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1.
Cancer Chemother Pharmacol ; 75(1): 67-75, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25374408

ABSTRACT

PURPOSE: Quantitative relationships between 9-ß-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) concentrations and lymphosuppression have not been reported, but would be useful for regimen design. A population pharmacokinetic/pharmacodynamic model was constructed in this study using data from 41 hematopoietic cell transplant (HCT) recipients conditioned with busulfan in combination with fludarabine (total dose 120 mg/m², Protocol 1519) or with fludarabine (total dose 250 mg/m²) with rabbit antithymocyte globulin (rATG, Protocol 2041). METHODS: Individual pharmacokinetic parameters were fixed to post hoc Bayesian estimates, and circulating absolute lymphocyte counts (ALC) were obtained during the 3 weeks prior to graft infusion. A semi-physiological cell-kill model with three lymphocyte transit compartments was applied and aptly characterized the time course of suppression of circulating ALC by fludarabine administration. Drug- and system-specific parameters were estimated using a maximum likelihood expectation maximization algorithm, and the final model was qualified using an internal visual predictive check. RESULTS: The final model successfully characterized the time course and variability in ALC. Pharmacodynamic parameters exhibited considerable between subject variability (38.9-211 %). The HCT protocol was the only covariate associated with the pharmacodynamic parameters, specifically the lymphocyte kill rate, the transit rate between lymphocyte compartments, and the baseline ALC. CONCLUSIONS: This model can be used to simulate the degree of lymphosuppression for design of future fludarabine-based conditioning regimens.


Subject(s)
Antimetabolites, Antineoplastic/pharmacokinetics , Immunosuppression Therapy/adverse effects , Immunosuppressive Agents/pharmacokinetics , Lymphopoiesis/drug effects , Models, Biological , Transplantation Conditioning/adverse effects , Vidarabine Phosphate/analogs & derivatives , Adolescent , Adult , Aged , Antimetabolites, Antineoplastic/adverse effects , Antimetabolites, Antineoplastic/blood , Antimetabolites, Antineoplastic/therapeutic use , Child , Cohort Studies , Half-Life , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/blood , Immunosuppressive Agents/therapeutic use , Leukemia, Myeloid/blood , Leukemia, Myeloid/immunology , Leukemia, Myeloid/metabolism , Leukemia, Myeloid/therapy , Lymphocyte Count , Middle Aged , Myeloproliferative Disorders/blood , Myeloproliferative Disorders/immunology , Myeloproliferative Disorders/metabolism , Myeloproliferative Disorders/therapy , Reproducibility of Results , Retrospective Studies , Vidarabine Phosphate/adverse effects , Vidarabine Phosphate/blood , Vidarabine Phosphate/pharmacokinetics , Vidarabine Phosphate/therapeutic use , Young Adult
2.
Clin Cancer Res ; 15(16): 5280-7, 2009 Aug 15.
Article in English | MEDLINE | ID: mdl-19671874

ABSTRACT

PURPOSE: Fludarabine monophosphate (fludarabine) is frequently administered to patients receiving a reduced-intensity conditioning regimen for allogeneic hematopoietic cell transplant (HCT) in an ambulatory care setting. These patients experience significant interpatient variability in clinical outcomes, potentially due to pharmacokinetic variability in 2-fluoroadenine (F-ara-A) plasma concentrations. To test such hypotheses, patient compliance with the blood sampling should be optimized by the development of a minimally intrusive limited sampling schedule (LSS) to characterize F-ara-A pharmacokinetics. To this end, we sought to create the first F-ara-A population pharmacokinetic model and subsequently a LSS. EXPERIMENTAL DESIGN: A retrospective evaluation of F-ara-A pharmacokinetics was conducted after one or more doses of daily i.v. fludarabine in 42 adult HCT recipients. NONMEM software was used to estimate the population pharmacokinetic parameters and compute the area under the concentration-time curve. RESULTS: A two-compartment model best fits the data. A LSS was constructed using a simulation approach, seeking to minimize the scaled mean squared error for the area under the concentration-time curve for each simulated individual. The LSS times chosen were 0.583, 1.5, 6.5, and 24 hours after the start of the 30-minute fludarabine infusion. DISCUSSION: The pharmacokinetics of F-ara-A in an individual HCT patient can be accurately estimated by obtaining four blood samples (using the LSS) and maximum a posteriori Bayesian estimation. CONCLUSION: These are essential tools for prospective pharmacodynamic studies seeking to determine if clinical outcomes are related to F-ara-A pharmacokinetics in patients receiving i.v. fludarabine in the ambulatory clinic.


Subject(s)
Blood Specimen Collection/methods , Hematopoietic Stem Cell Transplantation , Vidarabine Phosphate/analogs & derivatives , Adolescent , Adult , Aged , Child , Female , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/blood , Immunosuppressive Agents/pharmacokinetics , Male , Middle Aged , Models, Biological , Retrospective Studies , Time Factors , Transplantation Conditioning/methods , Vidarabine Phosphate/administration & dosage , Vidarabine Phosphate/blood , Vidarabine Phosphate/pharmacokinetics , Young Adult
3.
Biochem Pharmacol ; 59(3): 301-4, 2000 Feb 01.
Article in English | MEDLINE | ID: mdl-10609559

ABSTRACT

Conjugates of antiviral and antiblastic nucleoside analogs (NAs) with galactosyl-terminating peptides selectively enter hepatocytes after binding of the carrier galactose residues to the asialoglycoprotein receptor. Since NAs, when set free from the carrier within hepatocytes, partly exit from these cells into the bloodstream, we considered the possibility that administration of galactosyl-terminating conjugates of NAs could result in plasma concentrations of these drugs that would be higher in liver sinusoids than in capillaries of other organs. In the present study we demonstrated the validity of this hypothesis. We injected rats with a conjugate of adenine arabinoside (ara-A) with lactosaminated poly-L-lysine and found that the plasma concentrations of ara-A were >2-fold higher in blood of liver than in systemic circulation. Liver blood was collected from the inferior vena cava after closing below and above the outflows of the hepatic veins. The present result suggests that conjugation with galactosyl-terminating peptides might be a way to selectively increase the concentrations of NAs not only in hepatocytes, which have the asialoglycoprotein receptor, but also in cells infiltrating the liver, such as neoplastic cells of micrometastases nourished by hepatic sinusoids.


Subject(s)
Amino Sugars/blood , Antineoplastic Agents/blood , Liver Neoplasms/metabolism , Liver/metabolism , Polylysine/analogs & derivatives , Vidarabine Phosphate/analogs & derivatives , Vidarabine Phosphate/blood , Amino Sugars/therapeutic use , Animals , Antineoplastic Agents/therapeutic use , Liver Neoplasms/drug therapy , Male , Neoplasm Metastasis , Polylysine/blood , Polylysine/therapeutic use , Rats , Rats, Wistar , Vidarabine Phosphate/therapeutic use
4.
Pharmazie ; 51(10): 733-4, 1996 Oct.
Article in English | MEDLINE | ID: mdl-8941940

ABSTRACT

A rapid, simple and accurate HPLC method for the determination of fludarabine phosphate in human plasma is presented. Fludarabine phosphate from plasma was successfully purified. The samples were chromatographed on a LiChrosorb RP-18 (10 microns) column after purification using a Bakerbond Spe column. The mobile phase was methanol/phosphoric buffer pH 4.15 (20:80). The detection was carried out at 262 nm. The method was tested for linearity (range from 100 to 900 ng/ml), recovery (ca. 99.8%) and precision (C.V. = 3.2%).


Subject(s)
Antimetabolites, Antineoplastic/blood , Vidarabine Phosphate/analogs & derivatives , Chromatography, High Pressure Liquid , Chromatography, Thin Layer , Humans , Magnetic Resonance Spectroscopy , Spectrophotometry, Ultraviolet , Vidarabine Phosphate/blood
5.
Hepatology ; 14(1): 16-24, 1991 Jul.
Article in English | MEDLINE | ID: mdl-1712338

ABSTRACT

The woodchuck was selected to study the efficacy of liver-targeted antiviral drugs on hepadnavirus replication. Nineteen woodchucks chronically infected with woodchuck hepatitis virus were treated with adenine arabinoside monophosphate or acyclovir monophosphate, either free or conjugated with the liver-targeting molecule lactosaminated human serum albumin. Circulating woodchuck hepatitis virus DNA levels remained unchanged in untreated animals and in those receiving the carrier lactosaminated human serum albumin alone; in contrast, they were consistently lower after 5 days of treatment with the antiviral drugs. Free and conjugated adenine arabinoside monophosphate were active at doses of 10 and 0.75 mg/kg, respectively, and free and coupled ACVMP were active at doses of 20 and 2.6 mg/kg, respectively. These results indicate that the dosages of adenine arabinoside monophosphate and acyclovir monophosphate required to inhibit hepadnavirus growth can be sharply reduced by coupling the drugs to lactosaminated human serum albumin.


Subject(s)
Acyclovir/analogs & derivatives , Hepadnaviridae/drug effects , Hepatitis, Viral, Animal/microbiology , Serum Albumin , Vidarabine Phosphate/administration & dosage , Viremia/microbiology , Acyclovir/administration & dosage , Acyclovir/blood , Acyclovir/pharmacology , Animals , DNA, Viral/blood , Dose-Response Relationship, Drug , Drug Carriers , Hepadnaviridae/genetics , Hepadnaviridae/isolation & purification , Hepatitis, Viral, Animal/drug therapy , Humans , Marmota , Vidarabine Phosphate/blood , Vidarabine Phosphate/pharmacology , Viremia/drug therapy
6.
Lancet ; 2(8601): 13-5, 1988 Jul 02.
Article in English | MEDLINE | ID: mdl-2455204

ABSTRACT

Vidarabine (ara A) produces severe dose-dependent side-effects. To examine whether its monophosphate ester (ara-AMP) can be effective in the treatment of chronic hepatitis B when given in reduced dosage as a conjugate with lactosaminated human serum albumin (L-HSA), which selectively enters hepatocytes, five patients with chronic type B hepatitis (HBsAg/HBV-DNA positive for at least 2 years) were treated with the conjugate. The daily dose of conjugate given (35 mg/kg) contains 1.5 mg ara-AMP, whereas the usual daily dose of free ara-AMP is 5-10 mg/kg. In three patients HBV-DNA fell to undetectable levels and remained negative in two; in one of them anti-HBe developed. In the other two patients HBV-DNA decreased but was detectable during treatment--one received three cycles of therapy, and became HBV-DNA negative and anti-HBe positive 45 days after the end of treatment; the other remained HBeAg/HBV-DNA positive. No adverse effects were observed, and biochemical variables (including aminotransferases) remained unchanged or decreased with viraemia. No antibodies (IgM and IgG classes) that bound the conjugate were detected. Thus L-HSA-ara-AMP inhibits HBV replication as well as free ara-AMP but at a third to a sixth of the dose.


Subject(s)
Arabinonucleotides/pharmacology , Hepatitis B virus/physiology , Hepatitis B/drug therapy , Hepatitis, Chronic/drug therapy , Serum Albumin/pharmacology , Vidarabine Phosphate/pharmacology , Virus Replication/drug effects , Adult , DNA, Viral/analysis , Drug Administration Schedule , Drug Evaluation , Female , Hepatitis B/blood , Hepatitis, Chronic/blood , Humans , Infusions, Intravenous , Male , Serum Albumin/administration & dosage , Serum Albumin/blood , Serum Albumin/therapeutic use , Time Factors , Vidarabine Phosphate/administration & dosage , Vidarabine Phosphate/blood , Vidarabine Phosphate/therapeutic use
7.
J Natl Cancer Inst ; 80(6): 447-9, 1988 May 18.
Article in English | MEDLINE | ID: mdl-2452888

ABSTRACT

Fludarabine phosphate was studied in a phase I trial of a loading-dose/continuous-infusion schedule. The schedule was chosen to rapidly achieve and maintain concentrations that have been shown in vitro to achieve maximal inhibition of cell growth. The initial level was a loading dose of 20 mg/m2 followed by a 48-hour continuous iv (CIV) infusion of 30 mg/m2 every 24 hours. For the single-dose escalation, the loading dose was held constant while the CIV dose was increased to 45 mg/m2/24 hours for 48 hours. The dose-limiting toxicity was myelosuppression, especially leukopenia. No other significant toxicity was encountered. The maximum tolerated dose was 20 mg/m2 by iv push followed by a 48-hour CIV infusion of 30 mg/m2/24 hours for 48 hours. The recommended starting dose for phase II trials is 20 mg/m2 by iv push followed by a 48-hour CIV infusion of 30 mg/m2/24 hours. This dose level achieved the target plasma levels in the 2 patients studied.


Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Arabinonucleotides/administration & dosage , Neoplasms/drug therapy , Vidarabine Phosphate/administration & dosage , Adult , Aged , Drug Administration Schedule , Drug Evaluation , Female , Humans , Male , Middle Aged , Nervous System/drug effects , Vidarabine Phosphate/adverse effects , Vidarabine Phosphate/analogs & derivatives , Vidarabine Phosphate/blood
9.
Gut ; 25(12): 1392-8, 1984 Dec.
Article in English | MEDLINE | ID: mdl-6210232

ABSTRACT

With the aim of improving the chemotherapeutic index of adenine arabinoside 5-monophosphate (ara-AMP) in the treatment of chronic hepatitis B, this drug was conjugated with lactosaminated serum albumin (L-SA), a neoglycoprotein which only enters into hepatocytes where it is digested in lysosomes. In mice, the L-[3H]SA-ara-AMP conjugates, intravenously injected, selectively penetrated the liver, only small quantities were taken up by cells of spleen, bone marrow, intestine, and brain. After administration of the conjugate to mice with Ectromelia virus hepatitis, ara-AMP was selectively concentrated in liver in a pharmacologically active form. If L-SA-ara-AMP conjugates behave in man as in mouse, their administration to patients with chronic hepatitis B should result in a selective concentration of ara-AMP in liver with a more efficient inhibition of virus replication accompanied by lower toxicity for other tissues.


Subject(s)
Amino Sugars/metabolism , Arabinonucleotides/metabolism , Liver/metabolism , Serum Albumin/metabolism , Vidarabine Phosphate/metabolism , Amino Sugars/blood , Amino Sugars/pharmacology , Animals , Biopharmaceutics , Bone Marrow/metabolism , Brain/metabolism , DNA/biosynthesis , Ectromelia, Infectious/metabolism , Female , Hepatitis, Viral, Animal/metabolism , Intestinal Mucosa/metabolism , Mice , Serum Albumin/pharmacology , Spleen/metabolism , Thymidine/metabolism , Tissue Distribution , Vidarabine Phosphate/blood , Vidarabine Phosphate/pharmacology
10.
J Infect Dis ; 144(4): 358-64, 1981 Oct.
Article in English | MEDLINE | ID: mdl-6169773

ABSTRACT

Plasma levels of 9-beta-D-arabinofuranosyladenine-5'-phosphate (ara-AMP) and its metabolites 9-beta-D-arabinofuranosyladenine (ara-A and 9-beta-D-arabinofuranosylhypoxanthine (ara-Hx) were determined by high-performance liquid chromatography in four patients with chronic active hepatitis positive for hepatitis B surface antigen and eight patients with severe herpesvirus infections and normal liver function. Ara-AMP was given intravenously over a 30-min period in doses ranging from 10 to 30 mg of ara-A equivalent/kg per day. The metabolism of ara-AMP did not differ significantly between the two patient groups. Ara-AMP was quickly converted to ara-A, which was rapidly deaminated to ara-Hx. The mean half-lives of ara-AMP, ara-A, and ara-Hx were 0.14 hr, 0.17 hr, and 3.5 hr, respectively. Thus, ara-AMP is rapidly metabolized and does not act as a depot form of ara-A. Patients with chronic active hepatitis demonstrated increased bone marrow sensitivity to ara-AMP and a musculoskeletal pain syndrome not observed in patients treated for herpesvirus infections.


Subject(s)
Arabinonucleotides/blood , Hepatitis B/metabolism , Vidarabine Phosphate/blood , Adult , Aged , Arabinonucleosides/blood , Child , Female , Herpesviridae Infections/drug therapy , Humans , Hypoxanthines/blood , Kinetics , Male , Middle Aged , Vidarabine/blood , Vidarabine Phosphate/adverse effects , Vidarabine Phosphate/therapeutic use
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