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Titolo:
Effect of gastrointestinal inflammation and age on the pharmacokinetics oforal microemulsion cyclosporin A in the first month after bone marrow transplantation
Autore:
Schultz, KR; Nevill, TJ; Balshaw, RF; Toze, CL; Corr, T; Currie, CJ; Strong, DK;
Indirizzi:
British Columbia Childrens Hosp, Dept Pediat, Div Hematol Oncol Bone Marrow Transplantat, Vancouver, BC V6H 3V4, Canada British Columbia Childrens Hosp Vancouver BC Canada V6H 3V4 H 3V4, Canada Univ British Columbia, Dept Pediat, Div Hematol Oncol Bone Marrow Transplantat, Vancouver, BC V5Z 1M9, Canada Univ British Columbia Vancouver BC Canada V5Z 1M9 ver, BC V5Z 1M9, Canada Univ British Columbia, Dept Pharm, Vancouver, BC V5Z 1M9, Canada Univ British Columbia Vancouver BC Canada V5Z 1M9 ver, BC V5Z 1M9, Canada Vancouver Hosp, Leukemia BMT Program BC, Vancouver, BC, Canada Vancouver Hosp Vancouver BC Canada BMT Program BC, Vancouver, BC, Canada British Columbia Canc Agcy, Ctr Hlth Sci, Vancouver, BC V5Z 4E6, Canada British Columbia Canc Agcy Vancouver BC Canada V5Z 4E6 BC V5Z 4E6, Canada Univ British Columbia, Synect Corp, Vancouver, BC V5Z 1M9, Canada Univ British Columbia Vancouver BC Canada V5Z 1M9 ver, BC V5Z 1M9, Canada
Titolo Testata:
BONE MARROW TRANSPLANTATION
fascicolo: 5, volume: 26, anno: 2000,
pagine: 545 - 551
SICI:
0268-3369(200009)26:5<545:EOGIAA>2.0.ZU;2-M
Fonte:
ISI
Lingua:
ENG
Soggetto:
VERSUS-HOST DISEASE; DRUG-INTERACTIONS; P-GLYCOPROTEIN; CLINICAL PHARMACOKINETICS; POLARIZED EFFLUX; CACO-2 CELLS; RECIPIENTS; BIOAVAILABILITY; ABSORPTION; METABOLISM;
Keywords:
cyclosporin A; pharmacokinetics; bone marrow transplantation; graft-versus-host disease; mucositis; age-related effects;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
29
Recensione:
Indirizzi per estratti:
Indirizzo: Schultz, KR British Columbia Childrens Hosp, Dept Pediat, Div Hematol Oncol Bone Marrow Transplantat, 4480 Oak St, Vancouver, BC V6H 3V4, Canada British Columbia Childrens Hosp 4480 Oak St Vancouver BC Canada V6H 3V4
Citazione:
K.R. Schultz et al., "Effect of gastrointestinal inflammation and age on the pharmacokinetics oforal microemulsion cyclosporin A in the first month after bone marrow transplantation", BONE MAR TR, 26(5), 2000, pp. 545-551

Abstract

Cyclosporin A (CsA) absorption is highly variable in BMT patients, Neoral,a new microemulsion formulation of CsA, permits increased absorption with less variable pharmacokinetic parameters in non-BMT patients. We evaluated the pharmacokinetics of CsA after BMT in patients received microemulsion CsA. Two oral doses of 3mg/kg were given 48h apart between 14 and 28 days after allogeneic BMT in 20 adults, and one dose in seven children, while subjects were receiving a continuous i.v. infusion of CsA, Whole blood samples were taken throughout the dosing interval to calculate the incremental CsA exposure using maximum concentration (C-max), time to C-max (t(max)), concentration at 12 h after the dose (C12), the area under the concentration-timecurve (AUC), and to establish inter- and intra-patient pharmacokinetic variability. Drug exposure was substantially lower in children than in adults,with an AUC of 861 +/- 805 vs 2629 +/- 1487 mu mg x h/l (P=0.001), respectively, and absorption was delayed and diminished in both groups by comparison with solid organ recipients. Intra-patient variability in adults for AUCwas high at 0.59 +/- 0.34, while inter-patient variability, measured as the coefficient of variation (c.v.), was 0.55 for the first and 0.54 for the second dose. In adults, gastrointestinal (GI) inflammation due to either mucositis or GVHD resulted in a higher AUC of 3077 +/- 1551 mu g x h/l. compared to 1795 +/- 973 mu g x h/l (P = 0.02), and a similar trend was observedin children. AUC seemed little affected by the CsA formulation (liquid or capsule), or co-administration with liquids or food. Trough (12 h) CsA levels correlated poorly with incremental AUG. Sparse sample modeling of the AUC using two-point predictors taken at 2.5 and 5h after dosing accurately approximated AUC in adults (r(2) = 0.94), while 1.5 and 5 h was superior in children (r(2) = 0.98), These data suggest that 12 h postdose trough measurements of CsA may not be the most appropriate way to evaluate CsA blood concentrations in order to establish therapeutic efficacy in BMT patients. Based on this study, the dose of microemulsion CsA should be adjusted based on recipient age, and the presence of GI inflammation secondary to mucositis or GVHD. These data would suggest that sparse sampling at time points earlier than the trough more accurately reflects the AUC and may correlate more closely with therapeutic efficacy early post-BMT.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 07/07/20 alle ore 12:24:28