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Multiple-dose FTY720: tolerability, pharmacokinetics, and lymphocyte responses in healthy subjects.
J Clin Pharmacol. 2004 May; 44(5):532-7.JC

Abstract

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.

Authors+Show Affiliations

Novartis Pharma AG, Building WSJ 27.4093, 4002 Basel, Switzerland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Comparative Study
Journal Article
Randomized Controlled Trial

Language

eng

PubMed ID

15102874

Citation

Kovarik, John M., et al. "Multiple-dose FTY720: Tolerability, Pharmacokinetics, and Lymphocyte Responses in Healthy Subjects." Journal of Clinical Pharmacology, vol. 44, no. 5, 2004, pp. 532-7.
Kovarik JM, Schmouder R, Barilla D, et al. Multiple-dose FTY720: tolerability, pharmacokinetics, and lymphocyte responses in healthy subjects. J Clin Pharmacol. 2004;44(5):532-7.
Kovarik, J. M., Schmouder, R., Barilla, D., Riviere, G. J., Wang, Y., & Hunt, T. (2004). Multiple-dose FTY720: tolerability, pharmacokinetics, and lymphocyte responses in healthy subjects. Journal of Clinical Pharmacology, 44(5), 532-7.
Kovarik JM, et al. Multiple-dose FTY720: Tolerability, Pharmacokinetics, and Lymphocyte Responses in Healthy Subjects. J Clin Pharmacol. 2004;44(5):532-7. PubMed PMID: 15102874.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Multiple-dose FTY720: tolerability, pharmacokinetics, and lymphocyte responses in healthy subjects. AU - Kovarik,John M, AU - Schmouder,Robert, AU - Barilla,Denise, AU - Riviere,Gilles-Jacques, AU - Wang,Yibin, AU - Hunt,Thomas, PY - 2004/4/23/pubmed PY - 2004/12/17/medline PY - 2004/4/23/entrez SP - 532 EP - 7 JF - Journal of clinical pharmacology JO - J Clin Pharmacol VL - 44 IS - 5 N2 - 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. SN - 0091-2700 UR - https://www.unboundmedicine.com/medline/citation/15102874/Multiple_dose_FTY720:_tolerability_pharmacokinetics_and_lymphocyte_responses_in_healthy_subjects_ L2 - https://doi.org/10.1177/0091270004264165 DB - PRIME DP - Unbound Medicine ER -