Pimecrolimus: absorption, distribution, metabolism, and excretion in healthy volunteers after a single oral dose and supplementary investigations in vitro.

The absorption and disposition of pimecrolimus, a calcineurin inhibitor developed for the treatment of inflammatory skin diseases, was investigated in four healthy volunteers after a single oral dose of 15 mg of [(3)H]pimecrolimus. Supplementary information was obtained from in vitro experiments. Pimecrolimus was rapidly absorbed. After t(max) (1-3 h), its blood concentrations fell quickly to 3% of C(max) at 24 h, followed by a slow terminal elimination phase (average t(1/2) 62 h). Radioactivity in blood decreased more slowly (8% of C(max) at 24 h). The tissue and blood cell distribution of pimecrolimus was high. The metabolism of pimecrolimus in vivo, which could be well reproduced in vitro (human liver microsomes), was highly complex and involved multiple oxidative O-demethylations and hydroxylations. In blood, pimecrolimus was the major radiolabeled component up to 24 h (49% of radioactivity area under the concentration-time curve(0-24) h), accompanied by a large number of minor metabolites. The average fecal excretion of radioactivity between 0 and 240 h amounted to 78% of dose and represented predominantly a complex mixture of metabolites. In urine, 0 to 240 h, only about 2.5% of the dose and no parent drug was excreted. Hence, pimecrolimus was eliminated almost exclusively by oxidative metabolism. The biotransformation of pimecrolimus was largely catalyzed by CYP3A4/5. Metabolite pools generated in vitro showed low activity in a calcineurin-dependent T-cell activation assay. Hence, metabolites do not seem to contribute significantly to the pharmacological activity of pimecrolimus.

Righting response of artificially inclined maritime pine (Pinus pinaster) saplings to wind loading.

To determine if trees respond to dynamic and static loading in the same manner, 2-year-old maritime pine (Pinus pinaster Ait.) trees were subjected to different types of mechanical loading in the field. One block of trees (the control) were kept in pots and planted in the field at an angle of 0 or 45 degrees to the vertical. A similar block of leaning potted trees was planted nearby and subjected to frequent, unilateral wind loading for a period of 1 s every 2 min. Half the leaning trees were oriented toward the direction of wind loading and half were oriented along the axis of wind loading. The stem profile was measured three times during the growing season to quantify the rate of stem straightening. Compression wood formation and stem shape were measured in all plants. No differences in mean height or diameter were observed between blocks and all leaning trees straightened, but not at the same rate. Although no difference in the rate of apical straightening occurred between control and wind-treated trees, the righting response of the basal part of the stem of leaning trees subjected to wind was four times greater than that of leaning trees without wind. No differences in the righting response were observed between leaning trees growing toward and trees growing away from the source of wind. No significant differences in compression wood formation were found between control trees and wind-treated trees, indicating that other factors must determine the reorientation rate of leaning trees. Results are discussed with reference to the quality of compression wood in conifers and the mechanotransductive pathway in plants.

Phototropic response induced by wind loading in Maritime pine seedlings (Pinus pinaster Aït.).

Both woody and herbaceous plant species are known to respond to wind loading, with consequences for growth and morphology. Wind has usually been classified as a mechanical stress which is detrimental to plant growth. Few experiments exist whereby plants and, in particular, woody species are exposed to wind, as opposed to mechanical perturbation by touching, flexing or shaking. Such experiments have always been short term and often carried out in wind tunnels in a controlled greenhouse environment. This study introduces an experiment to test the responses of Maritime pine (Pinus pinaster Aït.) seedlings to recurrent and short wind loading in the field, over two growing seasons. These experiments provide evidence that periodic short-term exposure to wind can induce phototropic responses in the early stage of pine seedlings' development. An interpretation is proposed in terms of efficiency to light tracking and hypotheses are discussed concerning the underlying physiological process.

FTY720 and cyclosporine: evaluation for a pharmacokinetic interaction.

BACKGROUND: FTY720 is a sphingosine-1-phosphate receptor agonist intended for use in immunoprophylaxis regimens to prevent acute rejection after organ transplantation. OBJECTIVE: To evaluate the potential for a pharmacokinetic drug interaction between the immunomodulator FTY720 and cyclosporine to support the use of this drug combination in organ transplantation. METHODS: In this open-label, randomized crossover study, 12 subjects with psoriasis received a single dose of FTY720 1 mg alone and on day 5 of an 8-day course of cyclosporine 200 mg twice daily. The single-dose pharmacokinetics of FTY720 and the steady-state pharmacokinetics of cyclosporine were characterized when given alone and during coadministration. Routine safety data were collected, with special attention to total blood lymphocyte counts and heart rate. RESULTS: Cyclosporine coadministration compared with FTY720 given alone did not significantly alter FTY720 maximum concentration (C(max)) (0.57 +/- 0.17 vs 0.58 +/- 0.19. ng/mL, respectively) or AUC(0-t) (41 +/- 13 vs 41 +/- 13 ng. h/mL, respectively). Likewise for cyclosporine, FTY720 coadministration did not alter the steady-state Cmax compared with cyclosporine given alone (1452 +/- 308 vs 1376 +/- 149 ng/mL, respectively) or AUC(tau) (6385 +/- 1578 vs 6031 +/- 1051 ng. h/mL, respectively). Mean lymphocyte counts decreased from baseline by an average of 35% over the first 2 days after FTY720 administration and thereafter increased to prestudy values by day 5 similarly in the absence and presence of cyclosporine. The morning mean supine heart rate decreased approximately 10% and returned to prestudy rates by day 5 after administration of FTY720 alone and with cyclosporine. Heart rate changes were asymptomatic in all study participants. One subject experienced asymptomatic second-degree type 1 atrioventricular (Wenckebach) block. CONCLUSIONS: The pharmacokinetics of single-dose FTY720 and steady-state cyclosporine were not altered during coadministration.

Pharmacokinetics of an everolimus-cyclosporine immunosuppressive regimen over the first 6 months after kidney transplantation.

The pharmacokinetics of everolimus were characterized over the first 6 months post transplant in 731 patients receiving either 0.75 or 1.5 mg bid everolimus in addition to cyclosporine and corticosteroids. Pharmacokinetic data consisted of 4014 everolimus trough concentrations (Cmin) obtained in all patients and 659 area under the concentration-time curve (AUC) -profiles obtained at months 2, 3, and 6 in a subset of 261 patients. Cmins averaged 4.3 +/- 2.4 and 7.2 +/- 4.2 ng/mL at 0.75 and 1.5 mg bid, indicating a 20% under-proportionality at the upper dose level. Cmins were 19-34% lower in the first month compared with months 2 through 6-values. AUC was dose-proportional and stable over time, averaging 77 +/- 32 and 136 +/- 57 ng.h.mL-1 at the two dose levels. Within- and between-patient variability in AUC were 27% and 31%, respectively. There was no influence of sex, age (16-66 years), or weight (42-132 kg) on AUC. Everolimus exposure was significantly lower by an average 20% in blacks. Everolimus exposure was relatively stable over the first 6 months post transplant, with no major departure from dose-proportionality over the therapeutic dose range. Weight-adjusted dosing (mg/kg) does not appear warranted. Black patients may have lower bioavailability and/or higher clearance of everolimus compared with white patients.

Clinical development of an everolimus pediatric formulation: relative bioavailability, food effect, and steady-state pharmacokinetics.

The immunosuppressant everolimus used in organ transplantation is formulated as a conventional tablet for adults and a dispersible tablet that can be administered in water for pediatric use. As part of the pediatric clinical development program, the relative bioavailability and food effect for the dispersible tablet were evaluated in healthy adult subjects as a prelude to characterizing the steady-state pharmacokinetics in pediatric kidney allograft recipients. In a randomized, open-label, three-way crossover study, 24 healthy adults received single 1.5-mg oral doses of everolimus as (1) six 0.25-mg dispersible tablets in water, (2) two 0.75-mg conventional tablets, and (3) six 0.25-mg dispersible tablets in water after a high-fat breakfast. Cmax and AUC were evaluated by standard bioequivalence testing to determine relative bioavailability and to quantify the effect of food. In a multicenter open-label efficacy/safety trial, pediatric renal allograft recipients received 0.8 mg/m2 (maximum 1.5 mg) bid everolimus as dispersible tablets in water. Serial trough concentrations over the first week and a steady-state pharmacokinetic profile on day 7 posttransplant were collected in 19 patients ranging from ages 2 to 16 years old. The bioavailability of everolimus from the dispersible tablet was 10% lower relative to the conventional tablet, with a ratio (90% confidence interval) of 0.90 (0.76-1.07). After a high-fat meal, tmax was delayed by a median 2.5 hours, and Cmax was reduced by 50%. Overall absorption, however, was not affected by food inasmuch as the fed/fasting AUC ratio was 0.99 (0.83-1.17). In pediatric patients, steady state was reached between days 3 and 5. The corresponding steady-state parameters were as follows: Cmin, 4.4 +/- 1.7 ng/ml; Cmax, 13.6 +/- 4.2 ng/ml; and AUC, 87 +/- 27 ng.h/ml. Steady-state concentration-time profiles in pediatric transplant patients receiving the dispersible tablet were comparable to those of adult patients receiving the conventional tablet when both were dosed to yield similar trough concentrations. If a pediatric patient is converted from the everolimus dispersible tablet to the conventional tablet, this should be based on a 1:1 milligram switch with subsequent therapeutic drug monitoring to further individualize the dose as needed. The dispersible tablet formulation should be taken consistently either with or without food to minimize fluctuations in exposure over time.

Pharmacokinetic and pharmacodynamic assessments of HMG-CoA reductase inhibitors when coadministered with everolimus.

The authors assessed the mutual influence of the immunosuppressant everolimus (Certican) and the HMG-CoA reductase inhibitors atorvastatin and pravastatin when coadministered based on pharmacokinetic and pharmacodynamic measures. In this randomized, open-label, three-way crossover study, 24 healthy men received three single-dose oral treatments: 2 mg everolimus, 20 mg atorvastatin (n = 12) or 20 mg pravastatin (n = 12), and the respective statin coadministered with everolimus. Consecutive treatments were separated by a 14-day washout. The pharmacokinetics of all three drugs and total HMG-CoA reductase inhibitors were measured. Everolimus Cmax was reduced by 9% and 10% with atorvastatin and pravastatin coadministration; the corresponding decreases in everolimus AUC were 5% and 6%, respectively. Everolimus coadministration increased the Cmax of atorvastatin by 11% but had no influence on atorvastatin AUC. Coadministration of everolimus with pravastatin was associated with a 10% decrease in pravastatin Cmax and a 5% decrease in the AUC. The elimination half-lives of the two statins were unaffected by everolimus. Changes in total HMG-CoA reductase inhibitors in plasma exhibited generally similar patterns as for the parent statin exposures. Single-dose administrations of everolimus with either atorvastatin or pravastatin did not influence the pharmacokinetics of everolimus, atorvastatin, pravastatin, or total HMG-CoA reductase inhibitors in plasma to a clinically relevant extent.