Single 1 mg doses of FTY720 were well tolerated in healthy subjects and elicited a moderate decrease in peripheral blood lymphocyte count and a transient decrease in heart rate consistent with its pharmacological mode of action. FTY720 may be administered without regard to the timing of meals or their fat content.
FTY720 is a sphingosine-1-phosphate receptor agonist being developed as an immunomodulator for acute rejection prophylaxis after organ transplantation. This study was performed to characterize the pharmacokinetics of and lymphocyte response to multiple-dose FTY720. In this randomized, double-blind study, three groups of 20 healthy subjects each received either placebo, 1.25 mg/day FTY720, or 5 mg/day FTY720 for 7 consecutive days. FTY720 blood concentrations and lymphocyte counts were assessed over the weeklong treatment phase and over a month-long washout phase. The relationship between FTY720 blood concentrations and lymphocyte counts was explored by an inhibitory E(max) model. First-dose exposure was consistent with dose proportionality between the low- and high-dose groups. Blood levels accumulated fivefold over the treatment period. Exposure on day 7 was dose proportional for C(max) (5.0 +/- 1.0 vs. 18.2 +/- 4.1 ng/mL) and for AUC (109 +/- 24 vs. 399 +/- 85 ng.h/mL). Washout pharmacokinetics after the last dose indicated an elimination half-life averaging 8 days. Lymphocyte counts decreased by 80% in subjects receiving the lower dose to a nadir of 0.4 +/- 0.1 x 10(9)/L and by 88% in subjects receiving the upper dose to a nadir of 0.2 +/- 0.1 x 10(9)/L. Descriptive exposure-response modeling estimated that the lymphocyte response at 5 mg/day is near the maximal response achievable. By the end-of-study evaluation on day 35, lymphocyte counts had recovered to within 75% and 50% of baseline in the low- and high-dose groups, respectively. In summary, systemic exposure to FTY720 was consistent with dose-proportionality after both single- and multiple-dose administration. Total lymphocyte counts decreased from baseline by 80% and 88% at regimens of 1.25 and 5 mg/day, respectively. Exposure-response modeling provided evidence that 5 mg/day FTY720 resulted in a near-maximal dynamic effect of this drug on lymphocytes.
Pimecrolimus cream 1%, a nonsteroid inhibitor of inflammatory cytokines, offers an alternative to corticosteroids in the treatment of atopic dermatitis. Here we evaluate pimecrolimus blood concentrations and tolerability to pimecrolimus cream 1% in 22 infants below 2 years of age with atopic dermatitis (10-92% body surface area affected at baseline). Efficacy was assessed as a secondary objective. Pimecrolimus cream 1% was applied twice daily for 3 weeks. Blood concentrations were low, typically (96% of total 100 concentrations measured) below 2 ng/mL, the majority (71%) remaining below 0.5 ng/mL. The highest concentration observed was 2.26 ng/mL. At steady state, there was no indication of accumulation. Pimecrolimus was well tolerated locally and systemically, with no serious adverse events recorded. Most adverse events recorded (35 in 17/22 patients) were typical of the young pediatric population studied, of mild to moderate severity, and not considered to be study-medication related, with the exception of four local adverse effects limited to the site of cream application. No clinically relevant change was observed in physical examination, vital signs, or laboratory safety parameters. A rapid onset of therapeutic effect was observed within the first four days of treatment. Pimecrolimus cream 1% is well tolerated in infants 3 to 23 months of age treated for 3 weeks, and results in minimal systemic exposure.
Terbinafine-CYP2D6 inhibition was evaluated by assessing 48-hour concentration-time profiles of the tricyclic antidepressant desipramine in 12 healthy volunteers identified as extensive cytochrome P450 2D6 (CYP2D6) metabolizers by genotyping and phenotyping. Pharmacokinetics was evaluated at baseline (50 mg oral desipramine given alone), steady state (after 250 mg oral terbinafine for 21 days), and 2 and 4 weeks after terbinafine discontinuation. Pharmacodynamics was evaluated before and 2 hours after each desipramine administration, using Mini-Mental Status Examination (MMSE) and EGG. Terbinafine administration inhibited CYP2D6 metabolism, as indicated by the significant increase in desipramine C(max) (19 ng/ml vs. 36 ng/ml) and AUC0-infinity (482 ng.h/ml vs. 2383 ng.h/ml) and decrease in AUC0-24 and C(max) of the CYP2D6-mediated metabolite, 2-hydroxydesipramine. In addition, the C(max) and AGUC0-infinity of desipramine and metabolite were still elevated 4 weeks after terbinafine discontinuation. Caution should be exercised when coprescribing terbinafine and drugs metabolized by CYP2D6, particularly those with a narrow therapeutic index.
This was an open-label, randomized, three-period, three-treatment, multiple dose, crossover study in 12 healthy male and female subjects. This study evaluated single dose and steady-state pharmacokinetics of fluvastatin following single and multiple dose administrations of a new extended release fluvastatin 8 h matrix tablet, Lescol XL 80 mg and 160 mg doses once a day. The study also included a twice a day administration of an immediate release (IR) form of fluvastatin capsule, Lescol, for comparative purposes. All doses were administered for 7 days. The safety and tolerability were also assessed. The pharmacokinetics of fluvastatin were evaluated on days 1 and 7 following each treatment. Fluvastatin systemic exposure was 50% less when administered as Lescol XL 80 mg qd compared with Lescol IR 40 mg bid. Conversely, fluvastatin systemic exposure was 22% higher when administered as Lescol XL 160 mg qd compared with Lescol IR 40 mg bid. Single doses of Lescol XL 80 mg and 160 mg were dose proportional but, deviation (30%) from dose proportionality was observed for the Lescol XL 160 mg at steady-state. There appeared to be moderate (20%-40%) accumulation of serum fluvastatin maximal concentrations and exposure after multiple doses of Lescol XL tablets. Both Lescol XL 80 mg and 160 mg showed delayed absorption and longer apparent elimination half-life compared with fluvastatin IR capsule. Single and multiple doses of fluvastatin were generally well tolerated in this healthy volunteer population. Adverse event profiles were consistent with the published safety profile of the marketed formulations. Aside from one incidence of creatine phosphokinase (CPK) elevation (following Lescol XL 160 mg qd treatment), there were no safety concerns with any of the treatments when administered acutely (7 days).
The pharmacokinetics of single-dose FTY720 and steady-state cyclosporine were not altered during coadministration.
A non-microemulsion cyclosporine oral solution was recently recalled from the market because of the lack of bioequivalence when administered with apple juice compared with water as the diluent. This open-label, randomized, two-period, crossover study assessed the effect of apple juice on Neoral, a microemulsion cyclosporine oral solution. The study enrolled 34 subjects who received 180 mg Neoral oral solution diluted in 200 mL tap water or apple juice. Cyclosporine was measured in whole blood by a liquid chromatography method. Pharmacokinetic parameters were compared by standard bioequivalence tests. With water vs. apple juice, cyclosporine Cmax was 1263 +/- 203 vs. 1191 +/- 225 ng/mL and AUC was 4714 +/- 1117 vs. 4788 +/- 1320 ng h/mL, respectively. Bioequivalence was demonstrated for both parameters. These data were comparable with those from a previous study in which subjects received 180 mg Neoral oral solution with orange juice. Cyclosporine bioavailability is unaltered when Neoral is administered diluted in apple juice or orange juice compared with tap water which conforms to the cyclosporine product label.
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