Simultaneous determination of mycophenolate and its metabolite mycophenolate-7-o-glucuronide with an isocratic HPLC-UV-based method in human plasma and stability evaluation.

OBJECTIVES: Mycophenolic acid (MPA) is an immunosuppressive agent which is commonly used in a fixed dose regime in solid organ transplantation. For clinical trials and therapeutic drug monitoring measuring plasma concentrations is necessary. Also, stability issues have to be addressed. METHODS: We describe an isocratic, RP-based HPLC-UV method for simultaneous determination of MPA and its major metabolite Mycophenolic acid 7-o Glucuronide (MPAG) in human plasma. Pre-analytics included protein precipitation with acetonitrile. The method was validated according to EMA/FDA guidelines. Patient lithium-heparin plasma and blood was used for evaluation of short-term (72 hours at room temperature = RT) and long-term stability (2 years at -80 °C) without acidification. RESULTS: Linearity was assessed in the concentration range of 0.5-40.0 µg/mL for MPA and 5.0-350.0 µg/mL for MPAG, respectively. For MPA coefficient of variation was <7.0% (lower limit of quantification = LLOQ: 10.8%), for MPAG <9.6% (LLOQ: 10.6%). Bias ranged between -1.9 and +1.5% for MPA and for MPAG between -4.3 and -0.3%. The method showed agreement with a reference method for both analytes. MPA remained stable for 7 h (-1.6 to +8.4% change to the initial concentration) and MPAG for 24 h (-1.8 to -11.5% change) at RT in lithium heparin blood. After 2 years of storage at -80 °C MPA, MPAG concentrations and 95% CIs remained within ±15% of the initial value. CONCLUSION: The presented assay is applicable for clinical studies. Blood samples were stable for 7 hours at RT and plasma for 2 years stored at -80 °C.

Ch14.18 antibody produced in CHO cells in relapsed or refractory Stage 4 neuroblastoma patients: a SIOPEN Phase 1 study.

PURPOSE: This study aimed to assess the safety, pharmacokinetic and activity profiles of the human-mouse chimeric monoclonal anti-disialoganglioside GD2 antibody ch14.18 produced in Chinese hamster ovary (CHO) cells (ch14.18/CHO). METHODS: Sixteen children with recurrent/refractory neuroblastoma (median age 7.6 y) were enrolled in this Phase 1 dose-finding study. Patients received ch14.18/CHO courses of 10, 20 or 30 mg/m (2)/day as an eight-hour infusion over five consecutive days. Three courses at the same dose level were allowed unless disease progressed. Clearance and biodistribution of radiolabelled ch14.18/CHO in Balb/c and A/J mice were analyzed. RESULTS: A total of 41 ch14.18/CHO courses were given (10 × 3 courses, 5 × 2 courses, 1 × 1 course). Side effects were similar in expectedness, frequency and magnitude to those reported for ch14.18/SP2/0. The dose level of 20 mg/m(2)/day was confirmed. Toxicity was reversible and no treatment-related deaths occurred. In children, the peak plasma concentration was 16.51 µg/ml ± 5.9 µg/ml and the half-life was 76.91 h ± 52.5 h. A partial response following ch14.18/CHO was observed in 2/7 patients with residual disease. In mice, the half-lives were 22.7 h ± 1.9h for ch14.18/CHO and 25.0 h ± 1.9 h for ch14.18/SP2/0. The biodistribution of (125)I-ch14.18/CHO in mice with neuroblastoma was identical to (125)I-ch14.18/SP2/0, indicating GD 2 targeting activity in vivo. Ch14.18 produced in CHO cells showed an unchanged toxicity profile and pharmacokinetics in neuroblastoma patients compared with ch14.18 produced in SP2/0 cells, and evidence of clinical activity was observed. In mice, analysis of pharmacokinetics and biodistribution showed comparable results between ch14.18/CHO and ch14.18/SP2/0. Based on these results, ch14.18/CHO was accepted for prospective clinical evaluation.

Differential impact of the CYP3A5*1 and CYP3A5*3 alleles on pre-dose concentrations of two tacrolimus formulations.

OBJECTIVES: We investigated the pharmacokinetic and pharmacogenetic implications of conversion from a twice-daily (P-Tac) to a once-daily (A-Tac) tacrolimus (Tac) formulation. METHODS: We analyzed Tac levels in a cohort of 41 renal transplant patients with a stable graft function over a period of 1 year before and after conversion. RESULTS: After conversion, the patients had, on average, significantly lower Tac trough and dose-normalized trough levels (14%, P=0.0004 and 23%, P=0.001, respectively) despite similar doses. CYP3A5*3/*3 patients (n=27) required significantly lower Tac doses with both the formulations to reach Tac target levels (P-Tac 39%, P=0.011; A-Tac 36%, P=0.003) compared with *1/*3 patients (n=13). Interestingly, after the conversion, mean Tac trough levels and dose-normalized trough level remained almost constant in *1/*3 patients, but decreased significantly in *3/*3 patients (16%, P=0.001 and 25%, P=0.006). CONCLUSION: This study provides further evidence that the CYP3A5*1/*3 polymorphism significantly impacts Tac pharmacokinetics. Moreover, we show for the first time a pharmacogenetic effect on two different Tac formulations, as Tac trough levels of *3/*3 patients declined significantly after conversion to identical A-Tac doses.

Carbamazepine and lamotrigine plasma concentrations in epileptic patients during optimising therapy.

Therapeutic monitoring of antiepileptic drugs is important in process of optimisation of therapy of epileptic patients. Carbamazepine (CBZ) and Lamotrigine (LMT) are important drugs in therapy of epileptic patients which requires the monitoring of concentration of these drugs in serum. Ourstudy aim was the comparison and interpretation of the results of routine therapeutic monitoring of Carbamazepine and Lamotrigine in spotlight of antiepileptic therapy optimisation. We have analyzed 74 blood samples of epileptic patients who were in therapy with Carbamazepine or Lamotrigine. High pressure liquid chromatographywas used in determiningthe serum concentration of above mentioned drugs. Results of our study show the positive correlation between dosage and serum concentration of CBZ. (r = 0.78). The correlation coefficient between the dosage and serum concentration of LMT is higher than CBZ (r = 0.825). In the process of monitoring of serum concentration of CBZ, very important issue is the serum concentration of active metabolite named to carbamazepine-10,11-epoxide (CBZE). The correlation coefficient between the CBZ and its active metabolite was r = 0.57. During analysis of correlation between blood sampling time from last dose intake and serum concentration of respective drug in both drugs (CBZ and LMT) we have found the negative small correlation (r = -0.256 and r = -0.288). The results of our study contribute to other studies which confirm the complexity of therapeutic drug monitoring (TDM) process in general and particularly for CBZ and LMT. The process of TDM requires the selection of adequate analytical method and right appropriate interpretation of the serum concentration of these drugs.

Moxifloxacin does not alter ciclosporin pharmacokinetics in transplant patients: a multiple-dose, uncontrolled, single-centre study.

BACKGROUND: Moxifloxacin has a broad antibacterial spectrum and rapid bactericidal activity, and is thus a good option for the treatment of bacterial infections in patients who have undergone organ or bone marrow transplantation. Transplant patients also receive immunosuppressant therapy such as ciclosporin. OBJECTIVE: The primary objective of this study was to assess the steady-state pharmacokinetics of ciclosporin with and without concomitant treatment with moxifloxacin in transplant recipients. A secondary objective was to determine the safety and tolerability of the combined treatment. METHODS: Patients (n = 9) with stable graft function after bone marrow or renal transplantation and who were already receiving ciclosporin therapy were enrolled into the study. The patients were given ciclosporin (Sandimmun Optoral) capsules twice daily (total daily dosage 150-380 mg/day) throughout the study period. Moxifloxacin (Avolox) tablets 400 mg once daily were given on days 2-8 inclusive. The primary outcome measure was the change in ciclosporin pharmacokinetics on coadministration with moxifloxacin. Secondary outcomes were the steady-state pharmacokinetics of moxifloxacin and ciclosporin plus its metabolites in patients receiving moxifloxacin and ciclosporin concomitantly. Moxifloxacin pharmacokinetic parameters in the presence of ciclosporin were compared with previously published pharmacokinetic data for moxifloxacin in healthy individuals. RESULTS: No significant changes occurred in the concentration-time curves of ciclosporin and its metabolites following combination therapy with moxifloxacin. The geometric means of whole blood concentrations of ciclosporin and ciclosporin plus its metabolites on day 1 were similar to those on day 8 following combined administration of ciclosporin and moxifloxacin for 7 days. The ratio of combination treatment to monotherapy for ciclosporin was 1.01 (90% CI 0.91, 1.11) for the area under the blood concentration-time curve from time zero to 12 hours at steady state (AUC(12,ss)) and 0.96 (90% CI 0.88, 1.04) for the maximum steady-state blood drug concentration (C(max,ss)). For ciclosporin plus its metabolites the ratio was 1.07 (90% CI 0.99, 1.17) for AUC(12,ss) and 1.03 (90% CI 0.98, 1.09) for C(max,ss). The pharmacokinetic parameters for moxifloxacin were unaffected by the presence of ciclosporin. CONCLUSIONS: Concomitant administration of moxifloxacin does not alter the pharmacokinetic parameters of ciclosporin or ciclosporin plus its metabolites in immunosuppressed patients. Therefore, no dose adjustments or additional drug monitoring are required when ciclosporin is coadministered with moxifloxacin.

Prospectively assessed changes in lamotrigine-concentration in women with epilepsy during pregnancy, lactation and the neonatal period.

PURPOSE: To prospectively analyse the pharmacokinetics of lamotrigine (LTG) during pregnancy and lactation in a consecutive series of epileptic pregnant women. METHODS: Nine women on LTG-monotherapy were studied during pregnancy, delivery and lactation, until a mean of 3 weeks postpartum. Maternal blood samples were available from all trimesters as well as umbilical cord blood samples of the newborn 24 and/or 48 h postpartum. In 4 cases we additionally determined the LTG-concentration in breast milk. RESULTS: The median LTG-clearance was elevated by 197% during the first trimester, 236% and 248% during the second and third trimester respectively. A maximum of 264% was reached at delivery. An average LTG-dose increase by 250% had to be undertaken in order to obtain therapeutic serum levels. In puerperium LTG-clearance decreased again to reach the initial concentrations approximately at the third week postpartum. The median LTG-concentration ratio of the umbilical cord blood to maternal serum was 1.01 (range: 0.56-1.42), while the median LTG-concentration ratio of breast milk to maternal serum was 0.59 (range: 0.35-0.86). DISCUSSION: Our study confirms the therapeutic relevant changes of LTG-clearance during pregnancy and lactation in women on LTG-monotherapy. Since LTG crosses the placenta, a close monitoring of both mother and newborn is indispensable.

St John's wort extract (Ze 117) does not alter the pharmacokinetics of a low-dose oral contraceptive.

PURPOSE: St John's wort (Hypericum perforatum) is an herbal remedy that is widely used in the treatment of depression. Recent clinical data have demonstrated that St John's wort extracts interfere with the action of various drugs and possibly also with combined oral contraceptives. Therefore, we investigated the effects of a St John's wort extract (Ze 117) with low hyperforin content on the pharmacokinetics of ethinylestradiol and 3-ketodesogestrel. METHOD: Sixteen healthy female volunteers, who had taken a low-dose oral contraceptive (Lovelle contains 0.02 mg ethinylestradiol + 0.15 mg desogestrel) for at least 3 months, participated in the study. Pharmacokinetic data (AUC, C(max), t(max)) were determined the day before (reference) and after (test) a 14-day period of Ze 117 intake (250 mg twice daily). RESULTS: Before the co-administration of Ze 117 on day 7, the geometric mean (geometric coefficient of variation) for the AUC(0-24) of ethinylestradiol was 152.53 pg.h/ml (87.39%) and after co-administration on day 21 it was 196.57 pg.h/ml (78.14%). The respective values for ketodesogestrel were 36.37 pg.h/ml (34.18%) and 41.12 pg.h/ml (34.36%). The mean of individual ratios (reference-to-test) of log-transformed AUC values (90% confidence interval) were 0.951 (0.915-0.986) for ethinylestradiol and 0.968 (0.944-0.992) for ketodesogestrel indicating a small gain [corrected] in bioavilability, but bioequivalence nevertheless. CONCLUSION: These results indicate that the recommended dose of the hypericum extract Ze117, which has a low hyperforin content, does not interact with the pharmacokinetics of the hormonal components of the low-dose oral contraceptive.

Endothelin-1 gene variant Lys198Asn and plasma endothelin level in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a recognized risk factor for cardiovascular disorders. Thus, an association between endothelin-1 (EDN1) and OSA can be assumed. We investigated a cohort of 364 consecutive patients (age 57 +/- 10 years) with mild to severe OSA for the EDN1 variant Lys198Asn (G/T) and endothelin plasma levels and compared them with 57 controls. The Lys198Asn genotype was significantly associated with the apnea/hypopnea index (AHI) with a median of 30/h of sleep for GG, 27/h for GT and 59/h for TT genotype (p < 0.05). Further stratification of patients into 2 groups by body mass index (BMI) revealed a strong association between AHI and Lys198Asn polymorphism in 191 obese patients (p = 0.005), whereas in 173 nonobese patients, we observed no association. A substantial effect by BMI on OSA severity was seen with multiple linear regression (p < 0.001). However, this effect was modified by the Lys198Asn polymorphism and by gender: the AHI increase per unit of BMI was more pronounced in males than in females, and about 1.3 times greater in homozygous carriers of the mutant allele than in other carrier groups. EDN1 plasma levels of untreated OSA patients and of patients treated with nasal continuous positive airway pressure were not elevated compared with controls. Our results indicate that the Lys198Asn polymorphism is associated with the severity of OSA in obese subjects. The EDN1 plasma level cannot be used as a marker for OSA or its severity.

Enantiospecific pharmacokinetics of metoprolol in CYP2D6 ultra-rapid metabolizers and correlation with exercise-induced heart rate.

OBJECTIVE: Our objective was to study the enantioselective pharmacokinetics of metoprolol in CYP2D6 ultra-rapid metabolizers (UM) compared with extensive (EM) and poor (PM) metabolizers to quantify differential effects of metoprolol enantiomers on the beta1-adrenoreceptor blockade. METHODS: Twenty-nine healthy individuals were selected based on their CYP2D6 genotype, and 100 mg racemic metoprolol was administered. Plasma concentrations of R- and S-metoprolol and the metabolites SS-, SR-, RS-, and RR-hydroxymetoprolol were quantified by high-performance liquid chromatography. RESULTS: Mean (+/-SD) AUCs of S-metoprolol were 190 +/- 99 ng/ml x h in UMs, 366 +/- 158 in EMs, and 1,804 +/- 300 in PMs. For R-metoprolol, the AUCs were 127 +/- 72 ng/ml x h in UMs, 261 +/- 126 in EMs, and 1,746 +/- 319 in PMs. The concentrations of R-metoprolol and S-metoprolol, respectively, needed to obtain a half-maximum reduction in heart rate were estimated as 20 and 21 ng/ml in PMs, 11 and 17 ng/ml in EMs, and 7 and 11 ng/ml in UMs. CONCLUSION: A slight enantiopreference towards metabolism of R-metoprolol by CYP2D6 was observed in EMs and even more in the UM group, but the effect was far from being enantioselective.

Forces in anterior cruciate ligament during simulated weight-bearing flexion with anterior and internal rotational tibial load.

This study determined in-vitro anterior cruciate ligament (ACL) force patterns and investigated the effect of external tibial loads on the ACL force patterns during simulated weight-bearing knee flexions. Nine human cadaveric knee specimens were mounted on a dynamic knee simulator, and weight-bearing knee flexions with a 100N of ground reaction force were simulated; while a robotic/universal force sensor (UFS) system was used to provide external tibial loads during the movement. Three external tibial loading conditions were simulated, including no external tibial load (termed BW only), a 50N anterior tibial force (ATF), and a 5Nm internal rotation tibial torque (ITT). The tibial and femoral kinematics was measured with an ultrasonic motion capture system. These movement paths were then accurately reproduced on a robotic testing system, and the in-situ force in the ACL was determined via the principle of superposition. The results showed that the ATF significantly increased the in-situ ACL force by up to 60% during 0-55 degrees of flexion, while the ITT did not. The magnitude of ACL forces decreased with increasing flexion angle for all loading conditions. The tibial anterior translation was not affected by the application of ATF, whereas the tibial internal rotation was significantly increased by the application of ITT. These data indicate that, in a weight-bearing knee flexion, ACL provides substantial resistance to the externally applied ATF but not to the ITT.

Effects of the CYP2D6 gene duplication on the pharmacokinetics and pharmacodynamics of tramadol.

The analgesic drug tramadol is bioactivated by CYP2D6 to the opioid receptor agonist O-desmethyltramadol. Case reports indicated that carriers of the CYP2D6 gene duplication may be at high risk for opioid adverse events. However, the effects of the CYP2D6 duplication on kinetics and dynamics of tramadol have not been systematically studied. Pharmacokinetics and effects were monitored after a single dose of 100 mg racemic tramadol in 11 carriers of a CYP2D6 gene duplication allele (ultrarapid metabolizer [UM]) and compared with 11 carriers of 2 active CYP2D6 genes (extensive metabolizer [EM]). Pharmacodynamics was measured by cold pressure test, pupillometry, and standardized adverse event recording. The maximum plasma concentrations of the active metabolite (+)R,R-O-desmethyltramadol were significantly higher in the UM group compared with the EM group (P = 0.005; t test) with a mean difference of 14 ng/mL (95% confidence limit of difference, 2-26 ng/mL). Median (+)R,R-tramadol area under the curve was 786 and 587 mug.h.L in EMs and UMs, and the corresponding median (+)R,R-O-desmethyltramadol area under the curve was 416 and 448 mug.h.L (P = 0.005, t test). There was an increased pain threshold and pain tolerance and a stronger miosis after tramadol in UMs compared with EMs. Almost 50% of the UM group experienced nausea compared with only 9% of the EM group. In conclusion, pharmacokinetic differences between EMs and UMs were smaller than expected; nevertheless, UMs were more sensitive to tramadol than EMs. Therefore, tramadol may frequently cause adverse effects in southern European and Northern African populations with a high proportion of UMs.

Reduced-order preconditioning for bidomain simulations.

Simulations of the bidomain equations involve solving large, sparse, linear systems of the form Ax = b. Being an initial value problems, it is solved at every time step. Therefore, efficient solvers are essential to keep simulations tractable. Iterative solvers, especially the preconditioned conjugate gradient (PCG) method, are attractive since memory demands are minimized compared to direct methods, albeit at the cost of solution speed. However, a proper preconditioner can drastically speed up the solution process by reducing the number of iterations. In this paper, a novel preconditioner for the PCG method based on system order reduction using the Arnoldi method (A-PCG) is proposed. Large order systems, generated during cardiac bidomain simulations employing a finite element method formulation, are solved with the A-PCG method. Its performance is compared with incomplete LU (ILU) preconditioning. Results indicate that the A-PCG estimates an approximate solution considerably faster than the ILU, often within a single iteration. To reduce the computational demands in terms of memory and run time, the use of a cascaded preconditioner was suggested. The A-PCG was applied to quickly obtain an approximate solution, and subsequently a cheap iterative method such as successive overrelaxation (SOR) is applied to further refine the solution to arrive at a desired accuracy. The memory requirements are less than those of direct LU but more than ILU method. The proposed scheme is shown to yield significant speedups when solving time evolving systems.

Pharmacokinetics and pharmacodynamics of mycophenolic acid after enteric-coated mycophenolate versus mycophenolate mofetil in patients with progressive IgA nephritis.

Mycophenolic acid can be administered orally using mycophenolate mofetil or enteric-coated mycophenolate. In renal transplant patients on immunosuppressant combination therapy, the overall mycophenolic acid exposure after oral dosing with mycophenolate mofetil and enteric-coated mycophenolate is similar. This study compared pharmacokinetics and pharmacodynamics of mycophenolic acid after equivalent doses of enteric-coated mycophenolate (360 mg twice daily) or mycophenolate mofetil (500 mg twice daily) in 7 patients with progressive IgA nephritis (glomerular filtration rate 20-35 mL/min) using a randomized crossover design. The pharmacokinetics of mycophenolic acid concentrations and pharmacodynamics (using inosine 5'-monophosphate dehydrogenase activity as a bio-marker) were sequentially monitored for 12 hours. After enteric-coated mycophenolate treatment, the mycophenolic acid peak concentration (Cmax = 12.8 vs 6.0 microg/mL, P < .05) and the overall exposure were significantly higher (AUC = 60.9 vs 40.7 microg.h/mL, P < .05), and the apparent clearance was significantly lower (CL/F = 7.9 vs 10.7 L/h, P < .05) as compared to that after mycophenolate mofetil. Paradoxically, inosine 5'-monophosphate dehydrogenase activity was not significantly different. In conclusion, the steady-state mycophenolic acid exposure was higher during treatment with enteric-coated mycophenolate as compared to mycophenolate mofetil, which might be explained by more extensive enterohepatic recycling of mycophenolic acid after administration of enteric-coated mycophenolate, whereas inosine 5'-monophosphate dehydrogenase suppression was not different.

Conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in maintenance renal transplant recipients receiving tacrolimus: clinical, pharmacokinetic, and pharmacodynamic outcomes.

BACKGROUND: Mycophenolic acid (MPA) pharmacokinetics using the mycophenolate mofetil (MMF) formulation are known to differ between patients receiving tacrolimus or cyclosporine, but only limited data exist concerning concomitant use of tacrolimus and enteric-coated mycophenolate sodium (EC-MPS). METHODS: In this six-month, multicenter, open-label, single-arm trial, 63 maintenance renal transplant patients receiving tacrolimus were converted from mycophenolate mofetil (MMF) to EC-MPS. RESULTS: MPA concentration-time profiles in 21 patients showed that MPA exposure was similar with MMF or EC-MPS (mean area under the curve 39.9+/-11.6 microg x h/mL versus 43.7+/-17.4 microg x h/mL at day 14 post-conversion). Median time to peak concentration was 0.5 hr with MMF and 1.5 hr with EC-MPS. Inosine monophosphate dehydrogenase (IMPDH) activity was almost identical: area under the enzyme activity time curve (AEC) was 124.2+/-32.0 nmol x h/mg prot/h with MMF and 130.3+/-36.6 nmol x h/mg prot/h with EC-MPS at 14 days post-conversion; average daytime IMPDH activity was 10.3+/-2.7 nmol/h/mg protein and 10.9+/-2.7 nmol/h/mg protein, respectively. Maximal daytime inhibition of IMPDH activity was 67% with MMF and 62% with EC-MPS at day 14. One patient (1.6%) experienced mild biopsy-proven acute rejection. No graft losses or deaths occurred. Renal function remained stable (mean calculated creatinine clearance 70.6+/-26.8 mL/min with MMF and 68.8+/-25.4 mL/min six months post-conversion). Adverse events or infections with a suspected relation to EC-MPS occurred in 12 patients (19%). Four patients discontinued EC-MPS due to adverse events or infections. CONCLUSIONS: MMF and EC-MPS are associated with similar MPA exposure and equivalent pharmacodynamic effect. Conversion of tacrolimus-treated maintenance renal transplant patients from MMF to EC-MPS is safe and well-tolerated and does not compromise therapeutic efficacy.

Pharmacokinetics and pharmacodynamics of rosiglitazone in relation to CYP2C8 genotype.

OBJECTIVES: Rosiglitazone is metabolically inactivated predominantly via the cytochrome P450 (CYP) enzyme CYP2C8. The functional impact of the CYP2C8*3 allele coding for the Arg139Lys and Lys399Arg amino acid substitutions is controversial. The purpose of this was to clarify the role of this polymorphism with regard to the pharmacokinetics and clinical effects of rosiglitazone. METHODS: From a large sample of healthy volunteers, 14 carriers of the CYP2C8*1/*1 allele, 13 carriers of the *1/*3 allele, and 4 carriers the *3/*3 allele were selected for a clinical study. Rosiglitazone (8 mg) single-dose and multiple-dose pharmacokinetics and its effects on glucose level and body weight were monitored. Plasma and urine concentrations of rosiglitazone and desmethylrosiglitazone were measured, and kinetics was analyzed by noncompartmental and population-kinetic compartmental methods. RESULTS: Mean total clearance values were 0.033 L x h(-1) x kg(-1) (95% confidence interval [CI], 0.030-0.037 L x h(-1) x kg(-1)), 0.038 L x h(-1) x kg(-1) (95% CI, 0.033-0.044 L x h(-1) x kg(-1)), and 0.046 L x h(-1) x kg(-1) (95% CI, 0.033-0.058 L x h(-1) x kg(-1)) in carriers of CYP2C8 genotypes *1/*1, *1/*3, and *3/*3, respectively, on day 1 (P = .02, ANOVA [F test]). Rosiglitazone kinetics could be adequately described by a 1-compartmental model with first-order absorption. Besides CYP2C8 genotype, body weight was a significant covariate (P < .001, log-likelihood ratio test). Elimination half-lives were 4.3, 3.5, and 2.9 hours in CYP2C8*1/*1, *1/*3, and *3/*3 carriers, respectively. Clearance of desmethylrosiglitazone was also higher in CYP2C8*3 allele carriers, with mean values of 1.96 L/h (95% CI, 1.42-2.69 L/h), 2.22 L/h (95% CI, 1.61-3.04 L/h), and 2.47 L/h (95% CI, 1.80-3.39 L/h), respectively (P = .03). The plasma glucose area under the concentration curve was significantly lower after 14 days of taking rosiglitazone compared with day 1 (P = .01, paired t test), but no relationship of the glucose-lowering effect of rosiglitazone with CYP2C8 genotype was observed. CONCLUSIONS: This study showed that the CYP2C8*3 allele confers higher in vivo metabolic capacity than the wild-type CYP2C8*1 allele but the pharmacokinetic differences resulting from CYP2C8*3 were quantitatively moderate.

Effects of fluvastatin and cigarette smoking on CYP2C9 activity measured using the probe S-warfarin.

OBJECTIVE: The effect of cigarette smoking on CYP2C9 activity is unknown. We conducted a study to evaluate whether there is a difference in CYP2C9 activity in smokers versus non-smokers by examining S-warfarin AUC after CYP2C9 inhibition with fluvastatin. In addition, the effect of the CYP2C9 inhibitor fluvastatin was evaluated using S-warfarin as a probe. METHODS: A randomized, single dose, two-treatment crossover study of warfarin with a washout period of 21 days was performed. Eighteen healthy Caucasian smokers and non-smokers, genotyped as CYP2C9*1/*1 or CYP2C9*1/*2, received warfarin 10 mg plus vitamin K 10 mg to measure baseline CYP2C9 activity. Warfarin dosing was repeated after 18 days of fluvastatin 40 mg twice daily to evaluate CYP2C9 activity after inhibition. RESULTS: The S-warfarin AUC(0-infinity) between smokers and non-smokers did not differ by >25% after inhibition. There was no difference in S-warfarin AUC(0-infinity) during baseline (p = 0.45) or inhibition (p = 0.19) periods for smokers versus non-smokers. Fluvastatin increased the AUC of S-warfarin by 42+/-29% and 26+/-18% in smokers and nonsmokers, respectively. Linear regression analyses showed significant but weak correlations between peak concentrations (C(at 1 h)) or (-) 3S,5R-fluvastatin AUC(0-12 h) and extent of warfarin inhibition. For (+) 3R,5S-fluvastatin, a weak correlation was found between C(at 1 h) and extent of warfarin inhibition. CONCLUSIONS: Cigarette smoking does not affect CYP2C9 activity as evaluated using S-warfarin as a CYP2C9 probe. Fluvastatin is a weak inhibitor of CYP2C9 activity in both smokers and non-smokers.

The extent of induction of CYP3A by St. John's wort varies among products and is linked to hyperforin dose.

OBJECTIVE: Induction of CYP3A by St. John's wort (SJW) extracts with high hyperforin (HYF) content is well described. Since SJW products vary in the amount of HYF and other main constituents, the aim of the study was to evaluate the effect on CYP3A function of SJW preparations with a range from very low to high HYF content. METHODS: Forty-two male, healthy volunteers were randomized into six parallel SJW medication groups with varying composition especially with regard to HYF content. Midazolam plasma concentration profiles were characterized after a single oral dose of 7.5 mg midazolam on the day before and on the 14th day of SJW medication. RESULTS: All SJW preparations tested resulted in a decrease in midazolam AUC, although the extent of the effect differed. The extract LI 160 (HYF 41 mg/day) decreased midazolam AUC0-12h by 79.4% (95% CI -88.6; -70.1), which was significantly greater than the effect by any other medication (p<0.05). SJW powder tablets 2.7 g/day (HYF 12 mg/day) resulted in a midazolam AUC0-12h decrease of 47.9% (95% CI -59.7;-36.2), while 2.7 g/day SJW powder tablets that were almost devoid of HYF (0.13 mg/day) reduced midazolam AUC0-12h by only 21.1% (95% CI -33.9; -8.3). Considering all six SJW medications tested, the extent of midazolam AUC decrease correlated significantly with increasing HYF dose (r=-0.765, p<0.001), but not with hypericin dose (r=-0.067; p=0.673). CONCLUSION: The extent of induction of CYP3A varies among St. John's wort products and depends on hyperforin dose.

Accelerating large cardiac bidomain simulations by arnoldi preconditioning.

Bidomain simulations of cardiac systems often in volve solving large, sparse, linear systems of the form Ax=b. These simulations are computationally very expensive in terms of run time and memory requirements. Therefore, efficient solvers are essential to keep simulations tractable. In this paper, an efficient preconditioner for the conjugate gradient (CG) method based on system order reduction using the Arnoldi method (A-PCG) is explained. Large order systems generated during cardiac bidomain simulations using a finite element method formulation, are solved using the A-PCG method. Its performance is compared with incomplete LU (ILU) preconditioning. Results indicate that the A-PCG estimates an approximate solution considerably faster than the ILU, often within a single iteration. To reduce the computational demands in terms of memory and run time, the use of a cascaded preconditioner is suggested. The A-PCG can be applied to quickly obtain an approximate solution, subsequently a cheap iterative method such as successive overrelaxation (SOR) is applied to further refine the solution to arrive at a desired accuracy. The memory requirements are less than direct LU but more than ILU method. The proposed scheme is shown to yield significant speedups when solving time evolving systems.

Approaching an individual methotrexate regimen in leptomeningeal carcinomatosis.

BACKGROUND: Chemotherapeutic effects in leptomeningeal carcinomatosis (LC) vary widely between patients, presumably in part because drug elimination from cerebrospinal fluid (CSF) differs between individuals. An individual dosing, adapted to elimination, may improve treatment efficacy. OBJECTIVE: To discuss the feasibility of easily accessible elimination parameters for an individual dosing of chemotherapy in LC. MATERIALS AND METHODS: The elimination of intrathecally applied methotrexate (Mtx) was tested in 14 LC patients and compared to the literature data. Plasma drug levels and CSF albumin levels are suggested as elimination parameters. RESULTS AND DISCUSSION: Mtx disappeared from CSF and appeared in plasma with an expected wide variation (interindividual range of coefficients of variation (CV) of CSF Mtx levels 158-189%, intraindividual range of CV of plasma Mtx levels 35-64%). Our data together with reported data suggest that plasma Mtx levels mirror closely the Mtx elimination from CSF. The levels of CSF albumin and of plasma Mtx at defined sample times correlated negatively (r=-0.7), which reflects their largely common elimination from CSF. CONCLUSION: Both parameters seem appropriate to describe the Mtx elimination from CSF. They should allow to individually adapt Mtx dosing towards an improvement of Mtx availability in CSF and of treatment efficacy.