| 1. |
- Ederoth, Per, et al.
(författare)
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Blood-brain barrier transport of morphine in patients with severe brain trauma
- 2004
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 57:4, s. 427-435
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: In experimental studies, morphine pharmacokinetics is different in the brain compared with other tissues due to the properties of the blood-brain barrier, including action of efflux pumps. It was hypothesized in this clinical study that active efflux of morphine occurs also in human brain, and that brain injury would alter cerebral morphine pharmacokinetics. METHODS: Patients with traumatic brain injury, equipped with one to three microdialysis catheters in the brain and one in abdominal subcutaneous fat for metabolic monitoring, were studied. The cerebral catheter locations were classified as 'better' and 'worse' brain tissue, referring to the degree of injury. Morphine (10 mg) was infused intravenously over a 10-min period in seven patients in the intensive care setting. Tissue and plasma morphine concentrations were obtained during the subsequent 3-h period with microdialysis and regular blood sampling. RESULTS: The area under the concentration-time curve (AUC) ratio of unbound morphine in brain tissue to plasma was 0.64 (95% confidence interval 0.40, 0.87) in 'better' brain tissue (P < 0.05 vs. the subcutaneous fat/plasma ratio), 0.78 (0.49, 1.07) in 'worse' brain tissue and 1.00 (0.86, 1.13) in subcutaneous fat. The terminal half-life and T(max) were longer in the brain vs. plasma and fat, respectively. The relative recovery for morphine was higher in 'better' than in 'worse' brain tissue. The T(max) value tended to be shorter in 'worse' brain tissue. CONCLUSIONS: The unbound AUC ratio below unity in the 'better' human brain tissue demonstrates an active efflux of morphine across the blood-brain barrier. The 'worse' brain tissue shows a decrease in relative recovery for morphine and in some cases also an increase in permeability for morphine over the blood-brain barrier.
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| 2. |
- Magnusson, Marie, et al.
(författare)
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A placebo-controlled study of retinal blood flow changes by pentoxifylline and metabolites in humans
- 2006
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 61:2, s. 138-147
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To investigate the possible effects of pentoxifylline metabolites on retinal blood flow in humans. METHODS: A randomized, placebo-controlled, four-period cross-over study that was observer blinded and partly blinded for the eight participants. On one occasion a placebo was given as an intravenous (i.v.) infusion over 100 min. On the other three occasions pentoxifylline was administered as i.v. infusions over 100 min at a rate of 3 mg min(-1). Before two of the pentoxifylline infusions the subjects were pretreated with either ciprofloxacin or rifampicin. Retinal blood flow was measured by scanning laser doppler flowmetry (SLDF) in a selected area of the central temporal retina before, during and until 5 h after the end of infusion. Blood samples for concentration analyses of pentoxifyllin, R-M1, S-M1, M4 and M5 were taken serially and areas under the curves (AUCs) were calculated. Linear mixed models were used for the statistical analyses. RESULTS: Mean AUCs (ng h ml(-1)) were significantly increased for pentoxifylline (1964 vs. 1453) and S-M1 (5804 vs. 4227), but not R-M1 when pentoxifylline was co-administered with ciprofloxacin. The mean AUC for M5 was significantly reduced when subjects were pretreated with rifampicin (2041 vs. 3080). Pentoxifylline with and without pretreatment with rifampicin significantly increased retinal blood flow assessed as mean flow, pulsation (i.e. 1-systole/diastole), and diastolic flow (but not during systole), compared with placebo. The increases over placebo were more pronounced on diastolic flow, 9.7% (95% confidence interval 4.2, 15.5) than on mean flow, 4.6% (1.1, 8.3) after pentoxifylline administration. With pentoxifylline after rifampicin pretreatment the corresponding differences were 11.7% (5.8, 17.9) and 5.1% (1.4, 7.8) over placebo, respectively. After co-administration of pentoxifylline and ciprofloxacin we saw only a nonsignificant trend towards increased flow during diastole, but a significant decrease in pulsation. When AUCs for pentoxifylline and its metabolites were used as regressor variables to retinal mean flow we found that pentoxifylline, R-M1 and M5 had coefficients with a positive sign indicating that they enhanced the retinal blood flow. In contrast, S-M1 and M4 had coefficients with negative sign and thus appeared to decrease the blood flow in subjects treated with pentoxifylline. CONCLUSION: The R-M1 and M5 metabolites of pentoxifylline contributed significantly to the effects of pentoxifylline on retinal blood flow.
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| 3. |
- Bogason, Alex, et al.
(författare)
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Inverse relationship between leukaemic cell burden and plasma concentrations of daunorubicin in patients with acute myeloidleukaemia
- 2011
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 71:4, s. 514-521
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Tidskriftsartikel (refereegranskat)abstract
- center dot In vitro studies show that daunorubicin (DNR) cytotoxicity decreases with increasing cell density because of a high cellular uptake and depletion of drug in the medium. center dot It is not known whether such an effect also occurs in vivo. WHAT THIS STUDY ADDS center dot We have shown that a large leukaemic cell burden lowers the plasma concentration of DNR in patients with acute myeloid leukaemia. center dot Our analysis supports that a large leukaemic cell burden increases the central volume of distribution for DNR. center dot Our study indicates that a dose adjustment of DNR may be of importance in acute myeloid leukaemia patients with high white blood cell counts. AIMS It has been shown that the cellular uptake and cytotoxicity of anthracyclines decrease with increasing cell density in vitro, an event termed 'the inocculum effect'. It is not known whether such an effect occurs in vivo. In this study the relationships between white blood cell (WBC) count, plasma and cellular concentrations of daunorubicin (DNR) in patients with acute myeloid leukaemia were investigated. METHODS Plasma and mononuclear blood cells were isolated from peripheral blood from 40 patients with acute myeloid leukaemia at end of infusion (time 1 h), 5 and 24 h following the first DNR infusion. DNR concentrations were determined by high-pressure liquid chromatography and related to the WBC count at diagnosis. A population pharmacokinetic model was used to estimate the correlations between baseline WBC count, volume of distribution and clearance of DNR. RESULTS A clear but weak inverse relationship between the baseline WBC count and plasma concentrations of DNR (r2 = 0.11, P < 0.05) at time 1 was found. Furthermore, a clear relationship between baseline WBC count and DNR central volume of distribution using population pharmacokinetic modelling (dOFV 4.77, P < 0.05) was also noted. Analysis of plasma DNR and the metabolite daunorubicinol (DOL) concentrations in patients with a high WBC count support that the low DNR/DOL concentrations are due a distribution effect. CONCLUSION This study shows that the leukaemic cell burden influences the plasma concentrations of anthracyclines. Further studies are needed to explore if patients with high a WBC count may require higher doses of anthracyclines.
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| 4. |
- Fanta, Samuel, et al.
(författare)
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Developmental pharmacokinetics of ciclosporin : a population pharmacokinetic study in paediatric renal transplant candidates
- 2007
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 64:6, s. 772-784
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Tidskriftsartikel (refereegranskat)abstract
- Aims To use population pharmacokinetic modelling to characterize the influence of developmental and demographic factors on the pharmacokinetic variability of ciclosporin. Methods Pharmacokinetic modelling was performed in NONMEM using a dataset comprising 162 pretransplant children, aged 0.36–17.5 years. Ciclosporin was given intravenously (3 mg kg−1) and orally (10 mg kg−1) on separate occasions followed by blood sampling for 24 h. Results A three-compartment model with first-order absorption without lag-time best described the pharmacokinetics of ciclosporin. The most important covariate affecting systemic clearance (CL) and distribution volume (V) was body weight (BW; scaled allometrically), responsible for a fourfold difference in uncorrected ciclosporin CL and a sixfold difference in ciclosporin V. The other significant covariates, haematocrit, plasma cholesterol and creatinine, were estimated to explain 20–30% of interindividual differences in CL and V of ciclosporin. No age-related changes in oral bioavailability or in BW-normalized V were seen. The BW-normalized CL (CL/BW) declined with age and prepubertal children (<8 years) had an approximately 25% higher CL/BW than did older children. Normalization of CL for allometric BW (BW3/4) removed its relationship to age. Conclusion The relationship between CL and allometric BW is consistent with a gradual reduction in relative liver size, until adult values, and a relatively constant CYP3A4 content in the liver from about 6–12 months of age to adulthood. Ciclosporin oral bioavailability, known previously to display large interindividual variability, is not influenced by age. These findings can enable better individualization of ciclosporin dosing in infants, children and adolescents.
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| 5. |
- Jonsson, E Niclas, et al.
(författare)
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Population pharmacokinetics of levosimendan in patients with congestive heart failure
- 2003
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 55:6, s. 544-551
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: The aim of this study was to characterize the population pharmacokinetics of levosimendan in patients with heart failure (NYHA grades III and IV) and its relationship to demographic factors, disease severity and concomitant use of digoxin and beta-blocking agents. METHODS: Data from two efficacy studies with levosimendan administered by intravenous infusion were combined (190 patients in total). The data were analysed using a nonlinear mixed-effects modelling approach as implemented in the NONMEM program. The model development was done in three sequential steps. First the best structural model was determined (e.g. a one-, two- or three-compartment pharmacokinetic model). This was followed by the identification and incorporation of important covariates into the model. Lastly the stochastic part of the model was refined. RESULTS: A two-compartment model best described levosimendan pharmacokinetics. Clearance and the central volume of distribution were found to increase linearly with bodyweight. No other covariates, including concomitant use of digoxin and beta-blocking agents, influenced the pharmacokinetics. In the final model, a 76-kg patient was estimated to have a clearance +/- s.e. of 13.3 +/- 0.4 l h-1 and a central volume of distribution of 16.8 +/- 0.79 l. The interindividual variability was estimated to be 39% and 60% for clearance and central volume of distribution, respectively. Weight changed clearance by 1.5% [95% confidence interval (CI) 0.9%, 2.1%] and the central volume of distribution by 0.9% (95% CI 0.5%, 1.3%) per kg. CONCLUSIONS: The population pharmacokinetics parameters of levosimendan in this patient group were comparable to those obtained by traditional methods in healthy volunteers and patients with mild heart failure. Bodyweight influenced the clearance and the central volume of distribution, which in practice is accounted for by weight adjusting doses. None of the other covariates, including digoxin and beta-blocking agents, significantly influenced the pharmacokinetics of levosimendan.
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| 6. |
- Karlsson, Kristin E., et al.
(författare)
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Randomized exposure-controlled trials : Impact of randomization and analysis strategies
- 2007
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 64:3, s. 266-277
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Tidskriftsartikel (refereegranskat)abstract
- Aims: In the literature, five potential benefits of randomizing clinical trials on concentration levels, rather than dose, have been proposed: (i) statistical study power will increase; (ii) study power will be less sensitive to high variability in the pharmacokinetics (PK); (iii) the power of establishing an exposure-response relationship will be robust to correlations between PK and pharmacodynamics (PD); (iv) estimates of the exposure-response relationship are likely to be less biased; and (v) studies will provide a better control of exposure in situations with toxicity issues. The main aim of this study was to investigate if these five statements are valid when the trial results are evaluated using a model-based analysis. Methods: Quantitative relationships between drug dose, concentration, biomarker and clinical end-point were defined using pharmacometric models. Three randomization schemes for exposure-controlled trials, dose-controlled (RDCT), concentration-controlled (RCCT) and biomarker-controlled (RBCT), were simulated and analysed according to the models. Results: (i) The RCCT and RBCT had lower statistical power than RDCT in a model-based analysis; (ii) with a model-based analysis the power for an RDCT increased with increasing PK variability; (iii) the statistical power in a model-based analysis was robust to correlations between CL and EC 50 or Emax; (iv) under all conditions the bias was negligible (<3%); and (v) for studies with equal power RCCT could produce either more or fewer adverse events compared with an RDCT. Conclusion: Alternative randomization schemes may not have the proposed advantages if a model-based analysis is employed.
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| 7. |
- Kerbusch, Thomas, et al.
(författare)
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Population pharmacokinetic modelling of darifenacin and its hydroxylated metabolite using pooled data, incorporating saturable first-pass metabolism, CYP2D6 genotype and formulation-dependent bioavailability
- 2003
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 56:6, s. 639-652
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: A model describing the population pharmacokinetics of darifenacin and its hydroxylated metabolite was developed from a combined analysis of 18 studies. The relationships between explanatory covariates and pharmacokinetic parameters were explored. METHODS: Plasma concentration data from 337 individuals were pooled from 17 Phase 1 studies (median 28/33 darifenacin/metabolite observations per healthy subject), and one Phase 2 study (median 7/7 darifenacin/metabolite observations per subject) encompassing one intravenous and five different oral formulations (1-45 mg). RESULTS: Non-linear Mixed Effects Models (NONMEM Version VI) described both the population pharmacokinetics of darifenacin and its hydroxylated metabolite with a two-compartment disposition model with first order absorption. The values (mean +/- standard error of the mean) for clearance (CL) and volume of distribution of the central compartment were 40.2 +/- 2.0 l h-1 and 34.7 +/- 4.6 l h-1, respectively, in a typical male CYP2D6 homozygote-extensive metabolizer (Hom-EM). The absolute bioavailability (F) of darifenacin in a Hom-EM after doses of 7.5, 15 or 30 mg extended release formulation (CR) was 15, 19 and 25%, respectively. Factors influencing F were formulation (70-110% higher for CR compared with immediate release following equivalent daily doses), CYP2D6 genotype [heterozygote-extensive metabolizers (Het-EM) and poor metabolizers (PM) experienced 40 and 90%, respectively, higher exposure than Hom-EM irrespective of dose administered] and saturable first-pass metabolism (dose nonlinearity 1.05-1.43-fold). Race affected F, which was 56% lower in Japanese males. The CYP3A4 inhibitors ketoconazole and erythromycin increased F to approximately 100% and ketoconazole decreased CL by 67.5%. CL was 31% lower in females and 10% lower at night. Formulation affected the metabolite absorption/formation rate. Ketoconazole and erythromycin administration resulted in a decrease of 61.2 and 28.8% in exposure to the metabolite, respectively. The covariates race, gender and circadian rhythm accounted for only approximately half of the variability in the estimated exposures to darifenacin. CONCLUSIONS: The pooled analysis provided a descriptive integration of all characteristics and covariates of the pharmacokinetics of darifenacin and its metabolite, enabling interpolation and extrapolation of these key factors.
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| 8. |
- Lönnebo, Anna, et al.
(författare)
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An integrated model for the effect of budesonide on ACTH and cortisol in healthy volunteers
- 2007
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 64:2, s. 125-132
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Budesonide, a glucocorticosteroid, is used as a first-line treatment for asthma. The aim of the study was to develop a PK/PD model for the effect of budesonide on ACTH and cortisol. Methods: The modelling data were generated by conducting a single-blind, randomized, placebo-controlled cross-over study. Ten healthy volunteers inhaled placebo (Placebo Turbohaler) and 1600 μg budesonide (Pulmicort Turbohaler), with a wash-out period of 7 days between treatments. Baseline concentrations of cortisol and ACTH were measured after placebo treatment and concentrations of cortisol, ACTH and budesonide were assessed after budesonide treatment. A one-compartment disposition model was used for budesonide disposition. Based on indirect response models, two types of models, distinguishing between production driven by a sum of cosine functions and production driven by surges, were used in parallel to describe the data. Results: The surge-based approach was the most appropriate, based on goodness-of-fit, objective function values and number of parameters. The surge-based model that integrated both ACTH and cortisol data was chosen as the final model. The estimated half-lives of endogenous ACTH and cortisol were 9 and 113 min, respectively. The budesonide and ACTH concentrations producing 50% of the maximal response (IC50 and A50) were 0.325 μg l-1 and 4.96 pmol l-1. Conclusions: The present PK/PD model of the effect of budesonide on ACTH and cortisol can serve as a tool for further understanding of the hypothalamic-pituitary-adrenal (HPA) axis and be useful in the development of drugs interacting with the axis.
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| 9. |
- Ma, Guangli, et al.
(författare)
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Comparison of the agonist-antagonist interaction model and the pool model for the effect of remoxipride on prolactin
- 2010
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 70:6, s. 815-824
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Tidskriftsartikel (refereegranskat)abstract
- AIMS The tolerance to the prolactin response following administration of antipsychotic drugs has been modelled as a depletion of a prolactin pool (pool model) and a model where the tolerance is explained by a feedback loop including the dopamine interaction of prolactin release (agonist-antagonist interaction model, (AAI model)). The AAI model was superior to the pool model when analyzing data from clinical trials of risperidone and paliperidone. Here we evaluated the two models using the remoxipride data, designed to challenge the short-term prolactin response, from which the original pool model was built. METHODS The remoxipride data were collected from a study where eight healthy male subjects received two remoxipride infusions on five occasions. The intervals between the first and second dose on each occasion were 2, 8, 12, 24 and 48 h, respectively. The pool and AAI models were fitted using NONMEM. RESULTS According to the objective function values the pool model with a circadian rhythm function fitted the data slightly better, while the AAI model was better in describing the circadian rhythm of prolactin. Visual predictive checks revealed that the models predicted the prolactin profiles equally well. CONCLUSIONS According to the analysis performed here, a previous analysis of several clinical studies and literature reports on prolactin concentrations, it appears that the dopamine feedback mechanism included in the AAI model is better than the storage depletion mechanism in the pool model to estimate the bio-rhythm of prolactin time-course and the tolerance development across different populations, drugs, treatment schedules and time.
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| 10. |
- Mukonzo, Jackson K, et al.
(författare)
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A novel polymorphism in ABCB1 gene, CYP2B6*6 and sex predict single-dose efavirenz population pharmacokinetics in Ugandans.
- 2009
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Ingår i: British journal of clinical pharmacology. - : Wiley. - 1365-2125 .- 0306-5251. ; 68:5, s. 690-9
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Efavirenz exhibits pharmacokinetic variability causing varied clinical response. The aim was to develop an integrated population pharmacokinetic/pharmacogenetic model and investigate the impact of genetic variations, sex, demographic and biochemical variables on single-dose efavirenz pharmacokinetics among Ugandan subjects, using NONMEM. METHODS: Efavirenz plasma concentrations (n = 402) from 121 healthy subjects were quantified by high-performance liquid chromatography. Subjects were genotyped for 30 single nucleotide polymorphisms (SNPs), of which six were novel SNPs in CYP2B6, CYP3A5 and ABCB1. The efavirenz pharmacokinetics was described by a two-compartment model with zero- followed by first-order absorption. RESULTS: Apparent oral clearance (95% confidence interval) was 4 l h l(-1) (3.5, 4.5) in extensive metabolizers. In the final model, incorporating multiple covariates, statistical significance was found only for CYP2B6*6 and CYP2B6*11 on apparent oral clearance as well as ABCB1 (rs3842) on the relative bioavailability. Subjects homozygous for CYP2B6*6 (G516T, A785G) and *11 displayed 21 and 20% lower apparent oral clearance, respectively. Efavirenz relative bioavailability was 26% higher in subjects homozygous for ABCB1 (rs3842). The apparent peripheral volume of distribution was twofold higher in women compared with men. CONCLUSIONS: The model identified the four factors CYP2B6*6, CYP2B6*11, a novel variant allele in ABCB1 (rs3842) and sex as major predictors of efavirenz plasma exposure in a healthy Ugandan population after single-dose administration. Use of mixed-effects modelling allowed the analysis and integration of multiple pharmacogenetic and demographic covariates in a pharmacokinetic population model.
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