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Biomedical subjects

I Bekersky

Publications and source records attributed to I Bekersky.

At least 37 records · Page 2Linked to original sources
PubMed1999

Effects of rifampin on tacrolimus pharmacokinetics in healthy volunteers.

Tacrolimus is a marketed immunosuppressant used in liver and kidney transplantation. It is subject to extensive metabolism by CYP3A4 and is a substrate for P-glycoprotein-mediated transport. A pharmacokinetic interaction with rifampin, an antituberculosis agent and potent inducer of CYP3A4 and P-glycoprotein, and tacrolimus was evaluated in six healthy male volunteers. Tacrolimus was administered at doses of 0.1 mg/kg orally and 0.025 mg/kg/4 hours intravenously. The pharmacokinetics of tacrolimus were obtained from serial blood samples collected over 96 hours, after single oral and intravenous administration prior to and during an 18-day concomitant rifampin dosing phase. Coadministration of rifampin significantly increased tacrolimus clearance (36.0 +/- 8.1 ml/hr/kg vs. 52.8 +/- 9.6 ml/hr/kg; p = 0.03) and decreased tacrolimus bioavailability (14.4% +/- 5.7% vs. 7.0% +/- 2.7%; p = 0.03). Rifampin appears to induce both intestinal and hepatic metabolism of tacrolimus, most likely through induction of CYP3A and P-glycoprotein in the liver and small bowel.

Administration, Oral↗
PubMed1999

Bioequivalence of 1 and 5 mg tacrolimus capsules using a replicate study design.

Tacrolimus (FK506, Prograf) is marketed for the prophylaxis of organ rejection following allogenic liver or kidney transplantation. A previously conducted, randomized, 24-subject, crossover bioavailability study of 1 and 5 mg capsules (one period each) failed to demonstrate bioequivalence. A single-dose, four-period, four-sequence, randomized, crossover, replicate study (N = 32) was therefore used to evaluate the bioequivalence of the marketed 1 and 5 mg capsules in healthy volunteers. Tacrolimus blood concentrations were measured serially over 72 hours using a commercially available ELISA assay. Noncompartmental pharmacokinetic parameters were determined. Ninety percent CIs of log-transformed parameter ratios were 90.5-101.9, 87.1-101.7, and 89.7-103.8 for Cmax, AUC0-t, and AUC0-infinity, respectively. Since all values were within 80% to 125%, the capsules are bioequivalent. Based on %CVs, intersubject variability was approximately two to three times greater than intrasubject variability. The safety of single 5 mg oral tacrolimus doses administered to healthy volunteers at 7-day intervals was also ascertained.

Abdominal Pain↗
PubMed1998

AmBisome (liposomal amphotericin B): a comparative review.

AmBisome (NeXstarPharmaceuticals, San Dimas, CA) is a unilamellar liposomal formulation of amphotericin B that was recently approved for use as empirical treatment for presumed fungal infections in febrile neutropenic patients and for aspergillosis, candidiasis, and cryptococcosis infections refractory to amphotericin B. It is a small closed microscopic sphere (<100 nm in diameter) with an inner aqueous core (i.e., a true liposome). AmBisome remains as an intact sphere in vitro and for prolonged periods of time in vivo during the processes of systemic transport and pharmacologic action. As a consequence of its size and in vivo stability, AmBisome has physiochemical properties and a pharmacokinetic profile that are considerably different from those of currently available lipid-complexed amphotericin B formulations, with greatly increased area under the plasma concentration-time curve and much lower clearance at equivalent doses. AmBisome liposomes can be seen to accumulate at sites of fungal infection. Disruption of AmBisome liposomes occurs after attachment to the fungal cell wall and results in amphotericin B binding to fungal cell membrane ergosterol with subsequent cell lysis. AmBisome has been shown to penetrate the cell wall of both extracellular and intracellular forms of susceptible fungi.

Amphotericin B↗
PubMed1998

Tacrolimus (FK506) ointment for atopic dermatitis: a phase I study in adults and children.

BACKGROUND: Tacrolimus is a potent immunosuppressant used in organ transplant recipients; an ointment formulation is being developed as a therapeutic agent for atopic dermatitis. OBJECTIVE: Our purpose was to define the pharmacokinetics and evaluate tacrolimus 0.3% ointment as therapy for moderate to severe atopic dermatitis. METHODS: Thirty-nine patients, 5 to 75 years of age, received 14 applications over 8 days. Serial blood samples were collected on days 1 and 8, with predose samples collected on days 2 through 7. Overall response and signs/symptoms were rated daily on days 1 through 11. Incidence of adverse events and laboratory profile were determined. RESULTS: Mean area under the curve (0.9 to 42.5 ng x hr/ml) was highly variable and appeared to be related to size of application area. No systemic accumulation of tacrolimus was observed. Comparison to historical intravenous data indicates that absolute bioavailability of topical tacrolimus was less than 0.5%. Ninety-five percent of patients showed at least good improvement. All adverse events were transient. Burning was the most common application site adverse event and vasodilatation ("flushing/warmth") was the most common nonapplication site adverse event. No drug-related changes in laboratory profile were observed. CONCLUSION: The results of this study suggest that tacrolimus 0.3% ointment may be a safe and effective therapy for atopic dermatitis.

Administration, Cutaneous↗
PubMed1998

Tacrolimus pharmacokinetics in BMT patients.

The pharmacokinetics of tacrolimus following its administration as monotherapy or in combination with corticosteroids or methotrexate to 31 BMT patients are presented. All patients received i.v. tacrolimus initially and were subsequently switched to p.o. dosing. Patients received methotrexate by i.v. bolus on post-transplantation days 1, 3, 6 and 11. Patients were started on i.v. corticosteroids beginning on post-transplantation day 7. The noncompartmental pharmacokinetics of tacrolimus based on whole blood concentrations were determined following the i.v. and p.o. doses and were not different at steady-state compared to a single dose. The mean terminal elimination half-life of tacrolimus was 18.2 h following i.v. administration; the total body clearance was 71 ml/h/kg, the volume of distribution was 1.67 1/kg. Co-administration of methylprednisolone or methotrexate did not significantly alter tacrolimus pharmacokinetics. The p.o. bioavailability was 31-49%. Trough blood concentrations (Cmin) at 0 h (pre-dose) and 12 h (post-dose) correlated well to AUC(0-12)indicating that, as in solid organ transplantation, Cmin was a good index of drug exposure. Correlation at 0 h (r = 0.92) and at 12 h (r = 0.93) indicate that either time point can be used for therapeutic drug monitoring in patient management.

Administration, Oral↗
PubMed1998

Toxicological profile and pharmacokinetics of a unilamellar liposomal vesicle formulation of amphotericin B in rats.

AmBisome (ABLP) is a unilamellar liposomal preparation of amphotericin B that has demonstrated an improved safety profile compared to conventional amphotericin B. Single- and multiple-dose pharmacokinetics were determined by using noncompartmental methods for rats administered ABLP at 1, 3, 9, and 20 mg/kg/day. The toxicological profile was evaluated following 30 consecutive days of intravenous ABLP administration. Mean plasma amphotericin B concentrations reached 500 and 380 microg/ml (males and females, respectively) following 30 days of ABLP administration at 20 mg/kg. The overall apparent half-life was 11.2+/-4.5 h (males) or 8.7+/-2.2 h (females), and the overall clearance (CL) was 9.4+/-5.5 ml/h/kg (males) or 10.2+/-4.1 ml/h/kg (females). ABLP appears to undergo saturable disposition, resulting in a non-dose-proportional amphotericin B area under the curve and a lower CL at higher doses. Histopathological examination revealed dose-related transitional-cell hyperplasia in the transitional epithelium of the urinary tract (kidney, ureters, and urinary bladder) and moderate hepatocellular necrosis at the 20 mg/kg/day dose. Administration of ABLP in doses of up to 20 mg/kg/day resulted in 100-fold higher plasma amphotericin B concentrations, with significantly lower toxicity than that reported with conventional amphotericin B therapy.

Amphotericin B↗
PubMed1998

Safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) in neutropenic patients.

The safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) administered for empirical antifungal therapy were evaluated for 36 persistently febrile neutropenic adults receiving cancer chemotherapy and bone marrow transplantation. The protocol was an open-label, sequential-dose-escalation, multidose pharmacokinetic study which enrolled a total of 8 to 12 patients in each of the four dosage cohorts. Each cohort received daily doses of either 1.0, 2.5, 5.0, or 7.5 mg of amphotericin B in the form of AmBisome/kg of body weight. The study population consisted of patients between the ages of 13 and 80 years with neutropenia (absolute neutrophil count, <500/mm3) who were eligible to receive empirical antifungal therapy. Patients were monitored for safety and tolerance by frequent laboratory examinations and the monitoring of infusion-related reactions. Efficacy was assessed by monitoring for the development of invasive fungal infection. The pharmacokinetic parameters of AmBisome were measured as those of amphotericin B by high-performance liquid chromatography. Noncompartmental methods were used to calculate pharmacokinetic parameters. AmBisome administered as a 1-h infusion in this population was well tolerated and was seldom associated with infusion-related toxicity. Infusion-related side effects occurred in 15 (5%) of all 331 infusions, and only two patients (5%) required premedication. Serum creatinine, potassium, and magnesium levels were not significantly changed from baseline in any of the dosage cohorts, and there was no net increase in serum transaminase levels. AmBisome followed a nonlinear dosage relationship that was consistent with reticuloendothelial uptake and redistribution. There were no breakthrough fungal infections during empirical therapy with AmBisome. AmBisome administered to febrile neutropenic patients in this study was well tolerated, was seldom associated with infusion-related toxicity, was characterized by nonlinear saturation kinetics, and was effective in preventing breakthrough fungal infections.

Adult↗
PubMed1997

Recipient preconditioning and donor-specific bone marrow infusion in a pig model of total bowel transplantation.

BACKGROUND: In an outbred pig model of total bowel transplantation, we previously showed that simultaneous donor-specific bone marrow infusion (DSBMI), rather than promoting engraftment, sensitizes recipients and causes rejection; it also aggravates the risk of generalized graft-versus-host disease (GVHD) and infection, and tends to reduce recipient and graft survival. Small and large animal models of bone marrow-induced transplant tolerance suggest that some form of recipient preconditioning (RPC) may facilitate engraftment of co-transplanted bone marrow cells and fully expose their tolerogenic potential. METHODS: In a preclinical model, we prospectively studied the effect of RPC on simultaneous DSBMI and total (i.e., small and large) bowel transplantation. RPC consisted of whole body irradiation with 400 R (day 0); some recipients additionally received horse anti-pig antithymocyte globulin (days -2, -1, and 0). We studied six groups of outbred pigs, all of which underwent at least a total bowel transplant: group 1, nonimmunosuppressed control pigs (n=5); group 2, nonimmunosuppressed DSBMI pigs (n=13); group 3, tacrolimus pigs (n=7); group 4, DSBMI+tacrolimus pigs (n=15); group 5, RPC+nonimmunosuppressed DSBMI pigs (n=11); and group 6, RPC+DSBMI+tacrolimus pigs (n=14). RESULTS: RPC did not prolong overall survival at 7, 14, 21, and 28 days after transplant. Survival rates were 100%, 100%, 86%, and 71% in group 3; 71%, 43%, 29%, and 29% in group 6; 55%, 9%, 0%, and 0% in group 5; and 60%, 0%, 0%, and 0% in Group 1. Moreover, RPC (groups 5 and 6) increased the incidence of death from rejection, GVHD, and infection when compared with group 3. Survival was significantly higher for RPC+DSBMI+tacrolimus pigs (group 6), compared with RPC+nonimmunosuppressed DSBMI pigs (group 5). Survival greater than 28 days was noted only in pigs that received tacrolimus after transplant: 71% in group 3 versus 29% in group 6. With both RPC and DSBMI (groups 5 and 6), rejection, GVHD, and infection were not mutually exclusive events. In groups 5 and 6, at autopsy, the incidence of rejection and GVHD was 17%; rejection and infection, 17%; and GVHD and infection, 45%. A combination of all three immunologic events was noted in 14%. CONCLUSIONS: RPC, combined with DSBMI, and with or without posttransplant immunosuppression, does not prolong survival after total bowel transplantation. Rather, it increases the incidence of death from rejection, GVHD, infection, or a combination of these three immunologic events. According to this preclinical study, RPC and unmodified DSBMI do not improve patient and graft outcome after total bowel transplantation and need to be refined before being applied clinically.

Animals↗
PubMed1997

Tacrolimus oral bioavailability doubles with coadministration of ketoconazole.

OBJECTIVE: To quantitate the effect of ketoconazole, an azole antifungal agent and potent inhibitor of CYP3A4 and P-glycoprotein, on the bioavailability of tacrolimus, a substrate of the CYP3A system and of P-glycoprotein. SUBJECTS AND METHODS: The pharmacokinetics of tacrolimus were studied in six healthy volunteers (two women and four men) in a four-dose study after each received single doses of tacrolimus alone (0.1 mg/kg orally and 0.025 mg/kg intravenously) and with coadministered ketoconazole (200 mg orally at bedtime for 12 days). The dose of tacrolimus was reduced during the ketoconazole phase (0.04 mg/kg orally; 0.01 mg/kg intravenously). Ketoconazole and tacrolimus doses were separated by approximately 10 hours. Whole blood tacrolimus concentrations were determined by enzyme-linked immunosorbent assay. Estimated pharmacokinetic parameters in whole blood (mean +/- SD) before and with ketoconazole were calculated with noncompartmental techniques. RESULTS: Coadministration of ketoconazole did not consistently affect tacrolimus clearance (55.6 +/- 16.7 ml/hr/kg versus 42.5 +/- 7.6 ml/hr/kg), and steady-state volume of distribution was unchanged (0.99 +/- 0.26 L/kg versus 0.93 +/- 0.25 L/kg). However, a significant increase in tacrolimus bioavailability (14% +/- 5% versus 30% +/- 8%; p < 0.01) was observed with coadministered ketoconazole. Hepatic bioavailability was unchanged by the presence of ketoconazole (96% +/- 1% versus 97% +/- 1%). CONCLUSIONS: Because ketoconazole did not alter hepatic bioavailability and because 10 hours separated administration times of the drugs, it appears that the marked increase in tacrolimus bioavailability can be explained by ketoconazole having a local inhibitory effect on tacrolimus gut metabolism or on intestinal P-glycoprotein activity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Lack of interaction between tacrolimus (FK506) and methotrexate in bone marrow transplant recipients.

Tacrolimus (FK506) is a macrolide lactone effective in the control of graft-versus-host disease (GVHD). An interaction between high-dose methotrexate and a macrolide antibiotic (pristinamycin) leading to prolonged methotrexate exposure has been described. Because a randomized prospective trial comparing tacrolimus with cyclosporine (both in combination with methotrexate) following allogeneic BMT showed the tacrolimus plus methotrexate regimen to be more effective in prevention of GVHD, we assessed methotrexate pharmacokinetics in a subgroup of the participants of this trial to evaluate the possibility that an interaction of FK506 and methotrexate was the explanation for the clinical findings. Mean and median methotrexate levels at various time-points after the day 1 and 6 methotrexate doses were comparable in the tacrolimus and cyclosporine cohorts and were elevated in only three of 70 study patients. Area under the curve (AUC) concentrations were also similar after the day 1 and 6 methotrexate doses. Thus, no significant interaction between tacrolimus and methotrexate is apparent and the differences in efficacy between tacrolimus and cyclosporine are unlikely to be attributable to pharmacologic interactions with methotrexate.

Adolescent↗
PubMed1997

A highly sensitive enzyme-linked immunosorbent assay for the determination of tacrolimus in atopic dermatitis patients.

A highly sensitive enzyme-linked immunosorbent assay method has been developed for the determination of tacrolimus in human blood samples. The assay is a modification of the previously published assay with improved sensitivity. Following extraction of tacrolimus with methanol and sulfosalicylic acid, the samples are incubated for 2 h at room temperature on a Nunc Maxisorb plate that has been treated for nonspecific binding by precoating with polyclonal antibody. The analysis of human blood following the standard addition of tacrolimus (0.02-5.0 ng/ml) demonstrated excellent precision and accuracy over a 6-day period. The interday and intraday co-efficients of variation were 6.0-28.9 and 3.9-15.2%, respectively. The limit of quantitation was 0.05 ng/ml. The method was used to quantitate blood concentration of tacrolimus in patients following the administration of tacrolimus ointment.

Adult↗
PubMed1997

Tacrolimus (FK506): validation of a sensitive enzyme-linked immunosorbent assay kit for and application to a clinical pharmacokinetic study.

Tacrolimus (FK506) is a macrolide immunosuppressant approved for the prophylaxis of organ rejection in liver transplant. Immunoassays of low intra- and interday variability and high sensitivity are necessary to adequately characterize terminal elimination phase concentrations in pharmacokinetic studies. A new ELISA kit for the quantitation of tacrolimus in human whole blood has been validated for use in pharmacokinetic studies. Methanol sample extracts were dried and reconstituted in a horseradish peroxidase (HPR)-FK506 conjugate solution. The reconstituted samples and mouse anti-FK506 were added to a microplate, precoated with secondary antibody, and incubated, FK506 and the HPR-FK506 conjugate competed to bind with anti-FK506, which was immobilized by binding to the secondary antibody. Unbound FK506 was washed away, and substrate was added for color development. Once the reaction was stopped with 2 N H2SO4, the plate was read at 450 nm. The linear range was 0.5-60 ng/ml, with a limit of quantitation of 0.5 ng/ml. Interday precision and accuracy were < or = 10.4% C.V. and < or = 3% R.E. for quality control samples. The lack of interference from endogenous compounds was established by parallelism and recoveries of FK506 from six lots of control matrix. Cross-reactivity against the metabolites and analogs were not performed because the kit monoclonal antibody was from the same source as Kobayashi et al (1). The utility and sensitivity of the kit present a good method for the quantitation of tacrolimus in blood from pharmacokinetic studies. The method is robust and has been used to assay tacrolimus in several thousand whole blood samples by multiple analysts.

Animals↗
PubMed1996

A high-performance liquid chromatographic assay for the determination of amphotericin B serum concentrations after the administration of AmBisome, a liposomal amphotericin B formulation.

A sensitive and selective high-performance liquid chromatographic (HPLC) method has been developed for the determination of amphotericin B in human serum. After methanol deproteinization, amphotericin B and 3-nitrophenol (internal standard) are separated by reversed-phase chromatography and detected by ultraviolet absorbance. The analysis of human serum after the standard addition of amphotericin B (0.05-200.0 micrograms/mL) demonstrated excellent precision and accuracy over a five-day period. The HPLC assay uses two standard curve ranges. The high sensitivity curve range for low AmBisome dosage (1.0 mg/kg) is 0.05-20.0 micrograms/mL (curve 1), and the second curve range for the higher AmBisome dose regimens (2.5-5.0 mg/kg) is 0.5-200 micrograms/mL (curve 2). The intraday and interday coefficients of variations for standard curve 1 were 0.5-4.6% and 3.0-11.5%, respectively. The limit of quantitation was 0.05 microgram/mL. The intraday and interday coefficients of variation for standard curve 2 were 2.0-3.6 and 6.9-10.1, respectively. No interfering peak at the retention time for Amphotericin B and the internal standard were present in blank serums or serum samples spiked with fifteen potential co-administrated drugs with Amphotericin B treatment. The method was used to quantitate serum concentrations of amphotericin B in patients after the administration of AmBisome, a liposomal formulation of amphotericin B.

Amphotericin B↗
PubMed1995

A prospective study of FK506 versus CsA and pig ATG in a porcine model of small bowel transplantation.

Rejection remains a major barrier to successful bowel transplantation, and immunosuppressive protocols are far from standardized. In 88 nonrelated outbred pigs, we compared the effects of two immunosuppressive regimens--one with FK506, the other with cyclosporine (CsA) and pig antithymocyte globulin (ATG)--on incidence and severity of rejection in the early, critical posttransplant period. Group A (n = 14) was nonimmunosuppressed (controls). Group B (n = 17) received pig ATG (10 mg/kg/day x 10 days), CsA (3 mg/kg/day), prednisolone (2 mg/kg/day), and azathioprine (2.5 mg/kg/day); prednisolone and azathioprine were each reduced by 50% at 8 and 15 days posttransplant. Trough CsA whole-blood concentrations were > or = 400 ng/ml for the first 7 days, > or = 200 ng/ml thereafter. Group C (n = 13) received FK506 (0.2 mg/kg/day) and prednisolone (2 mg/kg/day); prednisolone was reduced by 50% at 8 and 15 days. FK506 whole-blood concentrations were > or = 20 ng/ml. All immunosuppression in groups B and C was given intravenously. We performed orthotopic small bowel transplants with systemic venous drainage. Recipient bowel was resected distal to the second portion of the duodenum and proximal to the rectum at transplant; bowel continuity was restored by duodenojejunostomy; ileostomy was created distally to allow access for daily biopsies. We graded interstitial and vascular rejection separately, according to a scoring system (no, mild, moderate, and severe rejection). Rejection-free graft survivals at 7, 14, and 21 days posttransplant were 38%, 19%, and 0% in group A; 93%, 93%, and 62% in group B; and 100%, 91%, and 82% in group C (P < 0.001). Comparing rejection in the immunosuppressed groups, group C (FK506) had a stronger tendency toward rejection than group B (CsA-ATG); significant differences between groups B and C were, however, noted only on individual days posttransplant, not over time. The death rate due to irreversible rejection was not significantly different in groups B and C (P = 0.8), but was significantly better in both of these immunosuppressed groups than in group A (P < 0.001). Pig survival was significantly longer in group C than in B (P = 0.001) due to a lower infection rate in group C. Posttransplant serum interleukin 2 and 7 levels did not correlate with rejection grades. Graft-versus-host reaction was noted only in the skin in 29% of group A, 73% of group B, and 77% of group C pigs; liver and native bowel were not involved.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗