Comparison of Plasma Concentrations of Posaconazole with the Oral Suspension and Tablet in Korean Patients with Hematologic Malignancies
Hyeon Jeong SuhInho KimJoo‐Youn ChoSang‐In ParkSeo Hyun YoonJeong‐Ok LeeYoungil KohKyoung‐Ho SongPyoeng Gyun ChoeKyung‐Sang YuEu Suk KimHong Bin KimSoo‐Mee BangNam Joong KimSang Hoon SongWan Beom ParkMyoung‐don Oh
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Abstract:
The posaconazole tablet formulation was developed to have improved bioavailability compared to the oral suspension.Here, we compared posaconazole plasma concentration (PPC) with the posaconazole oral suspension versus the tablet in Korean patients undergoing remission induction chemotherapy for hematologic malignancies.PPC was measured at 3, 8, and 15 days of treatment with the oral suspension (174 patients) or the tablet (40 patients).At all time-points, mean PPC was significantly higher with the tablet compared to the oral suspension.Our findings suggest that posaconazole tablets generate an optimal PPC earlier and in more patients than the oral suspension among Korean patients.Keywords:
Posaconazole
Suspension
We have identified GR138950, a potent antagonist of the angiotensin II receptor with high oral bioavailability, as our second drug candidate to GR117289. Using GR117289, a compound with moderate bioavailability (20%) in man as a lead, we pursued a strategy aimed at enhancing bioavailability. The strategy was based on SAR established around the diacid GR117289, and from this, it was proposed that a monoacid, in particular a trifluoromethanesulfonamide, should be better absorbed after oral administration and have enhanced oral bioavailability. This led to the identification of GR138950, a potent antihypertensive agent in the renal hypertensive rat, causing sustained falls in blood pressure after oral administration. Oral bioavailability of GR138950 in rats and dogs is high, confirming that GR138950 is well absorbed after oral administration. Moreover, the low plasma clearance and long plasma half-life suggest that this compound will be suitable for once a day administration. Furthermore, the preliminary data indicate that the high bioavailability of GR138950 seen in rats and dogs translates to man. These results demonstrate clearly that GR138950 has the potential to be a clinically effective antihypertensive agent. Further studies are in progress to evaluate GR138950 in the treatment of hypertension.
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The principal objective of this study was to evaluate whether repeated oral administration influences the pharmacokinetic behavior of the chemopreventive agent phenethyl isothiocyanate (PEITC) in rat. Animals were treated orally with 0.5, 1.0 and 5.0 mg/kg of the isothiocyanate for 4 days, and plasma levels at various times post-administration were determined by LC/MS after the first and last day. To determine absolute bioavailability, a group of animals was treated with a single (0.5 mg/kg) intravenous dose of PEITC. Following single oral dose administration, PEITC was rapidly absorbed, peak plasma concentrations being attained within the hour, and achieved an absolute bioavailability of 77%, but displayed dose-dependent pharmacokinetics, with bioavailability decreasing and clearance increasing moderately with dose; C(max) values did not rise proportionately to the dose and volume of distribution increased. At the higher doses of 1.0 and 5.0 mg/kg, repeated administration led to higher PEITC plasma C(max) concentrations and decreased plasma clearance of the isothiocyanate leading to enhanced bioavailability.
Phenethyl isothiocyanate
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N-[[[4-(5-Bromo-2-pyrimidinyloxy)-3-chlorophenyl]amino]carbonyl] - 2-nitrobenzamide (HO-221) is presently under development as an oral anticancer agent with a novel mode of action. However, HO-221 exhibits extremely poor bioavailability after oral administration because it is only slightly soluble in water (0.055 micrograms/ml at 37 degrees C). Our previous study revealed that the micronization of HO-221 to the submicron region improved this oral bioavailability. In this study, the oral pharmacokinetics of this micronized HO-221 was investigated in rats, dogs and monkeys. After oral administration, the agent was moderately absorbed with the Tmax of 6.5-8.0, 17.3-20.0 and 12.0 h, and eliminated with the terminal half-lives of 11.9-15.0, 66.8-78.3 and 42.3 h in rats, dogs and monkeys, respectively. The bioavailability was incomplete (3.7-21.4%). In rats, the plasma concentration did not increase proportionally with increasing oral doses. In dogs, food enhanced the bioavailability 2.2-fold with a standard meal and 3.6-fold with a high fatty meal as compared with fasting conditions.
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The bioavailability of oral pentazocine was studied in 5 healthy volunteers. Plasma concentrations were determined from 30 min up to 6 hr following oral administration (two 50‐mg tablets) and, at other occasions, after intravenous injection of 30 mg pentazocine. The average bioavailability was found to be 18.4 ± 7.8% (SD, n = 5). It is shown that this low bioavailability depend almost entirely on the first‐pass metabolism of pentazocine following oral administration by application of intravenous clearance concepts. The average beta‐phase half‐life was about the same following intravenous administration, 203 ± 71 (SD, n = 5) min as following oral administration, 177 ± 34 (SD, n = 5) min, with a total volume of distribution of 5.56 ± 1.63 (SD, n = 5) Llkg. It is suggested that the variations in bioavailability of orally administered pentazocine have the potential to contribute to variations in pharmacologic effects in patients.
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A validated HPLC analysis of eurycomanone (1), a bioactive quassinoid, in rat plasma following oral and intravenous administration of Eurycoma longifolia Jack extract was developed for pharmacokinetic and bioavailability studies. Relatively high plasma eurycomanone concentrations were detected after an intravenous injection of 10 mg/kg extract F2 containing 1.96 mg/kg of the quassinoid. However, it declined rapidly to zero after 8 h. Its mean elimination rate constant (ke), biological half-life (t1/2), volume of distribution (Vd) and clearance (CL) were 0.88 ± 0.19 h-1, 1.00 ± 0.26 h, 0.68 ± 0.30 L/kg and 0.39 ± 0.08 L/h/kg, respectively. Following oral administration of eurycomanone, its Cmax and Tmax values were detected as 0.33 ± 0.03 μg/mL and 4.40 ± 0.98 h, respectively. The plasma concentration of the quassinoid after oral administration was much lower than after intravenous application in spite of the oral dose being 5 times higher. The results indicate that eurycomanone is poorly bioavailable when given orally. A comparison of the AUC0→∞ obtained orally to that obtained after an intravenous administration (normalized for dose differences) revealed that the absolute bioavailability of the compound was low with 10.5 %. Furthermore, the compound appeared to be well distributed in the extravascular fluids because of its relatively high Vd value. The poor oral bioavailability was not attributed to instability problems because eurycomanone has been shown to be stable under different pH conditions. Thus, its poor oral bioavailability may be due to poor membrane permeability in view of its low P value and/or high first-pass metabolism.
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The absolute bioavailability of paracetamol (Tachipirina) administered in single doses orally and rectally was studied in nine healthy adult volunteers. The results of the rapid intravenous injection of 600 mg show that the kinetics of paracetamol can be represented by an open two-compartment model with introduction and elimination occurring in the central compartment. The oral administration shows an absolute bioavailability of 60-70% independent of the pharmaceutical form and gastric contents. The rectal administration shows a lower absolute bioavailability (of about 30-40%) substantially independent of dose in the range under consideration. The pharmaceutical form, food and the route of administration modify the plasma concentration-time curves of free paracetamol and of its main metabolites. A moderate inter-individual variation in the kinetics and the bioavailability was observed.
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