| 1. |
- Simonsson, Ulrika S H, et al.
(författare)
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Artemisinin autoinduction is caused by involvement of cytochrome P450 2B6 but not 2C9.
- 2003
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Ingår i: Clinical pharmacology and therapeutics. - 0009-9236 .- 1532-6535. ; 74:1, s. 32-43
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Tidskriftsartikel (refereegranskat)abstract
- Our goal was to investigate whether artemisinin autoinduction is caused by an increase in cytochrome P450 (CYP) 2B6 or CYP2C9 activities, we evaluated the effects of multiple-dose artemisinin administration on S-mephenytoin N-demethylation in healthy subjects.
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| 2. |
- Jönsson, Siv, et al.
(författare)
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A rational approach for selection of optimal covariate-based dosing strategies
- 2003
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 73:1, s. 7-19
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUND: At present, there is no rational approach for choosing a dosing strategy for individualization based on a covariate. An approach to use in establishment of an a priori dosing strategy for individualization is presented. Factors influencing the choice of such a dosing strategy are identified. METHODS: The approach requires definition of the following: target variable, seriousness of deviations from the target (ie, risk function), population model, covariate distributions, and constraints. Minimizing the total risk yields an optimal dosing strategy, estimated as dose sizes for different subpopulations and covariate cutoff values at which doses are increased or decreased. The method was illustrated with the use of simulated and real drug examples for the situation in which clearance is related to creatinine clearance. RESULTS: The estimated optimal cutoff(s) paralleled the median creatinine clearance in the population. The extent of variability in clearance explained by creatinine clearance was the main factor influencing the optimal ratios between adjacent dose sizes. An optimal dosing strategy was possible to estimate for the real drug. CONCLUSIONS: The method is simple to perform, although one difficulty lies in defining the target variable and risk function. Our results imply that commonly used constraints in dosing strategies based on renal function (ie, dose ratio of 2 and predetermined cutoffs) are nonoptimal in the sense we propose. Because an optimal dosing strategy may not be practical to use, the therapeutic cost that would result with any constraint can be assessed by comparison of the outcome after the desired and the optimal strategy.
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| 3. |
- Molander, L, et al.
(författare)
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Pharmacokinetics of nicotine in kidney failure
- 2000
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 68:3, s. 250-260
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Tidskriftsartikel (refereegranskat)abstract
- Background: Smoking is an important risk factor for cardiovascular and cerebrovascular complications in patients with chronic kidney failure. Very high plasma nicotine concentrations have been reported in patients with severe kidney failure, indicating that the disposition of nicotine in these patients may be different. The purpose of this study was to assess the pharmacokinetics of intravenously administered nicotine in healthy subjects and in patients with kidney failure. Methods: Nine healthy subjects (glomerular filtration rare [GFR], 84 to 143 mL/min/1.73 m2), four patients with mild kidney failure (GFR, 63 to 73 mL/min/1.73 m2), five patients with moderate kidney failure (GFR, 18 to 36 mL/min/1.73 m2), and six patients with severe kidney failure (GFR, 1 to 10 mL/min/1.73 m2) were recruited. Three patients were treated with continuous ambulatory peritoneal dialysis. An intravenous infusion of nicotine (0.028 mg/kg) was given for 10 minutes. Nicotine and cotinine concentrations were measured in plasma, urine, and peritoneal dialysate from 0 to 24 hours after start of infusion Results: There were significant correlations between GFR and total clearance, nonrenal and renal clearance of nicotine, area under the plasma concentration-time curve extrapolated to infinity, terminal elevation half-life, and mean residence time. Nonrenal clearance was 1303 mL/min and 661 mL/min in healthy subjects and patients with severe kidney failure, respectively. Only 1% to 2% of the nicotine dose was excreted unchanged in a 24-hour collection of peritoneal dialysate. The elimination of cotinine was also decreased in patients with kidney failure. Conclusion: Progressive kidney failure is associated with a gradual decrease of renal and nonrenal elimination of nicotine.
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| 4. |
- Tannergren, Christer, et al.
(författare)
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St John's wort decreases the bioavailability of R- and S-verapamil through induction of the first-pass metabolism
- 2004
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 75:4, s. 298-309
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:Our objective was to investigate the inducing effect of repeated oral administration of St John's wort on the jejunal transport and presystemic extraction of R- and S-verapamil in humans.METHODS:Jejunal single-pass perfusion experiments with 120-mg/L (244 micromol/L) R-/S-verapamil were performed in 8 healthy male volunteers for 100 minutes before and after 14 days of oral treatment with St John's wort (300 mg 3 times a day). The enantiomers of verapamil and the cytochrome P450 (CYP) 3A4-formed metabolite norverapamil in perfusate and plasma were quantified by chiral HPLC with fluorescence and tandem mass spectrometry detection, respectively.RESULTS:St John's wort did not affect the jejunal permeability or the fraction absorbed of either R- or S-verapamil. The values for area under the plasma concentration-time curve (AUC) for R- and S-verapamil decreased by 78% and 80%, respectively (P <.0001). The corresponding decreases in the maximum concentration were 76% and 78%, respectively (P <.0001), whereas the terminal half-life did not change significantly for any of the enantiomers. The AUC for R-verapamil was 6 times higher than that for S-verapamil in the control phase, and St John's wort did not change this ratio. The AUC values for R- and S-norverapamil decreased by 51% (P <.01) and 63% (P <.0001), respectively.CONCLUSIONS:Repeated administration of St John's wort significantly decreased the bioavailability of R- and S-verapamil. This effect is caused by induction of first-pass CYP3A4 metabolism, most likely in the gut, because the jejunal permeability and the terminal half-life were unchanged for both enantiomers.
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| 5. |
- Xie, Rujia, et al.
(författare)
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Clinical pharmacokinetics of irinotecan and its metabolites in relation with diarrhea
- 2002
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 0009-9236 .- 1532-6535. ; 72:3, s. 265-275
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- OBJECTIVES: Our objective was to build population pharmacokinetic models that describe plasma concentrations of irinotecan (CPT-11) and its metabolites 7-ethyl-10-hydroxycamptothecin (SN-38) and SN-38 glucuronide (SN-38G) and to investigate the pharmacokinetic-pharmacodynamic relationships between drug exposure and diarrhea, the major dose-limiting toxicity. METHODS: Data were obtained from 109 patients (65 men and 44 women) who received 1.5-hour (range, 0.75- to 2.25-hour) intravenous infusions of irinotecan at doses that ranged from 100 to 350 mg/m(2); 44 patients had a second course. The population pharmacokinetic models were developed to describe plasma concentration-time profiles. The area under the concentration-time curve from time zero to 60 hours [AUC (0-60)] was used as a measure of drug exposure to model the probabilities of diarrhea with use of a logistic regression model. RESULTS: A 3-compartment pharmacokinetic model best described the disposition of irinotecan, whereas SN-38 and SN-38G showed 2-compartmental characteristics. The population estimate of clearance for irinotecan was 31.6 L/h, and the volume of distribution at steady-state (V(SS)) was 263 L. The clearance divided by formation fraction (F(m)) was 712 L/h and 66.8 L/h for SN-38 and SN-38G, respectively. The V(SS)/F(m) was 72,000 L for SN-38 and 85.4 L for SN-38G. The frequencies of diarrhea scores in this study were 46% (grade 0), 28% (grade 1), 20% (grade 2), 4% (grade 3), and 2% (grade 4). Significant correlations between AUC(0-60) and diarrhea scores were found for irinotecan (P <.05) and SN-38G (P <.01) but not for SN-38 or the biliary index. CONCLUSIONS: In this population analysis, irinotecan and SN-38G AUC values were appropriate predictors of the risk for diarrhea, and SN-38G AUC showed the stronger relationship of the two. The developed population models may be useful in further clinical development of this agent.
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