Pharmacokinetics Of Daunorubicin Research Articles

Daunorubicin and Its Active Metabolite Pharmacokinetic Profiles in Acute Myeloid Leukaemia Patients: A Pharmacokinetic Ancillary Study of the BIG-1 Trial.

Daunorubicin pharmacokinetics (PK) are characterised by an important inter-individual variability, which raises questions about the optimal dose regimen in patients with acute myeloid leukaemia. The aim of the study is to assess the joint daunorubicin/daunorubicinol PK profile and to define an optimal population PK study design. Fourteen patients were enrolled in the PK ancillary study of the BIG-1 trial and 6–8 samples were taken up to 24 h after administration of the first dose of daunorubicin (90 mg/m2/day). Daunorubicin and daunorubicinol quantifications were assessed using a validated liquid chromatography technique coupled with a fluorescence detector method. Data were analysed using a non-compartmental approach and non-linear mixed effects modelling. Optimal sampling strategy was proposed using the R function PFIM. The median daunorubicin and daunorubicinol AUC0-tlast were 577 ng/mL·hr (Range: 375–1167) and 2200 ng/mL·hr (range: 933–4683), respectively. The median metabolic ratio was 0.32 (range: 0.1–0.44). Daunorubicin PK was best described by a three-compartment parent, two-compartment metabolite model, with a double first-order transformation of daunorubicin to metabolite. Body surface area and plasma creatinine had a significant impact on the daunorubicin and daunorubicinol PK. A practical optimal population design has been derived from this model with five sampling times per subject (0.5, 0.75, 2, 9, 24 h) and this can be used for a future population PK study.

Abstract PP01-01: A funny thing happened to me while trying to cure ovarian cancer; I became a cancer prevention research specialist

Abstract PP01-01: A funny thing happened to me while trying to cure ovarian cancer; I became a cancer prevention research specialist

Pharmacokinetics and pharmacogenomics of daunorubicin in children: a report from the Children's Oncology Group.

We explored the impact of obesity, body composition, and genetic polymorphisms on the pharmacokinetics (PK) of daunorubicin in children with cancer. Patients ≤21 years receiving daunorubicin as an infusion of any duration <24 h for any type of cancer were eligible. Plasma drug concentrations were measured by high-performance liquid chromatography. Body composition was measured by dual-energy X-ray absorptiometry. Obesity was defined as a BMI >95% for age or as body fat >30%. NONMEM was used to perform PK model fitting. The Affymetrix DMET chip was used for genotyping. The impact of genetic polymorphisms was investigated using SNP/haplotype association analysis with estimated individual PK parameters. A total of 107 subjects were enrolled, 98 patients had PK sampling, and 50 patients underwent DNA analysis. Population estimates for daunorubicin clearance and volume of distribution were 116 L/m(2)/h ± 14% and 68.1 L/m(2) ± 24%, respectively. Apparent daunorubicinol clearance and volume of distribution were 26.8 L/m(2)/h ± 5.6% and 232 L/m(2) ± 10%, respectively. No effect of body composition or obesity was observed on PK. Forty-four genes with variant haplotypes were tested for association with PK. FMO3-H1/H3 genotype was associated with lower daunorubicin clearance than FMO3-H1/H1, p = 0.00829. GSTP1*B/*B genotype was also associated with lower daunorubicin clearance compared to GSTP1*A/*A, p = 0.0347. However, neither of these associations was significant after adjusting for multiple testing by either Bonferroni or false discovery rate correction. We did not detect an effect of body composition or obesity on daunorubicin PK. We found suggestive associations between FMO3 and GSTP1 haplotypes with daunorubicin PK that could potentially affect efficacy and toxicity.

Pharmacokinetics of daunorubicin and daunorubicinol in infants with leukemia treated in the interfant 99 protocol

There is an extreme paucity of pharmacokinetic data for anticancer agents in infants. Therefore, we aimed at characterizing the pharmacokinetics for daunorubicin in infants and examined their relationship to age, body weight, and body surface area. Leukemia patients treated according to the Interfant 99 protocol received 30 mg/m(2) daunorubicin, with dose reduction to 3/4 for patients 6-12 months old and 2/3 for patients <6 months, respectively. Plasma samples from 21 patients (aged 0.05-1.88 years) were collected and analyzed for daunorubicin and daunorubicinol. Samples from 12 children (age 1.6-18.8 years), who received daunorubicin in an earlier investigation, were used for pharmacokinetic model building using the software NONMEM. Plasma concentration time profiles could be described using a two compartment model. Daunorubicin clearance was 43.9 L hr(-1) m(-2) +/- 65% and central volume of distribution 16.4 L m(-2) +/- 46%, whereas apparent clearance of daunorubicinol was 19.1 L hr(-1) m(-2) +/- 32% and apparent volume of distribution 228 L m(-2) +/- 80% (mean +/- interindividual variability). No age-dependency in any of the BSA-normalized pharmacokinetic parameters was observed. Consequently, due to the empirical dose reduction in infants the overall exposure to daunorubicinol in infants was smaller than would be expected from older children. Patients aged <6 months experienced more infections in the induction phase than the group aged 6-12 months at diagnosis. Other toxicities were similar in both groups. We observed no indication of an age-dependency in the pharmacokinetics of daunorubicin. Pediatr Blood Cancer 2010;54:355-360.

Liposomal daunorubicin plasmatic and renal disposition in patients with acute leukemia.

Liposomal formulations of anthracyclines have been developed to increase their delivery to solid tumors while reducing toxicity in normal tissues. DaunoXome (DNX, NeXstar) is a liposomal-encapsulated preparation of daunorubicin registered for treatment of Kaposi's sarcoma that during prior in vitro studies showed a toxicity to leukemic cells at least comparable to that of free daunorubicin. The aim of our study was to determine DNX pharmacokinetics in 11 poor-risk patients with acute leukemia treated with DNX 60 mg/m2 IV on days 1, 3, and 5. Blood and urine samples were collected at appropriate intervals after each of the three DNX administrations. The total amount of daunorubicin (free and entrapped) (t-DNR) and of its metabolite daunorubicinol (DNRol) was assayed by HPLC. The main pharmacokinetic parameters (t1/2alpha 4.54 +/- 0.87 h; VdSS 2.88 +/- 0.93 l/m2; Cl 0.47 +/- 0.26 l/h/m2) showed that in patients with acute leukemia liposomal-entrapped daunorubicin pharmacokinetics greatly differed from that observed for the conventional formulation. In fact, DNX produced mean plasma AUC levels (t-DNR AUC0-infinity 456.27 +/- 182.64 microg/ml/h) about 100- to 200-fold greater than those reported for the free drug at comparable doses due to a very much lower total body clearance. Volume of distribution at steady state was 200-to 500-fold lower than for the free drug. Plasma AUC of DNRol (17.62 +/- 7.13 microg/ml x h) was similar to or even greater than that observed with free daunorubicin for comparable doses. Cumulative urinary excretion showed that about 6% and 12% of the total dose of DNX administered was excreted in urine as daunorubicin and daunorubicinol, respectively. No major toxicity was encountered. Therefore, pharmacokinetic characteristics suggest that DNX may be more convenient than free daunorubicin in the treatment of acute leukemia. In fact, liposomal formulation may allow a reduction of daunorubicin captation in normal tissues. thus minimizing toxicity at least for the parent drug, and guarantee an unimpeded access to leukemic cells in the bloodstream and bone marrow, thus theoretically improving efficacy.

Age-related pharmacokinetics of daunorubicin and daunorubicinol following intravenous bolus daunorubicin administration in the rat.

Age-related differences in pharmacokinetics may be important in determining altered anthracycline cardiotoxicity in the senescent rat and also in older humans. This study examined the effect of aging on daunorubicin pharmacokinetics in the Fischer 344 rat. Daunorubicin 7.5 mg/kg was administered i.v. to 6- and 24-month-old male Fischer 344 rats and plasma and tissue sampling was performed over 168 h for assay of daunorubicin and daunorubicinol concentrations by high-performance liquid chromatography. Systemic clearance of daunorubicin was decreased in older compared to younger animals (56 +/- 4 versus 202 +/- 17 ml min-1 kg-1; P < 0.05). In addition, the area under the plasma daunorubicinol concentration/time curve was significantly increased in older rats. In the heart, the area under the concentration/time curve was significantly increased in senescence both in the case of daunorubicin (201 +/- 12 versus 86 +/- 4 micrograms h g-1; P < 0.05) and daunorubicinol (1347 +/- 118 versus 182 +/- 4 micrograms h g-1; P < 0.05). Furthermore, the peak mean concentrations of daunorubicin were increased in older compared to younger rats both in plasma (1078 +/- 82 versus 663 +/- 66 ng ml-1; P < 0.05) and in heart (27 +/- 1 versus 10 +/- 1 micrograms g-1; P < 0.05). This also was true for daunorubicinol in plasma (284 +/- 39 versus 168 +/- 27 ng ml-1; P < 0.05) and in myocardium (8.6 +/- 0.6 versus 2.4 +/- 0.2 micrograms g-1; P < 0.05). Following daunorubicin injection, the ratio of daunorubicinol to daunorubicin concentrations in tissues increased with time, particularly in plasma and heart in senescent rats. Thus, there are significant age-related changes in daunorubicin and daunorubicinol kinetics in the rat that could alter susceptibility to acute systemic toxicity and to chronic cardiotoxicity.

Daunorubicin and daunorubicinol pharmacokinetics in plasma and tissues in the rat

Recent evidence suggests that 13-hydroxy metabolites of anthracyclines may contribute to cardiotoxicity. This study was designed to determine the pharmacokinetics of daunorubicin and the 13-hydroxy metabolite daunorubicinol in plasma and tissues, including the heart. Fisher 344 rats received 5 mg kg-1 daunorubicin i.v. by bolus injection. Rats were killed at selected intervals for up to 1 week after daunorubicin administration for determination of concentrations of daunorubicin and daunorubicinol in the plasma, heart, liver, kidney, lung, and skeletal muscle. Peak concentrations of daunorubicin were higher than those of daunorubicinol in the plasma (133 +/- 7 versus 36 +/- 2 ng ml-1; P < 0.05), heart (15.2 +/- 1.4 versus 3.4 +/- 0.4 micrograms g-1; P < 0.05), and other tissues. However, the apparent elimination half-life of daunorubicinol was longer than that of daunorubicin in most tissues, including the plasma (23.1 versus 14.5 h) and heart (38.5 versus 19.3 h). In addition, areas under the concentration/time curves (AUC infinity) obtained for daunorubicinol exceeded those found for daunorubicin in almost all tissues, with the ratios being 1.9 in plasma and 1.7 in the heart. The ratio of daunorubicinol to daunorubicin concentrations increased dramatically with time from < 1 at up to 1 h to 87 at 168 h in cardiac tissue. Thus, following daunorubicin injection, cumulative exposure (AUC infinity) to daunorubicinol was greater than that to daunorubicin in the plasma and heart. If daunorubicinol has equivalent or greater potency than daunorubicin in causing impairment of myocardial function, it may make an important contribution to the pathogenesis of cardiotoxicity.

Daunorubicin pharmacokinetics and the correlation with P-glycoprotein and response in patients with acute leukaemia

The aim of this study was to examine the relationship between the pharmacokinetics of daunorubicin (DNR), overexpression of P-glycoprotein (Pgp) and treatment response in acute leukaemia. Twenty-seven patients with acute leukaemia received DNR as part of induction therapy. The plasma and cellular levels of DNR and its metabolite daunorubicinol (DOL) were determined using high-performance liquid chromatography. There were no significant differences between patients who went into complete remission (12/23) compared with those who did not respond for the following pharmacokinetic parameters: DNR and DOL plasma AUC (area under the curve) and DNR plasma half-life and clearance. There was a significant difference in the cellular DNR and DOL AUC between responders and non-responders (P < 0.02). Seven patients were Pgp positive and 18 Pgp negative. There was no correlation between patient response and the presence of Pgp (P > 0.1), nor was there any correlation between the cellular concentration of DNR or DOL and Pgp (P > 0.3). To our knowledge this is the first report examining the relationship between DNR pharmacokinetics, patient response and Pgp expression. Our data indicated that acute leukaemia patients responding to chemotherapy had higher cellular DNR and DOL than non-responders; also, overexpression of Pgp appeared not to be the sole explanation for the lower cellular DNR levels as expected from in vitro studies.

Pharmacokinetics of daunorubicin and doxorubicin in plasma and leukemic cells from patients with acute nonlymphoblastic leukemia.

The pharmacokinetics of daunorubicin and doxorubicin were studied in plasma and leukemic cells from 16 patients with acute nonlymphoblastic leukemia during 19 courses of treatment with the unconjugated or DNA-conjugated drugs. Daunorubicin and doxorubicin are high-clearance drugs with very high apparent volumes of distribution, indicating a pronounced tissue affinity. This was more pronounced in the case of doxorubicin and may explain the reduced cardiotoxicity of the DNA-complexes. Daunorubicin reached higher intracellular peak concentrations than doxorubicin, but the latter drug was retained much longer. The cell/plasma concentration ratio was higher for daunorubicin than for its reduced metabolite daunorubicinol. No doxorubicinol was found intracellularly. The observed differences in cellular pharmacokinetics between daunorubicin and doxorubicin may explain the difference between the clinical activity spectras of these two drugs. DNA-conjugation did not markedly modify the uptake of daunorubicin in the leukemic cells, whereas the mean intracellular accumulation of doxorubicin was 60% higher when the drug was administered as a DNA-conjugate. This may enhance the selectivity of doxorubicin in the treatment of acute leukemia.

Pharmacokinetics of daunorubicin as a determinant of response in acute myeloid leukemia.

Twenty-one adult patients with acute myeloid leukemia (AML) were treated with the EORTC LAM-6 remission induction protocol [daunorubicin (DNR) (45 mg/m2, days 1-3), cytarabine (200 mg/m2, days 1-7) and vincristine (1 mg/m2, day 2)]. Pharmacokinetics of DNR were studied at day 1. The concentration of DNR and daunorubicinol were determined in plasma, in white blood cells and in bone marrow. A large variability was observed with respect to (1) the plasma area under the curve (AUC) 0-24 h (range: 0.06-0.37 nmol X h/ml); (2) the white cell AUC 0-24 h (range: 0-441 nmol X h/10(9) cells); and (3) the 1 h bone marrow concentration (range: 0-27 nmol/10(9) cells). In eight patients treated twice, a small intraindividual variability of these parameters was observed. Concentrations in plasma did not correlate with cellular concentrations. All pharmacokinetic parameters in plasma and white cells did not correlate with response to therapy. In patients reaching complete remission (CR), however, the tumor load, as expressed by the number of blast cells present in the untreated bone marrow, was significantly lower than the number of blast cells in patients not reaching CR.

Pharmacokinetics of daunorubicin as a determinant of response in acute myeloid leukemia

Twenty-one adult patients with acute myeloid leukemia (AML) were treated with the EORTC LAM-6 remission induction protocol [daunorubicin (DNR) (45 mg/m2, days 1–3), cytarabine (200 mg/m2, days 1–7) and vincristine (1 mg/m2, day 2)]. Pharmacokinetics of DNR were studied at day 1. The concentration of DNR and daunorubicinol were determined in plasma, in white blood cells and in bone marrow. A large variability was observed with respect to (1) the plasma area under the curve (AUC) 0–24 h (range: 0.06–0.37 nmol × h/ml); (2) the white cell AUC 0–24 h (range: 0–441 nmol × h/109 cells); and (3) the 1 h bone marrow concentration (range: 0–27 nmol/ 109 cells). In eight patients treated twice, a small intraindividual variability of these parameters was observed. Concentrations in plasma did not correlate with cellular concentrations. All pharmacokinetic parameters in plasma and white cells did not correlate with response to therapy. In patients reaching complete remission (CR), however, the tumor load, as expressed by the number of blast cells present in the untreated bone marrow, was significantly lower than the number of blast cells in patients not reaching CR.

Cellular pharmacokinetics of daunorubicin: uptake by leukaemic cells in vivo and fate.

In 6 patients with acute myeloblastic leukaemia, daunorubicin was assayed in leukaemic cells from peripheral blood or bone marrow. The cells were separated from red blood cells and granulocytes by centrifugation on a Ficoll-Isopac gradient. The assay was performed by high performance liquid chromatography. Daunorubicin concentrations in peripheral leukaemic cells, 2 hours after the end of the infusion, were much higher than in plasma, the cell/plasma concentration ratio reaching about 350 and rising to almost 700 at 24 h. At that time, drug concentrations were even higher in the bone marrow leukaemic cells. The value of the assay of daunorubicin in cells as method for monitoring therapy is discussed.

Pharmacokinetics of daunorubicin after administration as free drug or as DNA complex in leukemic patients.

An earlier whole-body autoradiographic study in mice revealed large differences between the tissue distribution of daunorubicin (D) after administration as free drug as as DNA-linked D. Therefore, the pharmacokinetics of D administered as free drug or linked to DNA was studied in 15 adult patients with acute non-lymphoblastic leukemia. The data obtained following infusion of free drug over either 45 or 240 min could be fitted to a two-compartment open-body model. With the D-DNA infusion considerably higher plasma concentrations were achieved, with a slower distribution and elimination from plasma than seen after the administration of free drug. this confirmed earlier animal data indicating a different pharmacokinetic behavior of D when it was administered linked to DNA. Furthermore, different pharmacokinetic parameters were obtained for D during infusion and in the post-infusion phase after administration of DNA-linked D (P less than 0.005). This finding strongly indicates that the D-DNA acts as a slow-release preparation in humans, which might modify tissue distribution and toxic side-effects of the drug.