| 3141. |
- Sasaki, Tomohiro, et al.
(författare)
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Population Pharmacokinetic and Concentration-QTc Analysis of Delamanid in Pediatric Participants with Multidrug-Resistant Tuberculosis
- 2022
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Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 66:2
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Tidskriftsartikel (refereegranskat)abstract
- A population pharmacokinetic analysis of delamanid and its major metabolite DM-6705 was conducted to characterize the pharmacokinetics of delamanid and DM-6705 in pediatric participants with multidrug-resistant tuberculosis (MDR-TB). Data from participants between the ages of 0.67 and 17 years, enrolled in 2 clinical trials, were utilized for the analysis. The final data set contained 634 delamanid and 706 DM-6705 valid plasma concentrations from 37 children. A transit model with three compartments best described the absorption of delamanid. Two-compartment models for each component with linear elimination were selected to characterize the dispositions of delamanid and DM-6705, respectively. The covariates included in the model were body weight on the apparent volume of distribution and apparent clearance (for both delamanid and DM-6705); formulation (dispersible versus film-coated tablet) on the mean absorption time; age, formulation, and dose on the bioavailability of delamanid; and age on the fraction of delamanid metabolized to DM-6705. Based on the simulations, doses for participants within different age/weight groups that result in delamanid exposure comparable to that in adults following the approved adult dose were calculated. By concentration-QTc (QTcB [QT corrected by Bazett's formula]) analysis, a significant positive correlation was detected with concentrations of DM-6705. However, the modelpredicted upper bounds of the 90% confidence intervals of Delta QTc values were <10 ms at the simulated maximum concentration (C-max) of DM-6705 following the administration of the maximum doses simulated. This suggests that the effect on the QT interval following the proposed dosing is unlikely to be clinically meaningful in children with MDRTB who receive delamanid.
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| 3142. |
- Savelyeva, Anna, et al.
(författare)
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An Overview of Brevinin Superfamily : Structure, Function and Clinical Perspectives
- 2014
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Ingår i: Anticancer Genes. - London : Springer London. - 9781447164579 - 9781447164586 ; , s. 197-212
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Bokkapitel (refereegranskat)abstract
- Antimicrobial peptides are the backbone of first-line defense againstvarious microorganisms in the animal kingdom. Thus, not surprisingly, they aregaining attention in the science and medical fields as a rich repository of newpro-drugs. Below, we focus our attention on the Brevinin family of anuran peptides.While most of them show strong antibacterial activities, some, e.g. Brevinin-2R,appear to be promising anticancer molecules, exhibiting better a therapeutic windowthan widely-use anticancer drugs like doxorubicin. We briefly introduce thefield, followed by highlighting the promising therapeutic properties of Brevinins.Next, we provide information about the cloning and phylogenetic aspects ofBrevinin genes. In the final paragraphs of this chapter, we discuss possible largescaleproduction methods of Brevinins, giving examples of some systems that arealready in use. Towards the end, we discuss various means of modification ofbiologic properties of Brevinins, either by chemical modifications or by aminoacid substitution and sequence rearrangements. In this context, also other uniqueproperties of Brevinins are briefly mentioned. Finally, we discuss the future of theBrevinin field, particularly highlighting yet to be answered biologic questions, likefor example presumed anti-viral and antitumor activities of Brevinin familymembers.
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| 3143. |
- Savic, Radojka, et al.
(författare)
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Evaluation of an Extended Grid Method for Estimation Using Nonparametric Distributions
- 2009
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Ingår i: AAPS Journal. - : Springer Science and Business Media LLC. - 1550-7416. ; 11:3, s. 615-627
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Tidskriftsartikel (refereegranskat)abstract
- A nonparametric population method with support points from the empirical Bayes estimates (EBE) has recently been introduced (default method). However, EBE distribution may, with sparse and small datasets, not provide a suitable range of support points. This study aims to develop a method based on a prior parametric analysis capable of providing a nonparametric grid with adequate support points range. A new method extends the nonparametric grid with additional support points generated by simulation from the parametric distribution, hence the name extended-grid method. The joint probability density function is estimated at the extended grid. The performance of the new method was evaluated and compared to the default method via Monte Carlo simulations using simple IV bolus model and sparse (200 subject, two samples per subject) or small (30 subjects, three samples per subjects) datasets and two scenarios based on real case studies. Parameter distributions estimated by the default and the extended-grid method were compared to the true distributions; bias and precision were assessed at different percentiles. With small datasets, the bias was similar between methods (< 10%); however, precision was markedly improved with the new method (by 43%). With sparse datasets, both bias (from 5.9% to 3%) and precision (by 60%) were improved. For simulated scenarios based on real study designs, extended-grid predictions were in a good agreement with true values. A new approach to obtain support points for the nonparametric method has been developed, and it displayed good estimation properties. The extended-grid method is automated, using the program PsN, for implementation into the NONMEM.
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| 3144. |
- Savic, Radojka, et al.
(författare)
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Importance of shrinkage in empirical bayes estimates for diagnostics: problems and solutions
- 2009
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Ingår i: AAPS Journal. - : Springer Science and Business Media LLC. - 1550-7416. ; 11:3, s. 558-569
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Tidskriftsartikel (refereegranskat)abstract
- Empirical Bayes ("post hoc") estimates (EBEs) of etas provide modelers with diagnostics: the EBEs themselves, individual prediction (IPRED), and residual errors (individual weighted residual (IWRES)). When data are uninformative at the individual level, the EBE distribution will shrink towards zero (eta-shrinkage, quantified as 1-SD(eta (EBE))/omega), IPREDs towards the corresponding observations, and IWRES towards zero (epsilon-shrinkage, quantified as 1-SD(IWRES)). These diagnostics are widely used in pharmacokinetic (PK) pharmacodynamic (PD) modeling; we investigate here their usefulness in the presence of shrinkage. Datasets were simulated from a range of PK PD models, EBEs estimated in non-linear mixed effects modeling based on the true or a misspecified model, and desired diagnostics evaluated both qualitatively and quantitatively. Identified consequences of eta-shrinkage on EBE-based model diagnostics include non-normal and/or asymmetric distribution of EBEs with their mean values ("ETABAR") significantly different from zero, even for a correctly specified model; EBE-EBE correlations and covariate relationships may be masked, falsely induced, or the shape of the true relationship distorted. Consequences of epsilon-shrinkage included low power of IPRED and IWRES to diagnose structural and residual error model misspecification, respectively. EBE-based diagnostics should be interpreted with caution whenever substantial eta- or epsilon-shrinkage exists (usually greater than 20% to 30%). Reporting the magnitude of eta- and epsilon-shrinkage will facilitate the informed use and interpretation of EBE-based diagnostics.
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| 3145. |
- Savic, Radojka M., et al.
(författare)
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Evaluation of the Nonparametric Estimation Method in NONMEM VI
- 2009
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 37:1, s. 27-35
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: In NONMEM VI, a novel method exists for estimation of a nonparametric parameter distribution. The parameter distributions are approximated by discrete probability density functions at a number of parameter values (support points). The support points are obtained from the empirical Bayes estimates from a preceding parametric estimation step, run with the First Order (FO) or First Order Conditional Estimation (FOCE) methods. The purpose of this work is to evaluate this new method with respect to parameter distribution estimation. METHODS: The performance of the method, with special emphasis on the analysis of data with non-normal distribution of random effects, was studied using Monte Carlo (MC) simulations. RESULTS: The mean value (and ranges) of absolute relative biases (ARBs, %) in parameter distribution estimates with nonparametric methods preceded with FO and FOCE were 0.80 (0.1-3.7) and 0.70 (0-3), respectively, while for parametric methods, these values were 23.74 (3.3-97.5) and 4.38 (0.1-17.9), for FO and FOCE, respectively. The nonparametric estimation method in NONMEM could identify non-normal parameter distributions and correct bias in parameter estimates seen when applying the FO estimation method. CONCLUSIONS: The method shows promising properties when analyzing different types of pharmacokinetic (PK) data with both the FO and FOCE methods as preceding steps.
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| 3146. |
- Savic, Radojka M., et al.
(författare)
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Implementation of a Transit Compartment Model for Describing Drug Absorption in Pharmacokinetic Studies
- 2007
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 34:5, s. 711-726
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To compare the performance of the standard lag time model (LAG model) with the performance of an analytical solution of the transit compartment model (TRANSIT model) in the evaluation of four pharmacokinetic studies with four different compounds. Methods: The population pharmacokinetic analyses were performed using NONMEM on concentration–time data of glibenclamide, furosemide, amiloride, and moxonidine. In the TRANSIT model, the optimal number of transit compartments was estimated from the data. This was based on an analytical solution for the change in drug concentration arising from a series of transit compartments with the same first-order transfer rate between each compartment. Goodness-of-fit was assessed by the decrease in objective function value (OFV) and by inspection of diagnostic graphs. Results: With the TRANSIT model, the OFV was significantly lower and the goodness-of-fit was markedly improved in the absorption phase compared with the LAG model for all drugs. The parameter estimates related to the absorption differed between the two models while the estimates of the pharmacokinetic disposition parameters were similar. Conclusion: Based on these results, the TRANSIT model is an attractive alternative for modeling drug absorption delay, especially when a LAG model poorly describes the drug absorption phase or is numerically unstable.
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| 3147. |
- Savic, Radojka M., et al.
(författare)
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Population pharmacokinetics of cladribine in patients with multiple sclerosis
- 2017
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Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 56:10, s. 1245-1253
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Tidskriftsartikel (refereegranskat)abstract
- The aims of this study were to characterize the concentration-time course of cladribine (CdA) and its main metabolite 2-chloroadenine (CAde), estimate interindividual variability in pharmacokinetics (PK), and identify covariates explaining variability in the PK of CdA. This population PK analysis was based on the combined dataset from four clinical studies in patients with multiple sclerosis (MS): three phase I studies, including one food and one drug-drug interaction study, and one phase III clinical study. Plasma and urine concentration data of CdA and CAde were modeled simultaneously. The analysis comprised a total of 2619 CdA and CAde plasma and urine concentration observations from 173 patients with MS who received an intravenous infusion or oral tablet doses of CdA as a single agent or in combination with interferon (IFN) beta-1a. CdA PK data were best described by a three-compartment model, while a one-compartment model best described the PK of CAde. CdA renal clearance (CLR) was correlated with creatinine clearance (CLCR), predicting a decrease in the total clearance of 19%, 30% and 40% for patients with mild (CLCR = 65 ml/min), moderate (CLCR = 40 ml/min) and severe (CLCR = 20 ml/min) renal impairment, respectively. Food decreased the extent of CdA absorption by 11.2% and caused an absorption delay. Coadministration with IFN beta-1a was found to increase non-CLR (CLNR) by 21%, resulting in an increase of 11% in total clearance. Both CdA and CAde displayed linear PK after intravenous and oral administration of CdA, with CdA renal function depending on CLCR.
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| 3148. |
- Savolainen, Vincent, et al.
(författare)
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Phylogeny of the eudicots : a nearly complete familial analysis based on rbcL gene sequences
- 2000
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Ingår i: Kew bulletin. - 0075-5974 .- 1874-933X. ; 55:2, s. 257-309
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Tidskriftsartikel (refereegranskat)abstract
- A phylogenetic analysis of 589 plastid rbcL gene sequences representing nearly all eudicot families (a total of 308 families; seven photosynthetic and four parasitic families are missing) was performed, and bootstrap re-sampling was used to assess support for clades. Based on these data, the ordinal classification of eudicots is revised following the previous classification of angiosperms by the Angiosperm Phylogeny Group (APG). Putative additional orders are discussed (e.g. Dilleniales, Escalloniales, Vitales), and several additional families are assigned to orders for future updates of the APG classification. The use of rbcL alone in such a large matrix was found to be practical in discovering and providing bootstrap support for most orders. Combination of these data with other matrices for the rest of the angiosperms should provide the framework for a complete phylogeny to be used in macro-evolutionary studies.
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| 3149. |
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| 3150. |
- Scherlund, Marie
(författare)
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In situ gelling drug delivery systems for periodontal anaesthesia
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis local anaesthetic formulations based on PEO-PPO-PEO block copolymers (PEO and PPO being poly(ethylene oxide) and poly(propylene oxide), respectively) or nonionic cellulose ethers undergoing temperature- or dilution-induced thickening were investigated. The aim of the work was to develop formulations which can be easily administered to the periodontal pocket, stay at the application site, give a fast onset of anaesthesia and have a duration sufficient to perform periodontal scaling procedures. Emulsions, (mixed) micellar solutions and microemulsions fulfilling the requirements stated above were achieved by combining the active ingredients lidocaine and prilocaine with the nonionic block copolymers Lutrol® F127 and Lutrol® F68. The critical micellisation and gelation temperatures of the systems were found to be interconnected and influenced by the total polymer concentration and the polymer mixture composition, as well as the presence of cosolutes and pH. A low-viscous isotropic phase that turns into a high-viscous hexagonal phase as the water content increases was found by combining Lutrol® F68, water, a eutectic mixture of lidocaine and prilocaine and Akoline MCM. The system has a slower release rate compared to the microemulsion formulation which might make it suitable for indications where a longer duration is needed. Finally, a temperature-induced gelling system was achieved by adding lidocaine and prilocaine to mixtures of ethyl(hydroxyethyl)cellulose (EHEC) and sodium dodecyl sulfate (SDS), hexadecyltrimethylammonium bromide (CTAB) or myristoylcholine bromide systems at, or just below, the surfactant concentration found to give a maximum viscosity increase at room temperature. In particular, the myristoylcholine bromide system may be interesting considering its antibacterial properties and biodegradability.
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