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Dose Proportionality (dose + proportionality)
Selected AbstractsPharmacokinetics of gamithromycin in cattle with comparison of plasma and lung tissue concentrations and plasma antibacterial activityJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2010R. A. HUANG Huang, R. A., Letendre, L. T., Banav, N., Fischer, J., Somerville, B. Pharmacokinetics of gamithromycin in cattle with comparison of plasma and lung tissue concentrations and plasma antibacterial activity. J. vet. Pharmacol. Therap.33, 227,237. The pharmacokinetics (PK) and dose proportionality of gamithromycin (ZACTRAN®), a novel azalide, after a single intravenous (i.v.) dose of 3 mg/kg or subcutaneous (s.c.) injection at 3, 6 and 9 mg/kg body weight were studied in 13 male castrate and 13 female Angus cattle. Following i.v. administration, the mean area under the curve extrapolated to infinity (AUCinf) was 4.28 ± 0.536 ,g·h/mL, and mean elimination half-life (t1/2) was 44.9 ± 4.67 h, with a large volume of distribution (Vss) of 24.9 ± 2.99 L/kg and a high clearance rate (Clobs) of 712 ± 95.7 mL/h/kg. For cattle treated with s.c. injection of 3, 6 or 9 mg/kg, mean AUCinf values were 4.55 ± 0.690, 9.42 ± 1.11 and 12.2 ± 1.13 ,g·h/mL, respectively, and the mean elimination half-lives (t1/2) were 51.2 ± 6.10, 50.8 ± 3.80 and 58.5 ± 5.50 h. Gamithromycin was well absorbed and fully bioavailable (97.6,112%) after s.c. administration. No statistically significant (, = 0.05) gender differences in the AUCInf or elimination half-life values were observed. Dose proportionality was established based on AUCInf over the range of 0.5 to 1.5 times of the recommended dosage of 6 mg/kg of body weight. Further investigations were conducted to assess plasma PK, lung/plasma concentration ratios and plasma antibacterial activity using 36 cattle. The average maximum gamithromycin concentration measured in whole lung homogenate was 18 500 ng/g at first sampling time of 1 day (,24 h) after treatment. The ratios of lung to plasma concentration were 265, 410, 329 and 247 at 1, 5, 10 and 15 days postdose. The lung AUCinf was 194 times higher than the corresponding plasma AUCinf. The apparent elimination half-life for gamithromycin in lung was 90.4 h (,4 days). Antibacterial activity was observed with plasma collected at 6 h postdose with a corresponding average gamithromycin plasma concentration of 261 ng/mL. In vitro plasma protein binding in bovine plasma was determined to be 26.0 ± 0.60% bound over a range of 0.1,3.0 ,g/mL of gamithromycin. The dose proportionality of AUC, high bioavailability, rapid and extensive distribution to lung tissue and low level of plasma protein binding are beneficial PK parameters for an antimicrobial drug used for the treatment and prevention of bovine respiratory disease. [source] Pharmacological and pharmacokinetic evaluation of celecoxib prodrugs in ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2002Rao N.V.S. Mamidi Abstract This study demonstrates the utility of an in vitro , in vivo correlative approach in the selection and optimization of a prodrug candidate of celecoxib (CBX), a COX2 inhibitor. As an initial screening step, a comparative single oral dose pharmacokinetic study was conducted in rats for CBX and its three aliphatic acyl water-soluble prodrugs viz., CBX-acetyl (CBX-AC), CBX-propionyl (CBX-PR) and CBX-butyryl (CBX-BU) at high equimolar dose, 100 mg/kg. Only CBX-BU and CBX-PR converted rapidly to CBX and yielded approximately five-fold greater systemic exposure of CBX than CBX alone or CBX-AC. Rank order of systemic exposure of prodrugs in its intact form was CBX-AC >CBX-PR >CBX-BU. Further in vitro hydrolysis studies of CBX prodrugs in intestinal mucosal suspensions and liver homogenates indicated that CBX-BU is rapidly and completely converted to CBX, whereas CBX-PR and CBX-AC require longer incubation period for complete conversion to CBX. There was a very good correlation of the in vitro and in vivo data supporting CBX-BU as the prodrug of choice. Further in vitro pharmacological studies showed that COX2 selective inhibition is improved for CBX-BU as compared to CBX-AC and CBX-PR. Dose proportionality in pharmacokinetic studies of CBX-BU and CBX at equimolar oral doses confirmed that relative oral bioavailability of CBX was improved following CBX-BU administration and there was linearity in pharmacokinetics of CBX over a wide dose range (10,100 mg/kg), whereas CBX in its conventional form showed poor bioavailability and lack of dose linearity in pharmacokinetics. The oral bioavailability of CBX from CBX-BU was dose independent and was in the range 78,96%. At a 50% reduced molar dose, CBX-BU showed an equivalent efficacy to that of CBX in the in vivo carrageenan model. Based on the study, water-soluble CBX-BU prodrug can be considered for clinical development in view of its potential advantages.Copyright © 2002 John Wiley & Sons, Ltd. [source] Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionalityBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2002Donald J. Nichols Aims, To determine the absolute bioavailability, dose proportionality and the effects of food on the pharmacokinetics of single oral doses of sildenafil citrate. Methods, Three open-label, randomized crossover studies were conducted in healthy male subjects. Absolute bioavailability was determined by comparing pharmacokinetic data after administration of single oral and intravenous 50-mg doses of sildenafil (n=12 subjects). Food effects were examined by comparing pharmacokinetic data for sildenafil and its primary circulating metabolite, UK-103,320, after administration of a single oral 100-mg dose in the fasted and fed states (n=34 subjects). Dose proportionality was assessed from pharmacokinetic data obtained after administration of four single oral doses of sildenafil (25, 50, 100 and 200 mg) to 32 subjects. The safety and tolerability of sildenafil were also assessed in all of these studies. Results, The calculated absolute oral bioavailability of sildenafil was 41% (90% CI: 36,47). Food slowed the rate of absorption, delaying mean tmax by approximately 1 h and reducing Cmax by 29% (90% CI: 19,38). Systemic exposure, as assessed by the mean area under the plasma concentration,time curve (AUC), was reduced by 11% (90% CI: 6,16). These food effects were not considered to be of clinical significance. There was statistical evidence of nonproportionality in Cmax and AUC over the dose range 25,200 mg. However the degree of nonproportionality was small, with predicted increases in Cmax and AUC of 2.2- and 2.1-fold, respectively, for a doubling in dose, and was thought to be clinically nonsignificant. Sildenafil was well tolerated in the three studies; the majority of adverse events were mild and transient. Conclusions, Sildenafil had a mean absolute bioavailability of 41%. Food caused small reductions in the rate and extent of systemic exposure; these reductions are unlikely to be of clinical significance. Across the dose range of 25,200 mg, systemic exposure increased in a slightly greater than dose-proportional manner. [source] Pharmacokinetics of carisbamate (RWJ-333369) in healthy Japanese and Western subjectsEPILEPSIA, Issue 8 2009Peter Zannikos Summary Purpose:, To compare the pharmacokinetics of carisbamate (RWJ-333369) in healthy Japanese and Western adults, and to comparatively assess carisbamate safety and tolerability between the two populations. Methods:, An open-label study was conducted in 24 Japanese and 24 Caucasian healthy subjects. Subjects received a single oral dose of 250 mg carisbamate on day 1 followed by a 3-day washout period; twice-daily dosing of 250 mg carisbamate on days 5,8; subsequently, 500 mg on days 9,12 and a single dose of 500 mg on day 13. Plasma samples were collected for a pharmacokinetic analysis on days 1, 8, and 13. Plasma and urine samples were analyzed for carisbamate and its urinary metabolites by liquid-chromatography-mass-spectrometry. Results:, Following a single dose, carisbamate Cmax and area under the curve (AUC) geometric mean ratios were 16.4% and 28.8% higher in Japanese than in Caucasians, respectively; these differences were statistically significant and their 90% confidence intervals (CIs) fell outside of the 80,125% limits, which are considered not to be of clinical significance. With dose,body weight normalization, Cmax and AUC were similar in Japanese and Caucasian subjects and the 90% CIs were within the 80,125% boundaries. Carisbamate was well tolerated, and its mean oral clearance and half-life were similar in both groups, ranging from 35.1,41.4 ml/h/kg and 11.5,12.8 h. Discussion:, Carisbamate plasma exposure (AUC) and Cmax in Japanese subjects is ,20,25% higher than in Caucasians due to a higher mg/kg dose. After body weight normalization, carisbamate pharmacokinetics was similar between Japanese and Caucasian subjects following single and multiple dosing, and showed the same dose proportionality. [source] Pharmacokinetics of gamithromycin in cattle with comparison of plasma and lung tissue concentrations and plasma antibacterial activityJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2010R. A. HUANG Huang, R. A., Letendre, L. T., Banav, N., Fischer, J., Somerville, B. Pharmacokinetics of gamithromycin in cattle with comparison of plasma and lung tissue concentrations and plasma antibacterial activity. J. vet. Pharmacol. Therap.33, 227,237. The pharmacokinetics (PK) and dose proportionality of gamithromycin (ZACTRAN®), a novel azalide, after a single intravenous (i.v.) dose of 3 mg/kg or subcutaneous (s.c.) injection at 3, 6 and 9 mg/kg body weight were studied in 13 male castrate and 13 female Angus cattle. Following i.v. administration, the mean area under the curve extrapolated to infinity (AUCinf) was 4.28 ± 0.536 ,g·h/mL, and mean elimination half-life (t1/2) was 44.9 ± 4.67 h, with a large volume of distribution (Vss) of 24.9 ± 2.99 L/kg and a high clearance rate (Clobs) of 712 ± 95.7 mL/h/kg. For cattle treated with s.c. injection of 3, 6 or 9 mg/kg, mean AUCinf values were 4.55 ± 0.690, 9.42 ± 1.11 and 12.2 ± 1.13 ,g·h/mL, respectively, and the mean elimination half-lives (t1/2) were 51.2 ± 6.10, 50.8 ± 3.80 and 58.5 ± 5.50 h. Gamithromycin was well absorbed and fully bioavailable (97.6,112%) after s.c. administration. No statistically significant (, = 0.05) gender differences in the AUCInf or elimination half-life values were observed. Dose proportionality was established based on AUCInf over the range of 0.5 to 1.5 times of the recommended dosage of 6 mg/kg of body weight. Further investigations were conducted to assess plasma PK, lung/plasma concentration ratios and plasma antibacterial activity using 36 cattle. The average maximum gamithromycin concentration measured in whole lung homogenate was 18 500 ng/g at first sampling time of 1 day (,24 h) after treatment. The ratios of lung to plasma concentration were 265, 410, 329 and 247 at 1, 5, 10 and 15 days postdose. The lung AUCinf was 194 times higher than the corresponding plasma AUCinf. The apparent elimination half-life for gamithromycin in lung was 90.4 h (,4 days). Antibacterial activity was observed with plasma collected at 6 h postdose with a corresponding average gamithromycin plasma concentration of 261 ng/mL. In vitro plasma protein binding in bovine plasma was determined to be 26.0 ± 0.60% bound over a range of 0.1,3.0 ,g/mL of gamithromycin. The dose proportionality of AUC, high bioavailability, rapid and extensive distribution to lung tissue and low level of plasma protein binding are beneficial PK parameters for an antimicrobial drug used for the treatment and prevention of bovine respiratory disease. [source] Pharmacokinetics of ibafloxacin following intravenous and oral administration to healthy Beagle dogsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2002M. COULET The pharmacokinetics of ibafloxacin, a new veterinary fluoroquinolone antimicrobial agent, was studied following intravenous (i.v.) and oral administration to healthy dogs. The mean absolute bioavailability of ibafloxacin after oral doses of 7.5, 15 and 30 mg/kg ranged from 69 to 81%, indicating that ibafloxacin was well absorbed by dogs. Ibafloxacin was also absorbed rapidly [time of maximum concentration (tmax) 1.5 h], reaching a mean maximum concentration (Cmax) of 6 ,g/mL at 15 mg/kg, well distributed in the body [large volume of distribution at steady state (Vss) and Varea of 1.1 L/kg and 4 L/kg, respectively], and exhibited an elimination half-life of 5.2 h and a low total body clearance (8.7 mL/min/kg). Both Cmax and area under the concentration,time curve (AUC) showed dose proportionality over the dose range tested (7.5,30 mg/kg). The pharmacokinetics of ibafloxacin was similar following single and repeated dosage regimens, implying no significant accumulation in plasma. Food promoted the absorption of ibafloxacin by increasing Cmax and AUC, but did not change tmax. High amounts of the metabolites, mainly 8-hydroxy- and, 7-hydroxy-ibafloxacin were excreted in urine and faeces, either unchanged or as glucuronide conjugates. Following oral administration of 15 mg ibafloxacin/kg, the total recovery of ibafloxacin, its metabolites and conjugates in urine and faeces was 61.9,99.9% of the dose within 48 h. [source] Safety, Tolerability and Pharmacokinetics of TAS-108, a Novel Anti-Oestrogen, in Healthy Post-Menopausal Japanese Women: A Phase I Single Oral Dose StudyBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 5 2009Yuji Kumagai The present study was conducted to investigate the safety, tolerability and pharmacokinetics of TAS-108 following the administration at a single oral dose of 40 mg to up to 120 mg in 12 post-menopausal women and the effect of food on the pharmacokinetics of the drug. All adverse events were mild and involved transient symptoms that resolved without therapeutic intervention. TAS-108 was readily absorbed and plasma levels of TAS-108 steadily declined, apparently in a multi-exponential manner. Cmax and AUC0-12 were proportionally increased with increasing dose of TAS-108. The Cmax and AUC0-t of TAS-108 and its metabolite, deEt-TAS-108, were significantly increased to approximately 150% when TAS-108 was administered after a meal. Food did not affect the elimination half-life of TAS-108 or its metabolites. In this escalating dose-study of TAS-108, the drug was well tolerated by healthy post-menopausal Japanese women. The pharmacokinetics of TAS-108 indicated dose proportionality, and its bioavailability was significantly increased by food intake. [source] Pharmacokinetics of budesonide and formoterol administered via a series of single-drug and combination inhalers: four open-label, randomized, crossover studies in healthy adultsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2008Annika Eklund Abstract Objective: To investigate the pharmacokinetics of budesonide and formoterol administered concomitantly in healthy adults. Methods: Three single-dose, open-label crossover studies (n=28 each) were conducted (Study I: budesonide pMDI, formoterol DPI, budesonide pMDI+formoterol DPI; Study II: budesonide/formoterol pMDI, budesonide pMDI+formoterol DPI; Study III: budesonide/formoterol pMDI [three budesonide formulation strengths; constant formoterol]). Study IV (n=28) assessed steady state pharmacokinetics (budesonide/formoterol pMDI [two/four inhalations twice daily, 5-day treatment; four inhalations, single-dose]). Results: Study I: no pharmacokinetic interactions were observed between budesonide and formoterol. Study II: AUC ratios were 97.9% (budesonide) and 82.2% (formoterol) (budesonide/formoterol pMDI versus budesonide pMDI+formoterol DPI). Study III: formoterol AUC was comparable across budesonide/formoterol pMDI formulation strengths; budesonide AUC increased with formulation strength in proportion to fine particle dose. Study IV: dose proportionality was demonstrated for budesonide (AUC ratio, 104.3%) and suggested for formoterol (AUC ratio, 117.6%) with budesonide/formoterol pMDI (steady state); budesonide and formoterol AUC was higher with repeated versus single-dose budesonide/formoterol pMDI (four inhalations). Conclusions: No pharmacokinetic interactions were observed between budesonide and formoterol. Budesonide dose variation in budesonide/formoterol pMDI did not affect formoterol exposure. Steady state budesonide/formoterol pMDI dose-doubling yielded proportional increases in budesonide and formoterol exposure. Copyright © 2008 John Wiley & Sons, Ltd. [source] Pharmacokinetics and safety of oral almotriptan in healthy male volunteersBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2004J. McEwen Abstract Almotriptan (LAS 31416) is a new, oral, specific 5-hydroxytryptamine1B/1D receptor agonist for the treatment of migraine. The pharmacokinetics and safety of a range of oral doses were assessed in 23 healthy male volunteers. Peak plasma concentrations were reached between 1.5 and 4 h after dosing. The maximum plasma concentration and area under the curve showed dose proportionality over the dose range 5,200 mg. The elimination half-life was constant at approximately 3 h across all dose levels. A substantial proportion of the initial dose was excreted in urine (27%,39%) during 12 h post-dose and the main excretory product was unchanged drug. Three major urinary metabolites were detected, all of which were pharmacologically inactive. The most common events following almotriptan administration were headache, tiredness and mild nausea. Nine events (18%) were classed as probably related to almotriptan and these were all at the highest dose level of 200 mg. The maximum tolerated dose of almotriptan was, therefore, determined as 150 mg. In conclusion, almotriptan is well tolerated following single, oral doses up to 150 mg and has predictable pharmacokinetics. Copyright © 2004 John Wiley & Sons, Ltd. [source] Pharmacokinetics and dose proportionality of BMS-204352 after intraarterial administration to ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2002Rajesh Krishna Abstract BMS-204352 is a novel maxi-K channel opener that is being developed for the treatment for stroke. The current study was designed to evaluate the dose proportionality and pharmacokinetics of BMS-204352 in rats. In an open, parallel fashion, sixteen rats per gender received a single intraarterial dose of BMS-204352 as a 3-min infusion into the carotid artery at 0.4, 2.0, 5.0 and 10.0 mg/kg dose levels. Serial blood samples were collected for up to 24 h post-dose and plasma samples were analyzed for the concentrations of intact BMS-204352 using a validated liquid chromatographic mass spectrometric (LC/MS) method. Pharmacokinetic analysis was performed using a non-compartmental method. Results revealed a gender difference in the pharmacokinetics of BMS-204352 in rats at all doses excluding the first (i.e., 0.4 mg/kg) dose panel. BMS-204352 peak plasma concentration (Cmax) and area under the plasma concentration,time curve (AUC) values increased in a proportion greater than the increment in dose. Specifically, as dose increased in the ratio 1:5:12.5:25, Cmax increased in the ratio 1:7:18:31 in male rats and 1:7:22:51 in female rats. The respective AUC ratios were 1:6:20:42 in male rats and 1:12:29:77 in female rats. Mean total body clearance (CLT) values for BMS-204352 ranged from 879,3242 ml/h/kg over the four dose levels and generally decreased with increase in dose. Similarly, steady state volume of distribution (VSS) values ranged from 3621,8933 ml/kg over the four dose levels and generally decreased with increase in dose. However, mean residence time (MRT) and elimination half-life (T1/2) values for BMS-204352 were independent of dose and ranged from 2.42,4.54 to 2.08,4.70 h, respectively. In conclusion, BMS-204352 appears to exhibit dose-dependent pharmacokinetics in rats. In addition, there appeared to be some evidence of gender related differences in the pharmacokinetics of BMS-204352. Copyright © 2002 John Wiley & Sons, Ltd. [source] Pharmacokinetics of lovastatin extended-release dosage form (Lovastatin XL) in healthy volunteersBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2002Michael Lamson Abstract The purpose of this study was to evaluate pharmacokinetics and dose proportionality of lovastatin extended-release dosage form (ER-lovastatin) in the dosage levels of 10, 20 and 40 mg in 9 healthy male subjects. Each subject was randomized to receive a single oral dose of ER-lovastatin either 10, 20 or 40 mg in a three-way crossover design with a washout period of 7 days between the treatments. Subjects were served dinner at approximately 5:30 PM followed by dosing at approximately 10:00 PM in each study period. Serial plasma samples were collected up to 48 h after dosing and assayed for lovastatin and its active metabolite lovastatin acid using an LC/MS/MS method. The plasma concentration,time profiles of lovastatin and its active metabolite lovastatin acid exhibited delayed- and extended-release characteristics at each dose. Mean (±) values for the Cmax of lovastatin were 1.04±0.43, 2.03±0.65 and 4.03±3.02 ng/ml for the 10, 20 and 40 mg dosage, respectively. The corresponding values for the AUC0,48 h of lovastatin were 14.6±7.8, 34.1 ±13.7, and 53.9±35.6 ng h/ml. The same tendency was also found for Cmax and AUC0,48 h values of lovastatin acid. Results from this study demonstrated as the dose of ER-lovastatin increased from 10 to 40 mg, the Cmax and AUC0,48 h values of lovastatin as well as lovastatin acid appeared to increase linearly. Copyright © 2002 John Wiley & Sons, Ltd. [source] Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionalityBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2002Donald J. Nichols Aims, To determine the absolute bioavailability, dose proportionality and the effects of food on the pharmacokinetics of single oral doses of sildenafil citrate. Methods, Three open-label, randomized crossover studies were conducted in healthy male subjects. Absolute bioavailability was determined by comparing pharmacokinetic data after administration of single oral and intravenous 50-mg doses of sildenafil (n=12 subjects). Food effects were examined by comparing pharmacokinetic data for sildenafil and its primary circulating metabolite, UK-103,320, after administration of a single oral 100-mg dose in the fasted and fed states (n=34 subjects). Dose proportionality was assessed from pharmacokinetic data obtained after administration of four single oral doses of sildenafil (25, 50, 100 and 200 mg) to 32 subjects. The safety and tolerability of sildenafil were also assessed in all of these studies. Results, The calculated absolute oral bioavailability of sildenafil was 41% (90% CI: 36,47). Food slowed the rate of absorption, delaying mean tmax by approximately 1 h and reducing Cmax by 29% (90% CI: 19,38). Systemic exposure, as assessed by the mean area under the plasma concentration,time curve (AUC), was reduced by 11% (90% CI: 6,16). These food effects were not considered to be of clinical significance. There was statistical evidence of nonproportionality in Cmax and AUC over the dose range 25,200 mg. However the degree of nonproportionality was small, with predicted increases in Cmax and AUC of 2.2- and 2.1-fold, respectively, for a doubling in dose, and was thought to be clinically nonsignificant. Sildenafil was well tolerated in the three studies; the majority of adverse events were mild and transient. Conclusions, Sildenafil had a mean absolute bioavailability of 41%. Food caused small reductions in the rate and extent of systemic exposure; these reductions are unlikely to be of clinical significance. Across the dose range of 25,200 mg, systemic exposure increased in a slightly greater than dose-proportional manner. [source] | ||||||||||