AUC 0-last Research Articles

A study to explore the appropriateness of dosing regimen of vancomycin in critically ill patients in a tertiary care unit of India.

Vancomycin is used in proven or suspected MRSA and MRE infections. An AUC/MIC ratio of ≥400 is the current accepted critical PK/PD"efficacy" target of vancomycin activity. The present study was conducted to ascertain the appropriateness of practice of current dosage regimen of vancomycin (1 g BD) based on population pharmacokinetic approach. A single-center prospective study with the ICU setting of a tertiary care center was conducted. A total of 15 adult patients with sepsis treated with vancomycin were included over 15 months from May 2019 to July 2020. Blood samples were obtained at 5, 10, and 30 minutes and thereafter at 2 and 6 hours following the completion of the vancomycin infusion. The data obtained from HPLC estimation was analyzed using a population pharmacokinetic approach with NLME, Phoenix 8.3.2.166. The pharmacokinetic model was based on covariates such as bodyweight and urinary creatinine clearance to predict drug concentrations. A total of 83 vancomycin blood samples were analyzed. The mean AUC0-last and AUC0-∞ in patients who improved and died were (AUC(0-last)=293 (152.97); AUC(0-∞)=535.14 (353.67) and (AUC(0-last)=137.19 (51.37); AUC(0-∞)=582.12 (1036.09) respectively, the difference between the two outcome groups was not statistically significant (p=0.104). The pharmacokinetic model was best described by a two-compartment linear model. The goodness-of-fit plots showed that the final covariate pharmacokinetic model (having bodyweight and urinary creatinine clearance) adequately described the observed vancomycin concentrations. Based on the finding of the study it was concluded that 1 g BD dosing of vancomycin is inappropriate. Including covariates such as urinary creatinine clearance and weight in the pharmacokinetic model helped predict drug concentrations more accurately. However, further studies are required to demonstrate efficacy regarding applying this strategy.

Dosage Regimen Formulation and Therapeutic Effect Evaluation of Cyadox Nanosuspension Against Dairy Cow Mastitis Caused by Staphylococcus aureus.

In this study, the dosage regimen establishment of cyadox nanosuspension against dairy cow mastitis caused by Staphylococcus aureus (S. aureus) was used as example to provide a general reference for the other novel nanocrystal preparations. The effect of cyadox against S. aureus isolates from dairy cows were firstly estimated and then the dosing regimen of nanosuspension after intramammary administration was optimized according to the model of ex vivo pharmacokinetic (PK) and pharmacodynamic (PD). The therapeutic efficacy of the predicted dosage regimen was evaluated. The results demonstrated that cyadox has a concentration-dependent effect on S. aureus. The smallest and highest values of minimum inhibitory concentration (MIC) against 80 isolates was 8 and 64 μg/mL, respectively. The corresponding MIC 50 and MIC 90 was 16 and 32 μg/mL, respectively. The MIC against the pathogenic S. aureus SAHZ156001 in broth and milk were 16 and 32 μg/mL, respectively. The AUC 0-last and C max of cyadox in milk were 4442.877 μg*h/mL and 753.052 μg/mL, respectively. According to the inhibitory sigmoid E max modeling and dosage equation, the daily doses were predicted 1.6, 6.6, and 12.2 mL/gland to achieve bacteriostatic, bactericidal, and elimination effects. The dosage internal was daily administration for continuous three days. The clinical experiment showed that the efficient rates were 100, 100, and 90.9%, and the curative rates were 100, 81.8, and 63.6% in 12.2, 6.6 and 1.6 ml/gland groups, respectively. These results showed that cyadox nanosuspension had a good prospect as intramammary infusion to cure dairy cow mastitis infected by S. aureus. This study will be helpful for providing reference for nanocrystal preparation dosage regimen formulation.

Application of HPLC method using normal phase column in a comparative pharmacokinetic study of two sulpiride tablet formulations

An HPLC method using normal phase column eluted with an aqueous solvent and detected by fluorescence was applied to analyze sulpiride concentrations in plasma samples obtained from a comparative pharmacokinetic study. This comparative study was conducted to determine the bioequivalence of two tablet products (Dogmatyl and Sulpin) containing sulpiride on 12 normal healthy Chinese male volunteers in a single-dose, two-period, two-sequence, two-treatment crossover design. The pharmacokinetic parameters, AUC 0-last, AUC 0-inf, and C max, were calculated from plasma data and compared using the SAS General Linear Model computer program. A two one-sided t distribution test was also performed, as well as the 90% confidence interval method, to determine the mean difference of these three pharmacokinetic parameters. The results suggest that these two sulpiride tablet products are bioequivalent when orally administered in a 400 mg single dose of two tablets.

The single dose pharmacokinetic profile of a novel oral human parathyroid hormone formulation in healthy postmenopausal women

Parathyroid hormone (PTH), currently the only marketed anabolic treatment for osteoporosis, is available as the full-length hormone, human PTH1-84, or as the human PTH1-34 fragment (teriparatide).Both must be administered as a daily subcutaneous (sc) injection. A new oral formulation of human PTH1-34 (PTH134) is being developed as a more convenient option for patients.In this single-center, partially-blinded, incomplete cross-over study, the safety, tolerability, and exposure of oral PTH134 (teriparatide combined with 2 different quantities of the absorption enhancer 5-CNAC) were assessed in 32 healthy postmenopausal women.16 subjects were randomized to receive 4 single doses out of 6 different treatments: placebo, teriparatide 20μg sc, or 1, 2.5, 5 or 10mg of oral PTH134 formulated with 200mg 5-CNAC.Subsequently, another 16 subjects were randomized to receive 4 out of 6 different treatments: placebo, teriparatide 20μg sc, or 2.5 or 5mg of oral PTH134 formulated with either 100 or 200mg 5-CNAC. Doses were given ≥6days apart.All doses of PTH134 were rapidly absorbed, and showed robust blood concentrations in a dose-dependent manner. Interestingly, PTH1-34 disappeared from blood faster after oral than after sc administration. Specifically, 2.5 and 5mg PTH134 (containing 200mg 5-CNAC) demonstrated Cmax and AUC0-last values closest to those of sc teriparatide 20μg (Forsteo®).Mean+/−SD hPTH134 Cmax values were, respectively, 74+/−59, 138+/−101, 717+/−496, and 1624+/−1579pg/mL for 1, 2.5, 5, and 10mg doses of this peptide administered with 200mg 5-CNAC; while mean+/−SD AUC (0-last) values were, respectively, 30+/−40, 62+/−69, 320+/−269, and 627+/−633h*pg/mL. The corresponding estimates for teriparatide 20μg sc were 149+/−35 for Cmax and 236+/−58 for AUC (0-last)Ionized calcium remained within normal limits in all treatment groups except for 3 isolated events. Nine subjects withdrew due to treatment-related AEs. Of those, seven were taking PTH134 2.5 or 5mg: three withdrew for symptomatic hypotension (two of whom were in the 200mg 5-CNAC group), three because of delayed vomiting (two from the 200mg 5-CNAC group), one was proactively withdrawn by the investigator for symptomatic hypercalcemia (receiving 2.5mg/100mg 5-CNAC) at slightly supra-normal total calcium but normal ionized serum calcium levels. One subject receiving teriparatide and one receiving placebo withdrew for symptomatic hypotension. No serious AEs were reported.In conclusion, the study demonstrated potential therapeutically relevant PTH1-34 systemic exposure levels after oral administration of PTH1-34 formulated with the absorption enhancer 5-CNAC. Doses of 2.5 and 5mg of oral PTH134 achieved exposure levels closest to those of teriparatide 20μg sc, with a comparable incidence of AEs in healthy postmenopausal women.

The effects of concurrent administration of cytochrome P-450 inhibitors on the pharmacokinetics of oral methadone in healthy dogs

ObjectiveThe objective was to examine the effects of inhibiting cytochrome P450 (CYP) on the pharmacokinetics of oral methadone in dogs. Study designProspective non-randomized experimental trial. AnimalsSix healthy Greyhounds (three male and three female). MethodsThe study was divided into two phases. Oral methadone (mean = 2.1 mg kg−1 PO) was administered as whole tablets in Phase 1. In Phase 2 oral methadone (2.1 mg kg−1 PO) was administered concurrently with ketoconazole (13.0 mg kg−1 PO q 24 hours), chloramphenicol (48.7 mg kg−1 PO q 12 hours), fluoxetine (1.3 mg kg−1 PO q 24 hours), and trimethoprim (6.5 mg kg−1 PO q 24 hours). Blood was obtained for analysis of methadone plasma concentrations by liquid chromatography with mass spectrometry. The maximum plasma concentration (Cmax), time to Cmax (Tmax), and the area under the curve from time 0 to the last measurable time point above the limit of quantification of the analytical assay (AUC0–LAST) were compared statistically. ResultsThe Cmax of methadone was significantly different (p = 0.016) for Phase 1 (5.5 ng mL−1) and Phase 2 (171.9 ng mL−1). The AUC0–LAST was also significantly different (p = 0.004) for Phase 1 (13.1 hour ng mL−1) and Phase 2 (3075.2 hour ng mL−1). Conclusion and clinical relevanceConcurrent administration of CYP inhibitors with methadone significantly increased the area under the curve and plasma concentrations of methadone after oral administration to dogs. Further studies are needed assessing more clinically relevant combinations of methadone and CYP inhibitors.

Bioequivalence of a Generic Quetiapine (Ketipinor®) in Healthy Male Volunteers

Quetiapine is an atypical antipsychotic indicated for the treatment of schizophrenia and related psychoses. Uses of generic drugs are essential due to economic reason. Interchangeability of drugs is determined by bioequivalence studies. We aim to study the bioequivalence of a generic quetiapine (Ketipinor ® , Orion Corporation, Finland) and the innovator product (Seroquel ® , AstraZeneca, UK). The study was a randomized, two-way crossover design with a two-week washout period in 24 healthy Thai male volunteers. After a single 200-mg oral dosing, serial blood samples were collected at appropriate interval up to 48 h. Plasma quetiapine concentrations were determined by using a validated LC-MS/MS method. Pharmacokinetic parameters were estimated using the WinNonlin ® software with non- compartment model analysis. The mean ± SD of maximum plasma concentration (C max ), the area under the plasma concentration-time curve from 0 to 48 h (AUC 0-last ) and the area under the plasma concentration-time curve from 0 to infinity (AUC 0-∞ ) of Ketipinor ® v.s. Seroquel ® were 632.27 ± 304.43 v.s. 638.83 ± 214.49 ng/ml; 2,625.21 ± 972.14 v.s. 2,511.82 ± 704.21 ng.h/ml and 2,640.25 ± 979.10 v.s. 2,526.45 ± 704.37 ng.h/ml, respectively. The time to reach C max (T max ) of Ketipinor ® and Seroquel ® were 1.34 ± 1.11 and 1.01 ± 0.63 h., respectively. The T max of Ketipinor ® was within the acceptance range of ±20% of the median T max of the reference product. The 90% confidence interval of the ratios of the log-transformed data of C max , AUC 0-last and AUC 0-∞ were 80.75 - 102.60%, 91.32 - 108.42% and 88.47 - 106.77%, respectively, which were within the acceptance range of 80.00 - 125.00%. Power of the test for C max , AUC 0-last and AUC 0-∞ were 92.16%, 96.34% and 95.96%, respectively. In conclusion, Ketipinor ® was bioequivalent to Seroquel ® in terms of both the rate and extent of absorption under fasting condition.

Relative bioavailability and pharmacokinetic comparison of two 2-mg risperidone tablet formulations: A single dose, randomized-sequence, double-blind, 2-way crossover study in healthy male volunteers in thailand

Background: Data regarding the pharmacokinetic properties of risperidone in the Thai population are limited. A new generic tablet formulation was recently developed, but bioequivalence research is necessary to obtain marketing authorization for it in Thailand. Objective: The aim of this study was to evaluate and compare the pharmacokinetic properties of risperidone and its active metabolite, 9-hydroxyrisperidone (which reportedly contributes to the drug's pharmacodynamic effects), in a newly developed generic tablet formulation (test) and a branded formulation (reference) in healthy, fasting, male Thai volunteers. Methods: A single-dose, randomized-sequence, doubleblind, 2-way crossover design was used in this study. The study took place from October 21 through November 28, 2007. After a ≥10-hour overnight fast, volunteers were orally administered one 2-mg risperidone tablet, either the test formulation (Condrug International Company, Ltd.) or the reference formulation—according to the randomization schedule—followed by a 14-day washout period and administration of the alternate formulation. Blood samples were collected over a period of 96 hours. Risperidone and 9-hydroxyrisperidone plasma concentrations were simultaneously determined using a validated HPLC/ion trap mass spectrometry method. The plasma concentration-time curves of the active moiety, risperidone, and 9-hydroxyrisperidone were generated for each volunteer, from which the C max, T max, AUC 0-last, AUC 0-∞, and t ½ were determined using noncompart-mental analysis. The effects of formulation, period, sequence, and subject (within sequence) on pharmacokinetic parameters were analyzed using ANOVA. According to regulatory requirements set forth by Thailand, the Association of Southeast Asian Nations, and the US Food and Drug Administration, products meet the criteria for bioequivalence if the 90% CIs of the treatment ratios for C max and AUC are within the range of 0.80 to 1.25. Tolerability was assessed by patient interview, monitoring vital signs (ie, resting blood pressure, heart rate, body temperature), physical examination, and laboratory tests (ie, urinalysis, hematology, blood chemistry) before and after the study. Results: A total of 22 Thai male volunteers (mean [SD] age, 28.18 [8.27] years [range, 20.62–44.19 years]; weight, 62.43 [4.76] kg [range, 55.03–76.02 kg]; and body mass index, 21.76 [2.07] kg/m 2 [range, 18.9924.91 kg/m 2]) completed the study. The mean (SD) relative bioavailabilities of test to reference formulations determined from AUC of the active moiety, risperidone, and 9-hydroxyrisperidone were 1.06 (0.18), 1.07 (0.29), and 1.04 (0.17), respectively. The ANOVA suggested no statistically significant effect of formulation, period, or sequence on the studied pharmacokinetic parameters of the active moiety, risperidone, or 9-hydroxyrisperidone. The 90% CIs for the natural logarithm-transformed ratios of C max, AUC 0-last, and AUC 0-∞ were as follows: for active moiety, 0.94 to 1.03, 0.98 to 1.11, and 0.98 to 1.10, respectively; for risperidone, 0.90 to 1.10, 0.96 to 1.13, and 0.96 to 1.14, respectively; and for 9-hydroxyrisperidone, 0.91 to 1.03, 0.97 to 1.10, and 0.96 to 1.09, respectively. All met the criteria for bioequivalence. The most commonly reported adverse events (AEs) were somnolence (100.0%), orthostatic hypotension (13.6%), headache (4.5%), and syncope (2.3%). AEs were mild and disappeared within 1 day. No volunteers withdrew from the study because of AEs. Conclusions: The single-dose pharmacokinetic data in this small, all-male, selected sample of fasting, healthy volunteers met Thailand's regulatory criteria for assuming bioequivalence of the tested generic and reference 2-mg risperidone tablets. Both formulations were well tolerated.

Bioequivalence of two tablet formulations of clopidogrel in healthy argentinian volunteers: A single-dose, randomized-sequence, open-label crossover study

Background: Platelet activation is a major component in the pathogenesis of coronary thrombosis and myocardial infarction. Thienopyridines, particularly clopidogrel, are highly effective in reducing in-stent thrombosis and functional inhibition of adenosine diphosphate-induced platelet activation. Objective: The aim of this study was to evaluate the bioequivalence of a new generic formulation of clopidogrel 75-mg tablets (test) and the available branded formulation (reference) to meet regulatory criteria for marketing the test product in Argentina. Methods: This was a randomized-sequence, openlabel, 2-period crossover study conducted in healthy white volunteers in the fasted state. A single oral dose of the test or reference formulation was followed by a 7-day washout period, after which subjects received the alternative formulation. Blood samples were collected at baseline and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours after dosing. Clopidogrel concentrations were determined using an LC-MS/MS method. The formulations were considered bioequivalent if the 90% CI of the geometric mean ratios (test:reference) for C max and AUC 0-last were within the range from 80% to 125%. Adverse events were monitored throughout the study based on clinical parameters and patient reports. Results: Twenty-four volunteers (13 male, 11 female; mean [SD] age, 33.7 [5.2] years [range, 21–42 years]; weight, 72.4 [6.83] kg [range, 59–82 kg]) were enrolled in and completed the study. The geometric mean C max for the test and reference formulations was 877.76 and 913.49 pg/mL, respectively. The geometric mean AUC 0-t was 1911.53 and 2053.09 pg · h/mL, and the geometric mean AUC 0-∞) was 2021.33 and 2188.25 pg · h/mL. The geometric mean ratios (test:reference) for C max, AUC 0-t, and AUC 0-∞) were 96.09% (90% CI, 90.71–101.78), 93.10% (90% CI, 85.57–101.3), and 92.37% (90% CI, 85.06–100.31), respectively. There were no significant differences in pharmacokinetic parameters between groups. No adverse events were reported. Conclusion: In this single-dose study in healthy fasted volunteers, the test formulation of clopidogrel tablets met the US and Argentinian regulatory criterion for bioequivalence to the reference formulation.

Bioavailability and pharmacokinetic comparison between generic and branded azithromycin capsule: A randomized, double-blind, 2-way crossover in healthy male thai volunteers

Background: Azithromycin is a semisynthetic azalide antibiotic with extensive tissue penetration and a prolonged t 12. It is used once daily for 3 days in the treatment of a number of bacterial infections. However, based on a literature search, information concerning its pharmacokinetic properties, including the relative bioavailability of a newly developed generic capsule formulation compared with an established branded one in the Thai population, has not been reported. Objective: The aim of this study was to compare the relative bioavailability and other pharmacokinetic properties of a newly developed generic capsule formulation of azithromycin with those of an established branded formulation in healthy male volunteers in Thailand. Methods: A randomized, double-blind, 2-way crossover study was performed in healthy male Thai volunteers under fasting conditions with a washout of 30 days between the study periods. A single dose of 2 × 250-mg azithromycin capsules was orally administered, and blood samples were collected over a period of 120 hours. Plasma azithromycin concentrations were determined using a validated high-performance liquid chromatography method with fluorescence detection after derivatization with 9-fluorenylmethyloxycarbonyl chloride. A plasma concentration-time curve was generated for each volunteer from which the C max, T max, AUC 0-Iast, AUC 0−∞, t 1/2, and κ e were determined using noncompartmental analysis. Bioequivalence was defined using regulatory requirements set forth by Thailand, Association of Southeast Asian Nations, and the US Food and Drug Administration (bioequivalence acceptance range, 0.80–1.25). Results: A total of 14 volunteers completed the study. The mean age of volunteers was 20.8 years (range, 19–23 years), and the mean body weight was 62.8 kg (range, 50.6–70.0 kg). The mean (SD) T max, C max, AUC 0-last, and AUC 0−∞ values after administration of the generic and branded formulations were 1.46 (0.41) versus 1.54 (0.41) hours, 425.23 (208.45) versus 431.75 (198.16) ng/mL, 3919.77 (1549.65) versus 4344.79 (1654.98) ng · h/mL, and 4027.05 (1839.13) versus 4515.53 (2203.87) ng · h/mL, respectively. The relative bioavailability of the generic and branded formulations were 1.00 (0.17). The mean (SD) t1/2 values after administration of the generic and branded formulations were 26.43 (10.92) and 28.10 (13.13) hours, respectively. The analysis of variance results of the natural logarithm (In) -transformed values found no significant effect of formulation, period, or sequence on the studied pharmacokinetic parameters. The 90% CIs of the treatment ratios for the Intransformed values of C max, AUC 0-last, and AUC 0−∞ were 0.82 to 1.11, 0.91 to 1.06, and 0.91 to 1.08, respectively. All were within the standard bioequivalence acceptance range of 0.80 to 1.25. No adverse events were reported in this study. Conclusions: In this small study in a selected population of healthy male Thai volunteers, the C max and AUC were not statistically significantly different between generic and branded formulations of a single, 2 × 250-mg dose of azithromycin capsules. The generic and branded formulations were found to be bioequivalent. Both formulations were well tolerated.