61.
Ayoun Alsoud, Rami, et al.
(författare)
Combined quantitative tuberculosis biomarker model for time-to-positivity and colony forming unit to support tuberculosis drug development
2023
Ingår i: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 14
Tidskriftsartikel (refereegranskat) abstract
Biomarkers are quantifiable characteristics of biological processes. In Mycobacterium tuberculosis, common biomarkers used in clinical drug development are colony forming unit (CFU) and time-to-positivity (TTP) from sputum samples. This analysis aimed to develop a combined quantitative tuberculosis biomarker model for CFU and TTP biomarkers for assessing drug efficacy in early bactericidal activity studies. Daily CFU and TTP observations in 83 previously patients with uncomplicated pulmonary tuberculosis after 7 days of different rifampicin monotherapy treatments (10-40 mg/kg) from the HIGHRIF1 study were included in this analysis. The combined quantitative tuberculosis biomarker model employed the Multistate Tuberculosis Pharmacometric model linked to a rifampicin pharmacokinetic model in order to determine drug exposure-response relationships on three bacterial sub-states using both the CFU and TTP data simultaneously. CFU was predicted from the MTP model and TTP was predicted through a time-to-event approach from the TTP model, which was linked to the MTP model through the transfer of all bacterial sub-states in the MTP model to a one bacterial TTP model. The non-linear CFU-TTP relationship over time was well predicted by the final model. The combined quantitative tuberculosis biomarker model provides an efficient approach for assessing drug efficacy informed by both CFU and TTP data in early bactericidal activity studies and to describe the relationship between CFU and TTP over time.
62.
Belyaeva, Irina I., et al.
(författare)
Pharmacogenetics in Primary Headache Disorders
2022
Ingår i: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 12
Forskningsöversikt (refereegranskat) abstract
Primary headache disorders, such as migraine, tension-type headache (TTH), and cluster headache, belong to the most common neurological disorders affecting a high percentage of people worldwide. Headache induces a high burden for the affected individuals on the personal level, with a strong impact on life quality, daily life management, and causes immense costs for the healthcare systems. Although a relatively broad spectrum of different pharmacological classes for the treatment of headache disorders are available, treatment effectiveness is often limited by high variances in therapy responses. Genetic variants can influence the individual treatment success by influencing pharmacokinetics or pharmacodynamics of the therapeutic as investigated in the research field of pharmacogenetics. This review summarizes the current knowledge on important primary headache disorders, including migraine, TTH, and cluster headache. We also summarize current acute and preventive treatment options for the three headache disorders based on drug classes and compounds taking important therapy guidelines into consideration. Importantly, the work summarizes and discusses the role of genetic polymorphisms regarding their impact on metabolism safety and the effect of therapeutics that are used to treat migraine, cluster headache, and TTH exploring drug classes such as nonsteroidal anti-inflammatory drugs, triptans, antidepressants, anticonvulsants, calcium channel blockers, drugs with effect on the renin-angiotensin system, and novel headache therapeutics such as ditans, anti-calcitonin-gene-related peptide antibodies, and gepants. Genetic variants in important phase I-, II-, and III-associated genes such as cytochrome P450 genes, UGT genes, and different transporter genes are scrutinized as well as variants in genes important for pharmacodynamics and several functions outside the pharmacokinetic and pharmacodynamic spectrum. Finally, the article evaluates the potential and limitations of pharmacogenetic approaches for individual therapy adjustments in headache disorders.
63.
Berg, Staffan, et al.
(författare)
Evaluation in pig of an intestinal administration device for oral peptide delivery
2023
Ingår i: Journal of Controlled Release. - : Elsevier. - 0168-3659 .- 1873-4995. ; 353, s. 792-801
Tidskriftsartikel (refereegranskat) abstract
The bioavailability of peptides co-delivered with permeation enhancers following oral administration remains low and highly variable. Two factors that may contribute to this are the dilution of the permeation enhancer in the intestinal fluid, as well as spreading of the released permeation enhancer and peptide in the lumen by intestinal motility. In this work we evaluated an Intestinal Administration Device (IAD) designed to reduce the luminal dilution of drug and permeation enhancer, and to minimize movement of the dosage form in the intestinal lumen. To achieve this, the IAD utilizes an expanding design that holds immediate release mini tablets and places these in contact with the intestinal epithelium, where unidirectional drug release can occur. The expanding conformation limits movement of the IAD in the intestinal tract, thereby enabling drug release at a single focal point in the intestine. A pig model was selected to study the ability of the IAD to promote intestinal absorption of the peptide MEDI7219 formulated together with the permeation enhancer sodium caprate. We compared the IAD to intestinally administered enteric coated capsules and an intestinally administered solution. The IAD restricted movement of the immediate release tablets in the small intestine and histological evaluation of the mucosa indicated that high concentrations of sodium caprate were achieved. Despite significant effect of the permeation enhancer on the integrity of the intestinal epithelium, the bioavailability of MEDI7219 was of the same order of magnitude as that achieved with the solution and enteric coated capsule formulations (2.5–3.8%). The variability in plasma concentrations of MEDI7219 were however lower when delivered using the IAD as compared to the solution and enteric coated capsule formulations. This suggests that dosage forms that can limit intestinal dilution and control the position of drug release can be a way to reduce the absorptive variability of peptides delivered with permeation enhancers but do not offer significant benefits in terms of increasing bioavailability.
64.
Berg, Staffan, et al.
(författare)
In Vitro and In Vivo Evaluation of 3D Printed Capsules with Pressure Triggered Release Mechanism for Oral Peptide Delivery
2021
Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 110:1, s. 228-238
Tidskriftsartikel (refereegranskat) abstract
In this study a 3D printed capsule designed to break from the physiological pressures in the antropyloric region was evaluated for its ability to deliver the synthetic octapeptide octreotide in beagle dogs when co-formulated with the permeation enhancer sodium caprate. The pressure sensitive capsules were compared to traditional enteric coated hard gelatin capsules and enteric coated tablets. Paracetamol, which is completely absorbed in dogs, was included in the formulations and used as an absorption marker to give information about the in vivo performance of the dosage forms. The pressure sensitive capsules released drug in 50% of the dogs. In the cases where drug was released, there was no difference in octreotide bioavailability or C-max compared to the enteric coated dosage forms. When comparing all dosage forms, a correlation was seen between paracetamol C-max and octreotide bioavailability, suggesting that a high drug release rate may be beneficial for peptide absorption when delivered together with sodium caprate. (C) 2020 Published by Elsevier Inc.
65.
Björnsson, Bergthor, et al.
(författare)
Digital twins to personalize medicine
2020
Ingår i: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 12:1
Forskningsöversikt (refereegranskat) abstract
Personalized medicine requires the integration and processing of vast amounts of data. Here, we propose a solution to this challenge that is based on constructing Digital Twins. These are high-resolution models of individual patients that are computationally treated with thousands of drugs to find the drug that is optimal for the patient.
66.
Blomgren, Fredrik, et al.
(författare)
Two statins and cromolyn as possible drugs against the cytotoxicity of A beta(31-35) and A beta(25-35) peptides: a comparative study by advanced computer simulation methods
2022
Ingår i: RSC Advances. - : Royal Society of Chemistry (RSC). - 2046-2069. ; 12:21, s. 13352-13366
Tidskriftsartikel (refereegranskat) abstract
In this work, possible effective mechanisms of cromolyn, atorvastatin and lovastatin on the cytotoxicity of A beta(31-35) and A beta(25-35) peptides were investigated by classical molecular dynamics and well-tempered metadynamics simulations. The results demonstrate that all the drugs affect the behavior of the peptides, such as their ability to aggregate, and alter their secondary structures and their affinity to a particular drug. Our findings from the computed properties suggest that the best drug candidate is lovastatin. This medicine inhibits peptide aggregation, adsorbs the peptides on the surface of the drug clusters, changes the secondary structure and binds to MET35, which has been seen as the reason for the toxicity of the studied peptide sequences. Moreover, lovastatin is the drug which previously has demonstrated the strongest ability to penetrate the blood-brain barrier and makes lovastatin the most promising medicine among the three investigated drugs. Atorvastatin is also seen as a potential candidate if its penetration through the blood-brain barrier could be improved. Otherwise, its properties are even better than the ones demonstrated by lovastatin. Cromolyn appears to be less interesting as an anti-aggregant from the computational data, in comparison to the two statins.
67.
Boberg, Mikael
(författare)
Oral eflornithine treatment of late-stage human African trypanosomiasis
2022
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
Human African trypanosomiasis is a fatal disease unless treated. It is a parasitic vector borne disease endemic in sub-Saharan African countries. Eflornithine is a recommended treatment for gambiense human African trypanosomiasis (g-HAT) in the later disease stage when the parasites have infected the central nervous system. Eflornithine is currently dosed as a racemic mixture of D- and L-eflornithine via repeated intravenous infusions, which comes with several disadvantages. The work in this thesis aimed to assess the feasibility of an oral eflornithine treatment. A chiral liquid chromatography method was developed for separation and preparation of the D- and L-eflornithine enantiomers from the racemic mixture. The acquired enantiopure material was used to determine that L-eflornithine had higher antiparasitic in vitro potency compared to D-eflornithine. The in vitro findings were used with a mathematical modeling approach to predict survival in late-stage g-HAT patients treated with L-eflornithine using pharmacodynamic time-to-event modeling. The in vivo pharmacokinetics in the rat after oral or intravenous doses of enantiopure L-eflornithine was characterized using nonlinear mixed effects modeling and compared to the racemic mixture. Moreover, the distribution of D- and L-eflornithine to the third brain ventricle from the systemic circulation was examined using in vivo microdialysis. Clinical pharmacokinetics in plasma and cerebrospinal fluid for L-eflornithine was modeled using literature data. The pharmacokinetic model was used to predict drug exposure and estimate the probability of target attainment for oral L-eflornithine-based treatments against late-stage g-HAT. L-eflornithine administered as monotherapy dosed at 750 mg/kg/day four or twelve times daily could serve as efficacious regimens. In combination with nifurtimox, dose regimens of L-eflornithine at 375 mg/kg/day dosed two, four or twelve times daily could be efficacious. These results are based on in vitro and preclinical in vivo data as well as clinical data using a translational modeling and simulation approach. Future clinical pharmacokinetic studies are warranted to assess the feasibility of an oral L-eflornithine-based treatment and to establish optimal treatment strategies against late-stage g-HAT.
68.
Bosley, J. R., et al.
(författare)
Informing Pharmacokinetic Models With Physiological Data: Oral Population Modeling of L-Serine in Humans
2021
Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 12
Tidskriftsartikel (refereegranskat) abstract
To determine how to set optimal oral L-serine (serine) dose levels for a clinical trial, existing literature was surveyed. Data sufficient to set the dose was inadequate, and so an (n = 10) phase I-A calibration trial was performed, administering serine with and without other oral agents. We analyzed the trial and the literature data using pharmacokinetic (PK) modeling and statistical analysis. The therapeutic goal is to modulate specific serine-related metabolic pathways in the liver using the lowest possible dose which gives the desired effect since the upper bound was expected to be limited by toxicity. A standard PK approach, in which a common model structure was selected using a fit to data, yielded a model with a single central compartment corresponding to plasma, clearance from that compartment, and an endogenous source of serine. To improve conditioning, a parametric structure was changed to estimate ratios (bioavailability over volume, for example). Model fit quality was improved and the uncertainty in estimated parameters was reduced. Because of the particular interest in the fate of serine, the model was used to estimate whether serine is consumed in the gut, absorbed by the liver, or entered the blood in either a free state, or in a protein- or tissue-bound state that is not measured by our assay. The PK model structure was set up to represent relevant physiology, and this quantitative systems biology approach allowed a broader set of physiological data to be used to narrow parameter and prediction confidence intervals, and to better understand the biological meaning of the data. The model results allowed us to determine the optimal human dose for future trials, including a trial design component including IV and tracer studies. A key contribution is that we were able to use human physiological data from the literature to inform the PK model and to set reasonable bounds on parameters, and to improve model conditioning. Leveraging literature data produced a more predictive, useful model.
69.
Cardilin, Tim, 1989, et al.
(författare)
Exposure-response modeling improves selection of radiation and radiosensitizer combinations
2022
Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 49:2, s. 167-178
Tidskriftsartikel (refereegranskat) abstract
A central question in drug discovery is how to select drug candidates from a large number of available compounds. This analysis presents a model-based approach for comparing and ranking combinations of radiation and radiosensitizers. The approach is quantitative and based on the previously-derived Tumor Static Exposure (TSE) concept. Combinations of radiation and radiosensitizers are evaluated based on their ability to induce tumor regression relative to toxicity and other potential costs. The approach is presented in the form of a case study where the objective is to find the most promising candidate out of three radiosensitizing agents. Data from a xenograft study is described using a nonlinear mixed-effects modeling approach and a previously-published tumor model for radiation and radiosensitizing agents. First, the most promising candidate is chosen under the assumption that all compounds are equally toxic. The impact of toxicity in compound selection is then illustrated by assuming that one compound is more toxic than the others, leading to a different choice of candidate.
70.
Cardilin, Tim, 1989, et al.
(författare)
Optimization of additive chemotherapy combinations for an in vitro cell cycle model with constant drug exposures
2021
Ingår i: Mathematical Biosciences. - : Elsevier BV. - 0025-5564 .- 1879-3134. ; 338
Tidskriftsartikel (refereegranskat) abstract
Proliferation of an in vitro population of cancer cells is described by a linear cell cycle model with n states, subject to provocation with m chemotherapeutic compounds. Minimization of a linear combination of constant drug exposures is considered, with stability of the system used as a constraint to ensure a stable or shrinking cell population. The main result concerns the identification of redundant compounds, and an explicit solution formula for the case where all exposures are nonzero. The orthogonal case, where each drug acts on a single and different stage of the cell cycle, leads to a version of the classic inequality between the arithmetic and geometric means. Moreover, it is shown how the general case can be solved by converting it to the orthogonal case using a linear invertible transformation. The results are illustrated with two examples corresponding to combination treatment with two and three compounds, respectively.
