Pharmacokinetic and Pharmacodynamic Characteristics of Tripegfilgrastim, a Pegylated G-CSF, in Pediatric Patients with Solid Tumors.

A long-acting granulocyte colony-stimulating factor, tripegfilgrastim, was approved in Korea for the prevention of chemotherapy-induced neutropenia in adult patients. In this study, we evaluated the pharmacokinetics, pharmacodynamics, and safety of tripegfilgrastim in pediatric patients. A phase I, open-label, single ascending-dose study was performed in pediatric patients with solid tumors or lymphoma (ClinicalTrials.gov, NCT02963389). The patients were stratified according to age groups (aged 6 to 12 or 12 to 19 years) and received a single subcutaneous dose of tripegfilgrastim 60 µg/kg or 100 µg/kg. Tripegfilgrastim was administered 24 hours after the end of the chemotherapy, and serial blood sampling and safety monitoring were conducted. Twenty-seven patients with solid tumors were enrolled in this study. Tripegfilgrastim was detectable in plasma for an extended period (terminal half-life > 40 hours), and plasma concentrations increased slightly less than dose proportionally. The mean duration of grade 4 neutropenia was reduced as the average tripegfilgrastim concentration during the initial neutrophil recovery process increased. No substantial differences in the pharmacokinetic and pharmacodynamic responses were observed between the two age groups. When stratified by body weight, weighing more than 45 kg has a higher risk of a prolonged neutropenia period when receiving the lower dose (60 µg/kg) of tripegfilgrastim. Tripegfilgrastim was generally safe and well-tolerated in the pediatric patients. These results justify further clinical investigations of tripegfilgrastim at 100 µg/kg dose in pediatric patients.

Pharmacokinetic-pharmacodynamic modelling of neutrophil response to G-CSF in healthy subjects and patients with chemotherapy-induced neutropenia.

AIM: The objective of the present study was to use pharmacokinetic-pharmacodynamic modelling to characterize the effects of chemotherapy on the granulopoietic system and to predict the absolute neutrophil counts (ANCs) for patients with chemotherapy-induced neutropenia treated with filgrastim and pegfilgrastim. METHODS: Data were extracted from 10 phase I-III studies conducted in 110 healthy adults, and 618 adult and 52 paediatric patients on chemotherapy following administration of filgrastim or pegfilgrastim. The structural model accounted for ANC dynamics and the effects of filgrastim and pegfilgrastim, chemotherapy and corticosteroids. The impact of neutrophils on drug disposition was based on a drug receptor-binding model that assumed quasi-equilibrium and stimulation of the production and maturation of neutrophils upon treatment. The chemotherapy and corticosteroid effects were represented by kinetic-pharmacodynamic-type models, where chemotherapy stimulated elimination of neutrophil precursors at the mitotic stage, and corticosteroids stimulated neutrophil production. RESULTS: The systemic half-lives of filgrastim (2.6 h) and pegfilgrastim (10.1 h) were as expected. The effective half-life of chemotherapy was 9.6 h, with a 2-day killing effect. The rate of receptor elimination from mitotic compartments exhibited extreme interindividual variability (% coefficient of variation >200), suggesting marked differences in sensitivity to chemotherapy effects on ANCs. The stimulatory effects of pegfilgrastim were significantly greater than those of filgrastim. Model qualification confirmed the predictive capability of this model. CONCLUSION: This qualified model simulates the time course of ANC in the absence or presence of chemotherapy and predicts nadir, time to nadir and time of recovery from different grades of neutropenia upon treatment with filgrastim and pegfilgrastim.

A cell-level model of pharmacodynamics-mediated drug disposition.

We aimed to develop a cell-level pharmacodynamics-mediated drug disposition (PDMDD) model to analyze in vivo systems where the PD response to a drug has an appreciable effect on the pharmacokinetics (PK). An existing cellular level model of PD stimulation was combined with the standard target-mediated drug disposition (TMDD) model and the resulting model structure was parametrically identifiable from typical in vivo PK and PD data. The PD model of the cell population was controlled by the production rate k in and elimination rate k out which could be stimulated or inhibited by the number of bound receptors on a single cell. Simulations were performed to assess the impact of single and repeated dosing on the total drug clearance. The clinical utility of the cell-level PDMDD model was demonstrated by fitting published data on the stimulatory effects of filgrastim on absolute neutrophil counts in healthy subjects. We postulated repeated dosing as a means of detecting and quantifying PDMDD as a single dose might not be sufficient to elicit the cellular response capable of altering the receptor pool to visibly affect drug disposition. In the absence of any PD effect, the model reduces down to the standard TMDD model. The applications of this model can be readily extended to include chemotherapy-induced cytopenias affecting clearance of endogenous hematopoietic growth factors, different monoclonal antibodies and immunogenicity effects on PK.

Effects of age and sex on the hematology and blood chemistry of Tibetan macaques (Macaca thibetana).

Tibetan macaques (Macaca thibetana), also known as Chinese stump-tailed macaques, are a threatened primate species. Although Tibetan macaques are Old World monkeys in the genus of Macaca, limited age- and sex-related physiologic data are available for this particular species. We used 69 apparently healthy Tibetan male and female macaques to explore the effect of age and sex on physiologic parameters. Somatometric measurements, biochemistry, and hematologic parameters were analyzed. Significant age-related differences were found for weight, BMI, RBC count, Hgb, Hct, neutrophils, eosinophil count, ALT, AST, ALP, GGT, creatine kinase (muscle and brain subtypes), LDH, α-amylase, creatinine, apolipoprotein A1, total protein, albumin, cholesterol, HDL, and potassium. Significant differences by sex were noted for weight, BMI, ALT, total bilirubin, and indirect bilirubin. An interaction between age and sex accounted for statistically significant differences in the values for weight, BMI, and lymphocyte and eosinophil counts. These physiologic data will provide veterinarians and researchers with important age- and sex-specific reference ranges for evaluating experimental results from Tibetan macaques.

Cardiovascular safety of anagrelide in healthy subjects: effects of caffeine and food intake on pharmacokinetics and adverse reactions.

BACKGROUND: Essential thrombocythaemia (ET) is a rare clonal myeloproliferative disorder characterized by a sustained elevation in platelet count and megakaryocyte hyperplasia. Anagrelide is used in the treatment of ET, where it has been shown to reduce platelet count. Anagrelide is metabolized by cytochrome P450 (CYP) 1A2, and previous studies of the effect of food on the bioavailability and pharmacokinetics of anagrelide were conducted prior to the identification of the active metabolite, 3-hydroxyanagrelide. OBJECTIVES: The objectives of this study were to determine the effect of food and caffeine on the pharmacokinetics of anagrelide and its active metabolite, 3-hydroxyanagrelide, to monitor electrocardiogram (ECG) parameters following drug administration, and to document the relationship between palpitations, ECG changes and caffeine intake METHODS: Thirty-five healthy subjects who received 1 mg of anagrelide following either a 10-h fast or within 30 min of a standardized breakfast, including two cups of coffee, were studied. RESULTS: Time to maximum (peak) plasma concentration (C(max)) of anagrelide was 4.0 h in the fed and 1.5 h in the fasted group (p < 0.05); similar results were observed for 3-hydroxyanagrelide. The mean C(max) of anagrelide was 4.45 ± 2.32 ng/mL and 5.08 ± 2.99 ng/mL in the fed/caffeine and fasted groups, respectively; peak concentrations were higher for 3-hydroxyanagrelide in both the fed/caffeine and fasted groups. The most frequent adverse events (AEs) were headache (60 %) and palpitations (40 %). There were no serious AEs and all ECGs were normal, although significant reductions in PR interval, QRS length and QT interval were observed in both groups. Heart rate increased after anagrelide administration in both fed/caffeine and fasted states (p < 0.01); however, increased heart rate was significantly more frequent in the fed/caffeine state than in the fasted state (p < 0.001 for heart rate increase in the first hour after drug administration). There was a trend towards a greater heart rate increase in subjects reporting palpitations than in those without (mean heart rate ± SD at 1 h: 10.1 ± 6.4 vs. 8.0 ± 8.4 beats/min [p = 0.35]; at 4 h: 12.7 ± 7.5 vs. 9.1 ± 8.8 beats/min [p = 0.10], respectively). CONCLUSION: We conclude that food/caffeine delayed absorption of anagrelide. Anagrelide was generally well tolerated and had small effects on ECG parameters and heart rate. Caffeine may be implicated in a higher increase in heart rate and increased frequency of palpitations observed following administration of anagrelide with food/caffeine versus fasting.

Comparação entre Floseal® e eletrocauterio na hemostasia após artroplastia total do joelho / Comparison of Floseal® and electrocautery in hemostasis after total knee arthroplasty

OBJETIVO: Avaliar se a hemostasia com eletrocauterização em comparação ao uso do Floseal® durante artroplastias totais primárias de joelho, leva a diferentes taxas de sangramento peri-operatório.MÉTODOS: Foi realizado um estudo comparativo entre dois grupos: grupo de estudo com 10 casos de próteses primárias consecutivas com o uso do Floseal® como método hemostático, e grupo controle com 10 casos de próteses primárias consecutivas com uso de eletrocauterização como método hemostático. Foram avaliados parâmetros de sangramento como debito do dreno, infusão de líquidos, queda dos valores de hemoglobina e índice de transfusões sanguíneas.RESULTADOS: O grupo que fez uso de Floseal® apresentou em números absolutos menores valores de sangramento em relação ao grupo que fez hemostasia com eletrocautério tanto no débito do dreno pós-operatório quanto na infusão de líquidos e quantidade de transfusões sanguíneas. Nenhum parâmetro, porém, foi estatisticamente significativamente.CONCLUSÃO: A hemostasia com uso do Floseal® se mostrou semelhante à hemostasia com uso do eletrocautério, tornando-o uma alternativa aos pacientes que tenham contraindicação ao uso do bisturi elétrico.

OBJECTIVE: To evaluate whether hemostasis with eletrocauterization in comparison with Floseal® leads to different bleeding rates during total knee arthroplasty.METHODS: A comparative study was performed between two groups: group with ten consecutive total knee arthroplasties with Floseal® used as hemostatic method and control group with ten consecutive total knee arthroplasties with eletrocauterization as hemostatic method. Bleeding parameters such as debit of the drain, liquid infusion and blood transfusion rate were recorded.RESULTS: Floseal® group received less blood transfusion, less liquid infusion and lower drainage in absolute numbers compared to the control group. However, no parameter was statistically significant.CONCLUSION: Hemostasis with Floseal® is as effective as hemostasis with eletrocauterization, what makes it a viable alternative to patients with contraindication to electric scalpel use.Level of Evidence II, Prospective Comparative Study.

Pharmacokinetics and tolerability of anagrelide hydrochloride in young (18 - 50 years) and elderly (≥ 65 years) patients with essential thrombocythemia.

OBJECTIVE: To ascertain the role of patient age as an influencing factor in the pharmacokinetics of anagrelide and to clarify whether different dosing is required in young (18 - 50 years) vs. elderly (≥ 65 years) patients with essential thrombocythemia (ET). METHOD: This Phase II, multicenter, open-label study compared the pharmacokinetics, pharmacodynamics and tolerability of anagrelide and its active metabolite, 3-hydroxy-anagrelide, in young and elderly patients with ET. Three days prior to pharmacokinetic assessment, patients divided their normal daily anagrelide into a structured twice-daily dosing (BID) schedule. Serial blood samples were obtained for pharmacokinetic and pharmacodynamic analysis over a 12-h dosing interval. Anagrelide and 3-hydroxy-anagrelide plasma concentrations were normalized to a common dose (1 mg BID) to control for dosing differences between patients. Patients were monitored routinely for adverse events (AEs) and vital signs. RESULTS: A total of 24 patients (12 young; 12 elderly) completed the study. The dose-normalized anagrelide maximum observed plasma concentration (Cmax) and area under the plasma concentration vs. time curve over one dosing interval (AUCτ), were higher in elderly patients compared with young patients (Cmax: 3.63 vs. 2.66 ng/ml; p = 0.09, AUCτ: 10.3 vs. 6.4 ng×h/ml; p = 0.01). In contrast, the dose-normalized 3-hydroxy-anagrelide Cmax and AUCτ were lower in the elderly patients when compared with young patients (Cmax: 4.19 vs. 7.26 ng/ml; p = 0.02, AUCτ: 17.4 vs. 27.6 ng×h/ml; p = 0.03). No significant difference was observed in the geometric mean terminal half-life (t1/2) of anagrelide in elderly and young patients (1.4 vs. 1.3 h, respectively; p = 0.38), whereas the geometric mean t1/2 of 3-hydroxy-anagrelide was significantly longer in the elderly patients compared with the young patients (3.5 vs. 2.7 h, respectively; p = 0.01). There were no significant differences in platelet count or vital signs between the age groups. Anagrelide was well tolerated; there were no serious AEs or AEs that led to withdrawal from the study. CONCLUSIONS: To conclude, the differences observed in anagrelide and 3-hydroxy-anagrelide pharmacokinetics do not justify using a different dosing regimen in young vs. elderly patients with ET.

Efficacy and safety of eltrombopag in Japanese patients with chronic liver disease and thrombocytopenia: a randomized, open-label, phase II study.

BACKGROUND: Eltrombopag is an oral thrombopoietin receptor agonist that stimulates thrombopoiesis and shows higher exposure in East Asian patients than in non-Asian patients. We evaluated the pharmacokinetics, efficacy, and safety of eltrombopag in Japanese patients with thrombocytopenia associated with chronic liver disease (CLD). METHODS: Thirty-eight patients with CLD and thrombocytopenia (platelets <50,000/µL) were enrolled in this phase II, open-label, dose-ranging study that consisted of 2 parts. In the first part, 12 patients received 12.5 mg of eltrombopag once daily for 2 weeks. After the evaluation of safety, 26 patients were randomly assigned to receive either 25 or 37.5 mg of eltrombopag once daily for 2 weeks in the second part. RESULTS: Pharmacokinetics showed that the geometric means of the maximum plasma concentration (C(max)) and the area under the curve (AUC) in the 12.5 mg group were 3,413 ng/mL and 65,236 ng h/mL, respectively. At week 2, the mean increases from baseline in platelet counts were 24,800, 54,000, and 60,000/µL in the 12.5, 25, and 37.5 mg groups, respectively. The median platelet counts increased within 2 weeks of the beginning of administration in all groups, and remained at the same level throughout the 2-week post-treatment period in the 12.5 mg group, whereas the platelet counts peaked a week after the last treatment in both the 25 and 37.5 mg groups. Most adverse events reported were grade 1 or 2; 2 patients in the 37.5 mg group had drug-related serious adverse events. CONCLUSIONS: Eltrombopag ameliorated thrombocytopenia in Japanese patients with CLD and thrombocytopenia. The recommended dose for these patients is 25 mg daily for 2 weeks.

Development of an LC-MS/MS method for the quantitation of 55 compounds prescribed in combined cardiovascular therapy.

This paper reports an LC-MS/MS method with positive electrospray ionization for the screening of commonly prescribed cardiovascular drugs in human plasma, including compounds with antihypertensive (57), antidiabetic (12), hypolipemiant (5), anticoagulant (2) and platelet anti-aggregation (2) effects. Sample treatment consisted of a simple protein precipitation with MeOH/0.1 M ZnSO4 (4:1, v/v) solution after the addition of internal standard, followed by evaporation and reconstitution. Analytes separation was performed on a Polar-RP column (150 m x 2 mm, 4 µm) using a gradient elution of 15 min. The MS system was operated in MRM mode, monitoring one quantitation and one confirmation transition for each analyte. The recovery of the protein precipitation step ranged from 50 to 70% for most of the compounds, while some were considerably affected by matrix effects. Since several analytes fulfilled the linearity, accuracy and precision values required by the ICH guidelines, the method proved to be suitable for their quantitative analysis. The limits of quantitation varied from 0.38 to 9.1 µg/L and the limits of detection from 0.12 to 5.34 µg/L. The method showed to be suitable for the detection of plasma samples of patients under cardiovascular treatment with the studied drugs, and for 55 compounds reliable quantitative results could be obtained.

Experiencia en intercomparación de parámetros hematológicos empleando sangre fresca / Hematologic parameters interapperance experience fresh blood emplear

Se practicó una dinámica de evaluación externa experimental en hematología, empleando sangre fresca sin preservantes. Fue corroborada su homogeneidad y bioseguridad, transportada en cadena de frío a 33 laboratorios clínicos del Área Metropolitana de Caracas y establecidos los valores de referencia en el laboratorio organizador. Los coeficientes de variación encontrados fueron para hemoglobina (Hb) 5,1 por ciento, hematocrito (Hto) 5,4 por ciento, recuento de glóbulos blancos (GB) 8,7 por ciento, recuento de glóbulos rojos (GR) 4,3 por ciento, recuento de plaquetas (PLQ) 8,0 por ciento, VCM 3,2 por ciento, CHCM 4,2 por ciento y HCM 4,2 por ciento, considerados satisfactorios. Los índices de Desviación (ID) obtenidos fueron satisfactorios (ID<2,0) en un 97,0 por ciento para GB, 90,9 por ciento Hb, 66,7 por ciento PLQ, 63,6 por ciento GR, 48,5 por ciento Hto, 27,2 por ciento VCM; e inaceptables (ID>2,0) en un 81,8 por ciento para CHCM y 93,9 por ciento para HCM, posiblemente ligado a problemas de calibración de los instrumentos. La sangre fresca constituye una alternativa práctica y económica que puede impulsar la realización de programas de intercomparación a nivel local.

A dynamics of experimental external evaluation in hematology was carried out, employing fresh blood without preservatives. It was corroborated its homogeneity and biosafety, it was transported in chain of cold to the 33 participating clinical laboratories and established the reference values in our laboratory. The coefficient of variation found were: 5.1 percent Hemoglobin (HB), 5.4 percent haematocrit (HTO), 8.7 percent white blood cells (WBC), 4.2 percent red blood cells (RBC), 8.0 percent platelets (PLT), 3.2 percent MCV, 4.2 percent MCHC and 4,3 percent MHC, all considered satisfactory. The deviation index (DI) obtained were: satisfactory (DI<2.0) 97.0 percent WBC, 90.9 percent HB, 66.7 percent PLT, 63.6 percent RBC, 48.5 percent HTO, 27.2 percent MCV; unsatisfactory (DI>2.0) 81.8 percent MCHC and 93.9 percent MHC, this probably related to calibration problems of the instruments. Fresh blood constitutes a practical and economic alternative that can impulse the realization of intercomparison programs at local level.

Interconversion and tissue distribution of pentoxifylline and lisofylline in mice.

The aim of this study was to assess the interconversion pharmacokinetics and tissue distribution of pentoxifylline and the active (R)-enantiomer of its metabolite M1, lisofylline in male CD-1 mice. Both compounds were administered intravenously at a dose of 50 mg/kg on two separate occasions. Serum and tissues were collected at different time points following drug administration. In addition, the (S)-enantiomer of M1 was administered to a group of mice and serum samples were obtained. Analyte concentrations were measured by chiral HPLC. All serum concentration versus time data were fitted simultaneously to a pharmacokinetic model incorporating interconversion processes of parent drug and metabolites. The estimated conversion clearance of (-)-(R)-M1 to pentoxifylline (CL21) was six times greater than that for the reverse process (CL12). The interconversion of pentoxifylline and (+)-(S)-M1 was faster as reflected by the values of conversion clearances CL13 and CL31 which were approximately 16 and 7 times greater in comparison with the corresponding clearances for the interconversion of pentoxifylline and (-)-(R)-M1. When fitting pharmacokinetic data of both parent compounds to a one-compartment model, the values of elimination clearances assessed were close to those obtained on the basis of the interconversion model. After administration of pentoxifylline, tissue-to-serum AUC ratios ranged from 0.1 for liver and lungs to 0.32 for brain tissue. Serum levels of its metabolite, (-)-(R)-M1 were very low, whereas its tissue levels exceeded serum concentrations. The highest value of metabolite-to-parent AUC ratio (4.98) was observed in lungs. When (-)-(R)-M1 was given as a parent drug, tissue-to-serum AUC ratios in liver, kidney, and lungs were very close and ranged from 0.64 to 0.72. At the same time, levels of its metabolite, pentoxifylline were relatively low both in serum and all tissues studied. In consequence, metabolite-to-parent AUC ratios did not exceed the value of 0.27. In conclusion, reversible metabolism plays a modest role in the disposition of pentoxifylline and (-)-(R)-M1. It seems that pentoxifylline has less favourable pharmacokinetic properties than (-)-(R)-M1 due to lower concentrations attained in target organs. High levels of (-)-(R)-M1 observed after pentoxifylline administration in certain tissues such as liver or lungs suggest that pentoxifylline may constitute an effective prodrug for (-)-(R)-M1 in these organs.

Effects of different dialysis membranes on serum concentrations of epoetin alfa, darbepoetin alfa, enoxaparin, and iron sucrose during dialysis.

BACKGROUND: Numerous substances are administered during dialysis for anticoagulation and the treatment of anemia and iron deficiency. The availability of current dialysis membranes is diverse, but assessment of the effects of different membranes on these routinely administered substances is lacking. This prospective study appraises specific effects of 7 dialysis membranes (4 low-flux membranes, 3 high-flux membranes) on the handling of 4 commonly administered agents (epoetin alfa, darbepoetin alfa, enoxaparin, and iron sucrose) during dialysis. METHODS: Using a different membrane sequentially, 6 stable hemodialysis patients were treated with epoetin alfa, enoxaparin, and iron sucrose, and 6 patients with darbepoetin alfa. Serum concentrations (predialyzer and postdialyzer) of each substance were assessed after administration and after 4 hours of dialysis (predialyzer). RESULTS: Overall, use of low-flux membranes resulted in similar serum concentrations for all compounds. However, use of high-flux membranes showed reduced antifactor Xa levels immediately (predialyzer, P = 0.028; postdialyzer, P = 0.027) and 4 hours after (P = 0.001) administration of enoxaparin compared with low-flux membranes. Variable changes in darbepoetin concentrations also were found between the high-flux membranes during dialysis (P = 0.009). Although peak serum concentrations of all compounds were inversely proportional to body weight, the percentage of change during dialysis was not related to dosage or body weight. CONCLUSION: High-flux membranes may require greater doses of enoxaparin to ensure adequate anticoagulation during dialysis and may be associated with variable changes in darbepoetin concentrations. For other compounds, no noteworthy difference among membranes was defined.

Dosing regimen and hematologic effects of pentoxifylline and its active metabolites in normal dogs.

The disposition of pentoxifylline and two of its active metabolites (metabolite 1 [M1] and metabolite 5 [M5]) were studied following i.v. (8 mg/kg) and p.o. (30 mg/kg) administration to eight normal dogs using a randomized crossover design. Blood samples were collected at fixed time intervals after drug administration for determination of drug concentrations, platelet aggregation, and plasma fibrinogen. Complete blood counts, serum chemistry profiles, fibrinogen, and urinalysis were monitored at the beginning and end of each phase of the study (p.o. versus i.v. administration). Pentoxifylline was readily metabolized and bioavailable (50% +/- 26%). Both M1 and M5 were present throughout the study, with M5 predominating. Human drug therapeutic concentrations (1,000 ng/ml) were present for 170 +/- 24 minutes following i.v. administration and 510 +/- 85 minutes after p.o. dosing. These findings suggest that a 12-hour dosing regimen is appropriate. None of the dogs experienced any adverse effects after pentoxifylline administration. The lack of hematologic effects suggests that the immunologic effects of pentoxifylline may be of more importance in dogs.

Comparative bioavailability study of two controlled-release pentoxifylline tablet preparations.

The bioavailability of a generic preparation of pentoxifylline sustained-release (SR) tablet was evaluated in comparison with a proprietary product (Trental 400). For the study, 12 healthy male volunteers participated; the study was conducted according to a randomized, two-way crossover design. The bioavailability was compared using the parameters total area under the plasma level-time curve AUC0-infinity, peak plasma concentration Cmax, and time to reach peak plasma concentration Tmax. No statistically significant difference was observed between the values of the two products in all three parameters. The 90% confidence interval for the ratio of the logarithmic transformed AUC0-infinity values of the generic pentoxifylline over those of Trental 400 was found to lie between 0.83 and 1.00, while that of the parameter Cmax was between 0.91 and 1.29. In addition, elimination half-life t1/2 and apparent volume of distribution Vd were calculated. There was no statistically significant difference between the t1/2 Vd values obtained from the data of the two preparations.

Pharmacokinetics of pentoxifylline in dogs after oral and intravenous administration.

OBJECTIVE: To evaluate the pharmacokinetics of pentoxifylline (PTX) and its 5-hydroxyhexyl-metabolite, metabolite 1 (M1), in dogs after IV administration of a single dose and oral administration of multiple doses. ANIMALS: 7 sexually intact, female, mixed-breed dogs. PROCEDURE: A crossover study design was used so that each of the dogs received all treatments in random order. A drug-free period of 5 days was allowed between treatments. Treatments included IV administration of a single dose of PTX (15 mg/kg of body weight), oral administration of PTX with food at a dosage of 15 mg/kg (q 8 h) for 5 days, and oral administration of PTX without food at a dosage of 15 mg/kg (q 8 h) for 5 days. Blood samples were taken at 0.25, 0.5, 1, 1.5, 2, 2.5, and 3 hours after the first and last dose of PTX was administered PO, and at 5, 10, 20, 40, 80, and 160 minutes after PTX was administered IV. RESULTS: PTX was rapidly absorbed and eliminated after oral administration. Mean bioavailability after oral administration ranged from 15 to 32% among treatment groups and was not affected by the presence of food. Higher plasma PTX concentrations and apparent bioavailability were observed after oral administration of the first dose, compared with the last dose during the 5-day treatment regimens. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs, oral administration of 15 mg of PTX/kg results in plasma concentrations similar to those produced by therapeutic doses in humans, and a three-times-a-day dosing regimen is the most appropriate.