21.
Baverel, Paul, et al.
(författare)
Evaluation of the Nonparametric Estimation Method in NONMEM VI: Application to Real Data
2009
Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 36:4, s. 297-315
Tidskriftsartikel (refereegranskat) abstract
The aim of the study was to evaluate the nonparametric estimation methods available in NONMEM VI in comparison with the parametric first-order method (FO) and the first-order conditional estimation method (FOCE) when applied to real datasets. Four methods for estimating model parameters and parameter distributions (FO, FOCE, nonparametric preceded by FO (FO-NONP) and nonparametric preceded by FOCE (FOCE-NONP)) were compared for 25 models previously developed using real data and a parametric method. Numerical predictive checks were used to test the appropriateness of each model. Up to 1000 new datasets were simulated from each model and with each method to construct 90% and 50% prediction intervals. The mean absolute error and the mean error of the different outcomes investigated were computed as indicators of imprecision and bias respectively and formal statistical tests were performed. Overall, less imprecision and less bias were observed with nonparametric methods than with parametric methods. Across the 25 models, t-tests revealed that imprecision and bias were significantly lower (P < 0.05) with FOCE-NONP than with FOCE for half of the NPC outcomes investigated. Improvements were even more pronounced with FO-NONP in comparison with FO. In conclusion, when applied to real datasets and evaluated by numerical predictive checks, the nonparametric estimation methods in NONMEM VI performed better than the corresponding parametric methods (FO or FOCE).
22.
Bengtsson, Jörgen, 1976-
(författare)
Developmental Aspects of Drug Transport Across the Blood-Brain Barrier
2009
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
The developmental aspect of drug transport across the blood-brain barrier (BBB) was investigated. Microdialysis was used to study unbound morphine BBB transport at different ages in sheep. An in vitro study was performed to find differentially expressed genes in brain capillary-rich fractions of the brain in rats of different ages. Microdialysis and brain-to-plasma ratios were used to study the contribution of breast cancer resistance protein (Bcrp) to the transport of nitrofurantoin (NTF) across the BBB of rats during development as well as in adult rats and mice. A method of analysing morphine and its metabolites in plasma and microdialysis samples was developed and validated. The in vivo recovery of deuterated morphine, used as a calibrator in microdialysis experiments, was not affected by the presence of morphine in the tissue. A net influx of morphine was observed in premature lambs and adult sheep, in contrast to the efflux seen in other species. This influx decreased with age, indicating that the morphine transport across the BBB changes with age. In contrast, the transport of the morphine metabolite morphine-3-glucuronide (M3G) did not change with age. Microarray data indicated that several active transporters are differentially expressed with age. Moreover, the mRNA expression levels of Abcg2 (Bcrp) and Slc22a8 (organic anion transporter 3) changed with age when quantified using real-time polymerase chain reaction. In contrast, the expression of Abcb1 (P-glycoprotein) and occludin (a tight junction protein) did not change with age. In rats, the brain distribution of NTF decreased with age due to increased protein binding in plasma. The concentration ratio of unbound NTF across the BBB was low in the adult rat, due to intra-brain metabolism and/or efflux by other transporters. Bcrp did not appear to have a significant contribution in the developing rat or in knock-out mice compared to wild-type controls with regard to NTF BBB transport. In conclusion, in vitro studies showed that the expression levels of some genes changed with age, presumably affecting subsequent drug distribution to the brain. Further, in vivo studies showed that distribution across the BBB changed with age for morphine but not for M3G or NTF.
23.
24.
Bergman, Ebba, 1977-, et al.
(författare)
The Enterohepatic Disposition of Rosuvastatin in Pigs and The Impact of Concomitant Dosing with Cyclosporine and Gemfibrozil
2009
Ingår i: Drug Metabolism And Disposition. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0090-9556 .- 1521-009X. ; 37:12, s. 2349-2358
Tidskriftsartikel (refereegranskat) abstract
The hepatobiliary transport and local disposition of rosuvastatin in pig was investigated, along with the impact of concomitant dosing with two known multiple transport inhibitors; cyclosporine and gemfibrozil. 80 mg rosuvastatin was administered as an intrajejunal bolus dose in Treatments I, II and III (TI, TII, and TIII, respectively; n=6 per treatment). Cyclosporine (300 mg) and gemfibrozil (600 mg) were administered in addition to the rosuvastatin dose in TII and TIII, respectively. Cyclosporine was administered as a two hour intravenous infusion and gemfibrozil as an intrajejunal bolus dose. In Treatment IV (TIV, n=4) was 5.9 mg rosuvastatin administered as an intravenous bolus dose. The study was conducted using a pig model, which enabled plasma sampling from the portal (VP), hepatic (VH) and femoral veins and bile from the common hepatic duct. The biliary recovery of the administered rosuvastatin dose was 9.0±3.5% and 35.7±15.6% in TI and TIV, respectively. Rosuvastatin was highly transported into bile as the median AUCbile/AUCVH ratio was 1770 (1640-11300) in TI. Gemfibrozil did not have an effect on the plasma pharmacokinetics of rosuvastatin, most likely because the unbound inhibitor concentrations did not exceed the reported IC50-values. However, cyclosporine significantly reduced the hepatic extraction of rosuvastatin (TI; 0.89±0.06, TII; 0.46±0.13) and increased the AUCVP and AUCVH by 1.6 and 9.1-fold, respectively. In addition, the biliary exposure and fe, bile were reduced by ≈50%. The strong effect of cyclosporine was in accordance with inhibition of sinusoidal uptake transporters, such as members of the OATP-family, rather than canalicular transporters.
25.
Bergman, Ebba, 1977-
(författare)
The Hepatobiliary Transport of Rosuvastatin In Vivo
2009
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
In vivo studies of hepatobiliary disposition are challenging. The hepatobiliary system is complex, as its physiological localization, complex cellular structure with numerous transporters and enzymes, and the interindividual variability in protein expression and biliary flow will all affect the in vivo disposition of a drug under investigation. The research included in this thesis has focused on the involvement of hepatic transport proteins in the hepatobiliary disposition of rosuvastatin. The impact that several transport inhibitors had on the pharmacokinetics of rosuvastatin was investigated in healthy volunteers and in pigs. The effects were considerable, following inhibition of sinusoidal transport proteins by cyclosporine and rifampicin. These inhibitors significantly reduced the hepatic extraction of rosuvastatin by 50 and 35%, respectively, and the plasma exposure increased by factors of 9.1 and 6.3, respectively. Drug-drug interactions (DDI) resulting in markedly higher plasma exposures are important from a drug safety perspective as increased extrahepatic exposure of statins is associated with an increased risk of severe side-effects, such as myopathy which in rare cases could develop into rhabdomyolysis. The DDI caused by cyclosporine and rifampicin can probably be attributed to inhibition of hepatic uptake transporters. In contrast, inhibition of canalicular transporters by imatinib did not significantly affect the pharmacokinetics of rosuvastatin, which suggests that the intracellular concentration of the inhibitor in the hepatocyte was insufficient to affect the transport of rosuvastatin, or that imatinib is not a sufficiently potent inhibitor in vivo. Furthermore, gemfibrozil administered as a single dose into the jejunum in healthy volunteers and pigs did not affect the plasma or biliary pharmacokinetics of rosuvastatin. The previously reported DDI in humans upon repeated dosing with gemfibrozil might be explained by the accumulation of metabolites able to affect the disposition of rosuvastatin. The investigations presented in this thesis conclude that transport proteins are of considerable importance for the hepatobiliary disposition of rosuvastatin in vivo. The Loc-I-Gut catheter can be applied for the investigation of biliary accumulation and to determine bile specific metabolites, however it has limitations when conducting quantitative measurements. In the porcine model, hepatic bile can be collected for up to six hours and enables the determination of the hepatic extraction in vivo.
26.
Bergstrand, Martin, et al.
(författare)
Handling data below the limit of quantification in mixed effect models.
2009
Ingår i: AAPS Journal. - : Springer Science and Business Media LLC. - 1550-7416. ; 11:2, s. 371-380
Tidskriftsartikel (refereegranskat) abstract
The purpose of this study is to investigate the impact of observations below the limit of quantification (BQL) occurring in three distinctly different ways and assess the best method for prevention of bias in parameter estimates and for illustrating model fit using visual predictive checks (VPCs). Three typical ways in which BQL can occur in a model was investigated with simulations from three different models and different levels of the limit of quantification (LOQ). Model A was used to represent a case with BQL observations in an absorption phase of a PK model whereas model B represented a case with BQL observations in the elimination phase. The third model, C, an indirect response model illustrated a case where the variable of interest in some cases decreases below the LOQ before returning towards baseline. Different approaches for handling of BQL data were compared with estimation of the full dataset for 100 simulated datasets following models A, B, and C. An improved standard for VPCs was suggested to better evaluate simulation properties both for data above and below LOQ. Omission of BQL data was associated with substantial bias in parameter estimates for all tested models even for seemingly small amounts of censored data. Best performance was seen when the likelihood of being below LOQ was incorporated into the model. In the tested examples this method generated overall unbiased parameter estimates. Results following substitution of BQL observations with LOQ/2 were in some cases shown to introduce bias and were always suboptimal to the best method. The new standard VPCs was found to identify model misfit more clearly than VPCs of data above LOQ only.
27.
Bergstrand, Martin, et al.
(författare)
Mechanistic modeling of a magnetic marker monitoring study linking gastrointestinal tablet transit, in vivo drug release, and pharmacokinetics
2009
Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 86:1, s. 77-83
Tidskriftsartikel (refereegranskat) abstract
Magnetic marker monitoring (MMM) is a new technique for visualizing transit and disintegration of solid oral dosage forms through the gastrointestinal (GI) tract. The aim of this work was to develop a modeling approach for gaining information from MMM studies using data from a food interaction study with felodipine extended-release (ER) formulation. The interrelationship between tablet location in the GI tract, in vivo drug release, and felodipine disposition was modeled. A Markov model was developed to describe the tablet's movement through the GI tract. Tablet location within the GI tract significantly affected drug release and absorption through the gut wall. Food intake decreased the probability of tablet transition from the stomach, decreased the rate with which released felodipine left the stomach, and increased the fraction absorbed across the gut wall. In conclusion, the combined information of tablet location in the GI tract, in vivo drug release, and plasma concentration can be utilized in a mechanistically informative way with integrated modeling of data from MMM studies.
28.
Bergström, Christel A S, et al.
(författare)
Hepatitis C virus NS3 protease inhibitors : large, flexible molecules of peptide origin show satisfactory permeability across Caco-2 cells
2009
Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 38:5, s. 556-563
Tidskriftsartikel (refereegranskat) abstract
The purpose of this study was to investigate the intestinal absorption of tripeptide-based compounds intended for treatment of hepatitis C virus (HCV) infection. The intestinal permeability of 11 HCV NS3 protease inhibitors (Mw 687-841, ClogD(pH 7.4) 1.2-7.3 and 10-13 hydrogen bond donors/acceptors) was measured using Caco-2 cells. Each compound was investigated in the apical to basolateral (a-b) and basolateral to apical (b-a) direction at pH 7.4. For compounds displaying efflux the experiment was repeated in the presence of 1 microM GF120918 to investigate possible involvement of P-glycoprotein (Pgp; ABCB1). All compounds displayed intermediate to high permeability. Seven of them showed extensive efflux, with 31-114-fold higher permeability in the b-a direction than the a-b direction. Addition of the Pgp inhibitor GF120918 reduced the b-a transport rate for the effluxed compounds. However, for inhibitors with a C-terminal carboxylic acid and the acidic bioisosteres thereof the efflux was still significant. Hence, the negative charge resulted in efflux by other ABC-transporters than Pgp. From this study it can be concluded that small changes in the overall structure can lead to a large variation in permeability and efflux as shown by the inhibitors herein, properties that also may influence the resulting inhibition potency of the compounds when performing cell-based pharmacological assays.
29.
Björklund, L., et al.
(författare)
Aspirin in cardiology - benefits and risks
2009
Ingår i: INTERNATIONAL JOURNAL OF CLINICAL PRACTICE. - : Hindawi Limited. - 1368-5031 .- 1742-1241. ; 63:3, s. 468-477
Forskningsöversikt (refereegranskat)
30.
Björkman, Sven, et al.
(författare)
Pharmacokinetics and dose requirements of factor VIII over the age range 3-74 years : a population analysis based on 50 patients with long-term prophylactic treatment for haemophilia A
2009
Ingår i: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 65:10, s. 989-998
Tidskriftsartikel (refereegranskat) abstract
PURPOSE: The three aims of this investigation were (1) to develop a population pharmacokinetic (PK) model for factor VIII (FVIII) in haemophilia A patients, with estimates of inter-occasion and inter-individual variance, (2) to investigate whether appropriate dosing of FVIII for regular prophylaxis can be calculated according to patient characteristics, and (3) to present dosing recommendations for initiating prophylactic treatment. METHODS: A population PK model was developed using data from four PK studies on patients aged 7-74 years. The model was tested on sparse FVIII data from 42 outpatient visits by haemophilia prophylaxis patients aged 3-66 years. Dose requirements for prophylaxis were calculated both according to the population model and from empirical Bayesian estimates of FVIII PK in the individual patients. RESULTS: The study data were well characterised by a two-compartment PK model. Body weight, age and type of FVIII preparation (plasma-derived or recombinant) were identified as significant covariates. Inter-occasion variance was lower than inter-individual variance for both clearance and volume of the central compartment. The model could reasonably predict FVIII PK in the sparse clinical data. Model-predicted doses (based on age and body weight) to maintain a recommended 0.01 U/mL trough level of FVIII with administration on alternate days started at around 60 U/kg in the small children, decreasing to 10 U/kg or less in middle age. However, "true" dose requirements, as estimated from individual PK parameter data, showed a much greater variation. CONCLUSION: Appropriate dosing of FVIII for prophylactic treatment cannot be calculated only from body weight and/or age. However, plausible starting doses for most patients would be 1,000 U every other day. FVIII levels should then be checked for dose adjustment.
