-11-07Bibliographically approved
Dahlgren, D., Roos, C., Peters, K., Lundqvist, A., Tannergren, C., Sjögren, E., . . . Lennernäs, H. (2019). Evaluation of drug permeability calculation based on luminal disappearance and plasma appearance in the rat single-pass intestinal perfusion model. European journal of pharmaceutics and biopharmaceutics, 142, 31-37
Open this publication in new window or tab >>Evaluation of drug permeability calculation based on luminal disappearance and plasma appearance in the rat single-pass intestinal perfusion model
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2019 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 142, p. 31-37Article in journal (Refereed) Published
Abstract [en]

The rat single-pass intestinal perfusion (SPIP) model is commonly used to investigate gastrointestinal physiology and membrane drug transport. The SPIP model can be used with the intestinal segment inside or outside the abdomen. The rats can also be treated with parecoxib, a selective cycloxygenase-2 inhibitor that has been shown to affect some intestinal functions following abdominal surgery, such as motility, epithelial permeability, fluid flux and ion transport. However, the impact of extra-abdominal placement of the intestinal segment in combination with parecoxib on intestinal drug transport has not been investigated. There is also uncertainty how well intestinal permeability determinations based on luminal drug disappearance and plasma appearance correlate in the rat SPIP model. The main objective of this rat in vivo study was to investigate the effect of intra- vs. extra abdominal SPIP, with and without, pretreatment with parecoxib. The effect was evaluated by determining the difference in blood-to-lumen Cr-51-EDTA clearance, lumen-to-blood permeability of a cassette-dose of four model compounds (atenolol, enalaprilat, ketoprofen, and metoprolol), and water flux. The second objective was to compare the jejunal permeability values of the model drugs when determined based on luminal disappearance or plasma appearance. The study showed that the placement of the perfused jejunal segment, or the treatment with parecoxib, had minimal effects on membrane permeability and water flux. It was also shown that intestinal permeability of low permeability compounds should be determined on the basis of data from plasma appearance rather than lumina] disappearance. If permeability is calculated on the basis of luminal disappearance, it should preferably include negative values to increase the accuracy in the determinations.

Keywords
Intestinal perfusion, Intestinal permeability, Intestinal physiology, Intestinal fluid transport
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-396541 (URN)10.1016/j.ejpb.2019.06.011 (DOI)000488654000004 ()31201856 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 115369
Available from: 2019-11-07 Created: 2019-11-07 Last updated: 2019-11-07Bibliographically approved
Ahnfelt, E., Degerstedt, O., Lilienberg, E., Sjögren, E., Hansson, P. & Lennernäs, H. (2019). Lipiodol-based emulsions used for transarterial chemoembolization and drug delivery: Effects of composition on stability and product quality. Journal of Drug Delivery Science and Technology, 53, Article ID UNSP 101143.
Open this publication in new window or tab >>Lipiodol-based emulsions used for transarterial chemoembolization and drug delivery: Effects of composition on stability and product quality
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2019 (English)In: Journal of Drug Delivery Science and Technology, ISSN 1773-2247, Vol. 53, article id UNSP 101143Article in journal (Refereed) Published
Abstract [en]

Transarterial chemoembolization with emulsion-based formulations using doxorubicin hydrochloride (DOX) and Lipiodol (R) is the golden standard for the loco-regional treatment of unresectable hepatocellular carcinoma (HCC). However, from a pharmaceutical quality perspective these emulsions are poorly characterized. In this study, clinically relevant Lipiodol (R)-based emulsions were characterized in terms of emulsion stability, continuous phase classification and droplet-size distribution. Also, the solubility of DOX in the different emulsion components and the distribution of DOX to the lipid phase were investigated. These are key features to investigate due to the claimed tumor-seeking properties of Lipiodol (R). The in vitro release of DOX was studied in a miniaturized dialysis method and an empirical release model was applied to adjust for the passage of DOX across the dialysis membrane. The most stable emulsion ( > 72 h) was classified as water-in-oil (w/o), had the highest distribution of DOX to the lipid phase (20%) and an aqueous-to-lipid phase ratio of 1:4. The composition of the aqueous phase was a mixture (v/v) of iohexol (85%) and water (15%). Emulsions containing iohexol and a high aqueousto-lipid phase ratio (1:2-1:4) displayed prolonged in vitro release profiles of DOX. This study further emphasizes the medical need to standardize these emulsion-based drug delivery systems.

Place, publisher, year, edition, pages
ELSEVIER, 2019
Keywords
Emulsion, Lipiodol (R), Miniaturized dialysis method, In vitro release, Pharmaceutical quality, Liver cancer
National Category
Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-395729 (URN)10.1016/j.jddst.2019.101143 (DOI)000487963600044 ()
Funder
Swedish Research Council, 521-2011-373
Available from: 2019-10-24 Created: 2019-10-24 Last updated: 2019-10-24Bibliographically approved
Dubbelboer, I. R., Pavlovic, N., Heindryckx, F., Sjögren, E. & Lennernäs, H. (2019). Liver Cancer Cell Lines Treated with Doxorubicin under Normoxia and Hypoxia: Cell Viability and Oncologic Protein Profile. Cancers, 11(7), Article ID 1024.
Open this publication in new window or tab >>Liver Cancer Cell Lines Treated with Doxorubicin under Normoxia and Hypoxia: Cell Viability and Oncologic Protein Profile
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2019 (English)In: Cancers, ISSN 2072-6694, Vol. 11, no 7, article id 1024Article in journal (Refereed) Published
Abstract [en]

Hepatocellular carcinoma is often treated with a combination of doxorubicin and embolization, exposing it to high concentrations and hypoxia. Separation of the possible synergistic effect of this combination in vivo is difficult. Here, treatment with doxorubicin, under hypoxia or normoxia in different liver cancer cell lines, was evaluated. Liver cancer cells HepG2, Huh7, and SNU449 were exposed to doxorubicin, hypoxia, or doxorubicin + hypoxia with different duration. Treatment response was evaluated with cell viability, apoptosis, oxidative stress, and summarized with IC50. The protein profile of a 92-biomarker panel was analyzed on cells treated with 0 or 0.1 mu M doxorubicin during 6 or 72 h, under normoxia or hypoxia. Hypoxia decreased viability of HepG2 and SNU499. HepG2 was least and SNU449 most tolerant to doxorubicin treatment. Cytotoxicity of doxorubicin increased over time in HepG2 and Huh7. The combination of doxorubicin + hypoxia affected the cells differently. Normalized protein expression was lower for HepG2 than Huh7 and SNU449. Hierarchical clustering separated HepG2 from Huh7 and SNU449. These three commonly used cell lines have critically different responses to chemotherapy and hypoxia, which was reflected in their different protein expression profile. These different responses suggest that tumors can respond differently to the combination of local chemotherapy and embolization.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
IC50, doxorubicin, liver cancer, cell lines, hypoxia, normoxia
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-395927 (URN)10.3390/cancers11071024 (DOI)000479322800134 ()31330834 (PubMedID)
Funder
Swedish Cancer Society, CAN2018/602Swedish Cancer Society, CAN2017/518Swedish Cancer Society, CAN2013/1273Swedish Research Council, 2018-03301Swedish Society for Medical Research (SSMF), S17-0092
Available from: 2019-10-30 Created: 2019-10-30 Last updated: 2019-10-30Bibliographically approved
Eriksson, J., Thorn, H., Sjögren, E., Holmsten, L., Rubin, K. & Lennernäs, H. (2019). Pulmonary Dissolution of Poorly Soluble Compounds Studied in an ex Vivo Rat Lung Model. Molecular Pharmaceutics, 16(7), 3053-3064
Open this publication in new window or tab >>Pulmonary Dissolution of Poorly Soluble Compounds Studied in an ex Vivo Rat Lung Model
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2019 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 16, no 7, p. 3053-3064Article in journal (Refereed) Published
Abstract [en]

Many inhaled drugs are poorly water soluble, and the dissolution rate is often the rate-limiting step in the overall absorption process. To improve understanding of pulmonary drug dissolution, four poorly soluble inhalation compounds (AZD5423 (a developmental nonsteroidal glucocorticoid), budesonide, fluticasone furoate (FF), and fluticasone propionate (FP)) were administered as suspensions or dry powders to the well-established isolated perfused 4 rat lung (IPL) model. Two particle size distributions (d50 = 1.2 mu m and d50 = 2.8 mu m) were investigated for AZD5423. The pulmonary absorption rates of the drugs from the suspensions and dry powders were compared with historical absorption data for solutions to improve understanding of the effects of dissolution on the overall pulmonary absorption process for poorly soluble inhaled drugs. A physiologically based biopharmaceutical in silico model was used to analyze the experimental IPL data and to estimate a dissolution parameter (K-ex vivo). A similar in silico approach was applied to in vitro dissolution data from the literature to obtain an in vitro dissolution parameter (Kin vitro). When FF, FP, and the larger particles of AZD5423 were administered as suspensions, drug dissolution was the rate-limiting step in the overall absorption process. However, this was not the case for budesonide, which has the highest aqueous solubility (61 mu M), and the smaller particles of AZD5423, probably because of the increased surface area available for dissolution (d50 = 1.2 mu m). The estimated dissolution parameters were ranked in accordance with the solubility of the drugs, and there was good agreement between k(ex vivo) and k(in vitro). The dry powders of all the compounds were absorbed more slowly than the suspensions, indicating that wetting is an important parameter for the dissolution of dry powders. A wetting factor was introduced to the in silico model to explain the difference in absorption profiles between the suspensions and dry powders where AZD5423 had the poorest wettability followed by FP and FF. The IPL model in combination with an in silico model is a useful tool for investigating pulmonary dissolution and improving understanding of dissolution-related parameters for poorly soluble inhaled compounds.

Keywords
inhalation, lung dissolution, isolated perfused lung model, pulmonary drug delivery, pulmonary drug absorption
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-390996 (URN)10.1021/acs.molpharmaceut.9b00289 (DOI)000474475400020 ()31136181 (PubMedID)
Funder
AstraZeneca
Available from: 2019-08-19 Created: 2019-08-19 Last updated: 2019-08-19Bibliographically approved
Dubbelboer, I. R., Dahlgren, D., Sjögren, E. & Lennernäs, H. (2019). Rat intestinal drug permeability: A status report and summary of repeated determinations. European journal of pharmaceutics and biopharmaceutics, 142, 364-376
Open this publication in new window or tab >>Rat intestinal drug permeability: A status report and summary of repeated determinations
2019 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 142, p. 364-376Article in journal (Refereed) Published
Abstract [en]

Intestinal permeability is a key biopharmaceutical variable in pharmaceutical research and development, and regulatory assessment. In situ rat models are often used to predict the corresponding human intestinal permeability data. The rat single-pass intestinal perfusion (SPIP) and intestinal closed loop (ICL) models are commonly applied. The primary objective of this study was to collect, summarize, and evaluate all the available intestinal permeability data for drugs that have been obtained using these two in-situ rat models. The permeability data were also investigated for variability between the experimental designs. The literature survey found 635 permeability determinations for 90 drugs. The studies were performed on the jejunum (n = 284), whole small intestine (n = 111), colon (n = 108), ileum (n = 101), and duodenum (n = 30). All the SPIP (n = 484) and ICL (n = 147) permeability values were summarized in an easily accessible database. There was wide variability in the intestinal permeability to each drug between studies, which was unrelated to the permeability class of the drug. There was no relationship between rat intestinal permeability and luminal pH, luminal drug concentration, rat strain, experimental method, or intestinal region. There was, however, a correlation between permeability values determined in the same laboratory. This report showed that the SPIP and ICL methods are important in situ models for understanding and predicting intestinal drug absorption. However, conclusions based on permeability values sourced from different laboratories may not be reliable. Because each permeability study is unique and because between- and even within-laboratory variability can be substantial, data from individual studies should preferably be interpreted separately.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-396542 (URN)10.1016/j.ejpb.2019.07.005 (DOI)000488654000038 ()31283980 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme
Available from: 2019-11-07 Created: 2019-11-07 Last updated: 2019-11-07Bibliographically approved
Sjögren, E., Stahle, L., Quiding, H., Jonzon, B., Halldin, M. M. & Sundgren, A. K. (2019). The effect of intradermal microdosing of a transient receptor potential cation channel subfamily V member 1 antagonist on heat evoked pain and thermal thresholds in normal and ultraviolet-C exposed skin in healthy volunteers. European Journal of Pain, 23(10), 1767-1779
Open this publication in new window or tab >>The effect of intradermal microdosing of a transient receptor potential cation channel subfamily V member 1 antagonist on heat evoked pain and thermal thresholds in normal and ultraviolet-C exposed skin in healthy volunteers
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2019 (English)In: European Journal of Pain, ISSN 1090-3801, E-ISSN 1532-2149, Vol. 23, no 10, p. 1767-1779Article in journal (Refereed) Published
Abstract [en]

Background Three TRPV1 (Transient Receptor Potential Vanilloid Receptor 1) antagonists were developed for testing in situ in human skin (Sjogren et al., 2016; Sjogren et al., 2018; Sjogren et al., 2018). The first human study using these compounds and capsaicin, was performed to determine the required local antagonist concentrations needed for target engagement (Proof of Mechanism, PoM) (Sjogren et al., 2018). In this paper, the aim was to address a TRPV1 antagonist's ability to inhibit a more complex pain signal and to define translational endpoints that could be used in further drug development, when progressing orally bioavailable TRPV1 antagonists as novel analgesic medications. Method This was a single centre, placebo-controlled, clinical proof of principle (PoP) study in 25 healthy volunteers. The subjects were exposed to UV irradiation, causing a local tissue inflammation. Three different doses of AZ12048189 were administered to assess pain perception through quantitative sensory testing (QST) and erythema using Laser Doppler scanning. Results AZ12048189 increased the warmth detection threshold (WDT) and the heat pain threshold (HPT) and decreased the intensity of supra threshold heat pain (STHP). AZ12048189 did not, however, have any significant effects as assessed using mechanical stimulation or Laser Doppler. Conclusions This study validated translational tools to confirm target engagement for TRPV1 antagonists; WDT, HPT and STHP have utility in this respect, after oral administration of a TRPV1 antagonist. This study also proved that TRPV1 antagonists can inhibit a more complex, non-capsaicin dependent thermally induced pain signal.

Place, publisher, year, edition, pages
WILEY, 2019
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-398863 (URN)10.1002/ejp.1451 (DOI)000480962200001 ()31314954 (PubMedID)
Funder
AstraZeneca
Available from: 2019-12-11 Created: 2019-12-11 Last updated: 2019-12-11Bibliographically approved
Suarez-Sharp, S., Cohen, M., Kesisoglou, F., Abend, A., Marroum, P., Delvadia, P., . . . Zhang, X. (2018). Applications of Clinically Relevant Dissolution Testing: Workshop Summary Report. AAPS Journal, 20(6), Article ID 93.
Open this publication in new window or tab >>Applications of Clinically Relevant Dissolution Testing: Workshop Summary Report
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2018 (English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 20, no 6, article id 93Article in journal (Refereed) Published
Abstract [en]

This publication summarizes the proceedings of day 3 of a 3-day workshop on "Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development." Specifically, this publication discusses the current approaches in building clinical relevance into drug product development for solid oral dosage forms, along with challenges that both industry and regulatory agencies are facing in setting clinically relevant drug product specifications (CRDPS) as presented at the workshop. The concept of clinical relevance is a multidisciplinary effort which implies an understanding of the relationship between the critical quality attributes (CQAs) and their impact on predetermined clinical outcomes. Developing this level of understanding, in many cases, requires introducing deliberate but meaningful variations into the critical material attributes (CMAs) and critical process parameters (CPPs) to establish a relationship between the resulting in vitro dissolution/release profiles and in vivo PK performance, a surrogate for clinical outcomes. Alternatively, with the intention of improving the efficiency of the drug product development process by limiting the burden of conducting in vivo studies, this understanding can be either built, or at least enhanced, through in silico efforts, such as IVIVC and physiologically based pharmacokinetic (PBPK) absorption modeling and simulation (M&S). These approaches enable dissolution testing to establish safe boundaries and reject drug product batches falling outside of the established safe range (e.g., due to inadequate in vivo performance) enabling the method to become clinically relevant. Ultimately, these efforts contribute towards patient-centric drug product development and allow regulatory flexibility throughout the lifecycle of the drug product.

Place, publisher, year, edition, pages
SPRINGER, 2018
Keywords
clinically relevant specifications, dissolution, IVIVC/IVIVR, PBPK absorption modeling and simulation, safe space
National Category
Pharmacology and Toxicology Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-362086 (URN)10.1208/s12248-018-0252-3 (DOI)000442911800001 ()30151612 (PubMedID)
Available from: 2018-10-03 Created: 2018-10-03 Last updated: 2018-10-03Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-4318-6039

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