Mean Absorption Time Research Articles

Comparative Pharmacokinetics of Intravenous and Subcutaneous Omeprazole in Sheep and Goats.

Abomasal ulcers are a challenge in animal farming, affecting health, welfare, and productivity. Omeprazole's (OPZ) efficacy in treating these ulcers is known, but data on its pharmacokinetics (PK) in adult goats and sheep are lacking. The purpose of this research was to investigate and contrast OPZ's PK in these animals following a single intravenous (IV, 1 mg/kg) and subcutaneous (SC, 2 mg/kg) doses. Sheep and goats had similar exposure levels for all administration routes, with no significant AUC(0-∞)D variations. Half-life was short in both species (sheep: 0.20 h; goats: 0.31 h). Goats had a higher volume of distribution after IV administration. Clearance was rapid, and extraction ratio values were high for both goats and sheep (43% and 30%, respectively). SC administration showed similarities in Cmax and Tmax values between species. Both goats and sheep had high bioavailability (about 80%) levels and comparable mean absorption times (MAT). Despite some PK parameters' variances, systemic exposure to OPZ is similar in sheep and goats. SC administration's high bioavailability suggests it as a convenient field application route. Further investigations are needed to understand OPZ's effectiveness in small ruminants with abomasal ulcers and improve dosing regimens for clinical use.

Pharmacokinetic Pattern of Menbutone in Calves after Single Intravenous and Intramuscular Administration.

Menbutone is a choleretic agent currently used in Europe to treat digestive disorders in livestock and dogs. Pharmacokinetic parameters were established in 4-month Holstein calves after intravenous (IV) and intramuscular (IM) administration. The drug was administered to 12 animals (10 mg/kg) for both IV and IM routes following a crossover design. Plasma samples were collected at various time points over 24 h and analyzed by reverse-phase high-performance liquid chromatography with a photodiode-array detector, following a method validated according to European Medicines Agency guidelines. Pharmacokinetic parameters were calculated using compartmental and non-compartmental methods. Menbutone followed a two-compartment open model after IV injection, with a total clearance (Cl) of 71.9 ± 13.5 mL/h/kg, an elimination half-life (t½β) of 4.53 ± 2.45 h, and a volume of distribution at steady-state (Vss) of 310.4 ± 106.4 mL/kg. Non-compartmental elimination half-life (t½λ) was 4.2 ± 1.1 h. After IM administration, drug pharmacokinetics was best described by a one-compartment open model. The peak plasma concentration (Cmax) was 15.1 ± 4.3 µg/mL; the time to reach Cmax (tmax), 1.66 ± 0.55 h; and the mean absorption time (MAT), 2.50 ± 1.42 h. Absorption was high, with a fraction of the dose absorbed (F) of 83.5 ± 22.4%. Menbutone was rapidly eliminated from plasma for both routes of administration, with a fast and high IM bioavailability.

Pharmacokinetics of Enrofloxacin and Its Metabolite Ciprofloxacin in Nanyang Cattle.

The objective of this study was to determine the pharmacokinetics of enrofloxacin and its metabolite, ciprofloxacin, in Nanyang cattle after a single intravenous (IV), and intramuscular (IM) administration of enrofloxacin at 2.5 mg/kg body weight (BW). Blood samples were collected at predetermined time points. Enrofloxacin and ciprofloxacin concentrations in plasma were simultaneously determined using a high-performance liquid chromatography (HPLC) assay method and subjected to a non-compartmental analysis. After IV administration, enrofloxacin had a mean (±SD) volume of distribution at steady state (VSS) of 1.394 ± 0.349 L/kg, a terminal half-life (t1/2λz) of 3.592 ± 1.205 h, and a total body clearance (Cl) of 0.675 ± 0.16 L/h/kg. After IM administration, enrofloxacin was absorbed relatively slowly but completely, with a mean absorption time (MAT) of 6.051 ± 1.107 h and a bioavailability of 99.225 ± 7.389%. Both compounds were detected simultaneously in most plasma samples following both routes of administration, indicating efficient biotransformation of enrofloxacin to ciprofloxacin. After IV injection, the peak concentration (Cmax) of ciprofloxacin was 0.315 ± 0.017 μg/mL, observed at 0.958 ± 0.102 h. Following IM injection, the corresponding values were 0.071 ± 0.006 μg/mL and 3 ± 1.095 h, respectively. Following IV and IM administration, the conversion ratio of enrofloxacin to ciprofloxacin was calculated as 59.2 ± 9.6% and 31.2 ± 7.7%, respectively. The present results demonstrated favorable pharmacokinetic profiles for enrofloxacin, characterized by complete absorption with relatively slow kinetics, extensive distribution, efficient biotransformation to ciprofloxacin, and prolonged elimination in Nanyang cattle.

Pharmacokinetics of antitubercular drugs in patients hospitalized with HIV-associated tuberculosis: a population modeling analysis.

Early mortality among hospitalized HIV-associated tuberculosis (TB/HIV) patients is high despite treatment. The pharmacokinetics of rifampicin, isoniazid, and pyrazinamide were investigated in hospitalized TB/HIV patients and a cohort of outpatients with TB (with or without HIV) to determine whether drug exposures differed between groups. Standard first-line TB treatment was given daily as per national guidelines, which consisted of oral 4-drug fixed-dose combination tablets containing 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol. Plasma samples were drawn on the 3rd day of treatment over eight hours post-dose. Rifampicin, isoniazid, and pyrazinamide in plasma were quantified and NONMEM ® was used to analyze the data. Data from 60 hospitalized patients (11 of whom died within 12 weeks of starting treatment) and 48 outpatients were available. Median (range) weight and age were 56 (35 - 88) kg, and 37 (19 - 77) years, respectively. Bioavailability and clearance of the three drugs were similar between TB/HIV hospitalized and TB outpatients. However, rifampicin's absorption was slower in hospitalized patients than in outpatients; mean absorption time was 49.9% and 154% more in hospitalized survivors and hospitalized deaths, respectively, than in outpatients. Higher levels of conjugated bilirubin correlated with lower rifampicin clearance. Isoniazid's clearance estimates were 25.5 L/h for fast metabolizers and 9.76 L/h for slow metabolizers. Pyrazinamide's clearance was more variable among hospitalized patients. The variability in clearance among patients was 1.70 and 3.56 times more for hospitalized survivors and hospitalized deaths, respectively, than outpatients. We showed that the pharmacokinetics of first-line TB drugs are not substantially different between hospitalized TB/HIV patients and TB (with or without HIV) outpatients. Hospitalized patients do not seem to be underexposed compared to their outpatient counterparts, as well as hospitalized patients who survived vs who died within 12 weeks of hospitalization.

High-Dose Methylphenidate and Carboxylesterase 1 Genetic Variability in Patients With Attention-Deficit/Hyperactivity Disorder: A Case Series.

Methylphenidate (MPH) is widely used to reduce symptoms of attention-deficit/hyperactivity disorder. Methylphenidate is metabolized by the carboxylesterase 1 (CES1) enzyme. Some patients need a very high dose of MPH to reach desired clinical effects, without having adverse effects. This may be due to differences in MPH pharmacokinetics (PK), potentially caused by DNA variants in CES1 , the gene encoding the enzyme that metabolizes MPH. Here we describe 3 patients requiring high-dose MPH and investigated the CES1 gene. The 3 patients were using short-acting MPH in a dose of 180 to 640 mg instead of the maximum advised dose of around 100 mg MPH in the Netherlands. Plasma concentrations of MPH were determined at scheduled time points (day-curve). Methylphenidate plasma concentrations were used for PK analysis using an earlier published 2-compartment PK population model of MPH. Individual data of the 3 patients were compared with simulated population data, when equivalent doses were used. In addition, CES1 was genotyped (number of gene copies and single nucleotide polymorphisms) using real-time polymerase chain reaction. Pharmacokinetic analysis in all 3 patients showed lower plasma concentrations of MPH in comparison with the population data. The mean absorption time and volume of distribution of the central compartment were equal, but the elimination clearance was higher. However, CES1 genotyping revealed no variations that could explain a higher metabolism of MPH. In these 3 cases, we could not demonstrate a correlation between MPH clearance and known genetic variants of the CES1 gene.

Celecoxib-Loaded Self-micellizing Solid Dispersion Suppresses Its Delayed Absorption in Rats with Impaired Gastrointestinal Motility.

The aim of this study was to develop a self-micellizing solid dispersion of celecoxib (SMSD/CEL) with enhanced dissolution to suppress a delay in absorption under impairment of gastrointestinal (GI) secretion and motility induced by severe pain. Soluplus®-based SMSD/CEL was prepared by lyophilization and physiochemically characterized. A pharmacokinetic study of orally-dosed CEL samples was carried out in rats with propantheline (PPT)-induced the impairment of GI secretion and motility. SMSD/CEL was micellized in aqueous media with a mean diameter of 153 nm, and it showed improved dissolution behavior of CEL under acidic conditions with 2.1-fold higher dissolved CEL at 120 min than crystalline CEL. SMSD/CEL was found to be in an amorphous state, and there was no significant crystallization even after storage under accelerated conditions for 8 weeks, indicating relatively high storage stability of the amorphous form. Orally-dosed crystalline CEL in PPT-treated rats showed a delayed mean absorption time (MAT) and area under the curve of plasma concentration versus time from 0 to 4 h (AUC0-4) was reduced to 12% compared with that in normal rats, whereas SMSD/CEL suppressed the delay and decrease of absorption in PPT-treated rats. From these findings, SMSD/CEL might be efficacious to suppress poor and delayed absorption of CEL for better pain medication in the presence of impaired GI secretion and motility associated with severe pain.

Is the One-Compartment Model with First Order Absorption a Useful Approximation?

PurposeThe one-compartment model with first order absorption (ka1C) has been extensively used to fit oral data. But when the disposition parameters of the drug are not available, the bias in the parameter estimates remains unclear. In this paper, the effect of potential misspecification of the area under the curve (AUC) and the mean absorption time (MAT) was evaluated for three relatively slowly absorbed drugs/formulations.MethodsAssuming a three-compartment disposition model with an input (absorption) rate described as a sum of two inverse Gaussian functions (2IG3C) as the true model, the deviations of AUC and MAT estimated with simpler models were analyzed. Simpler models, as the ka1C model (Bateman function), the one-compartment model with IG input function (IG1C) and the gamma density function were fitted to the oral data alone, and compared to the fits obtained with the 2IG3C model which also uses the 3C disposition parameters of the drug. Data from pharmacokinetic studies of trospium, propiverine and ketamine in healthy volunteers were analyzed using a population approach.ResultsThe Bateman function (ka1C) allowed a robust estimation of the population mean AUC, but the individual estimates were highly biased. It failed in evaluating MAT. The simple alternative models did not improve the situation.ConclusionsThe Bateman function appears to be useful for estimating the population mean value of AUC after oral administration. The results reemphasize the fact that insight into the absorption process can be only gained when also intravenous reference data are available.

Pharmacokinetics and bioavailability of meloxicam in Pekin ducks following intravenous, intramuscular and oral administration

ObjectiveTo determine the pharmacokinetics and bioavailability of meloxicam following intravenous (IV), intramuscular (IM), and oral administrations at a dose of 1.0 mg kg–1 in Pekin ducks. Study designRandomized experimental trial. AnimalsA total of 18 clinically healthy male Pekin ducks. MethodsPekin ducks were randomly assigned to three groups of six ducks: IV, IM and oral. Meloxicam (1.0 mg kg–1) was administered to each Pekin duck. A non-compartmental analysis was used to evaluate pharmacokinetic parameters. ResultsNo local or systemic adverse effects were observed in any bird. Meloxicam was detected in the plasma up to 120 hours following IV, IM or oral administration. The elimination half-life of the IV route was slightly shorter than that of the IM and oral routes (p < 0.05). Following IV administration, volume of distribution at steady state and total clearance were 133.17 mL kg–1 and 6.68 mL kg–1 hour–1, respectively. The mean absorption time was 2.29 hours for IM and 1.13 hours for oral route. There were significant differences between IM and oral administration for the peak plasma concentration (Cmax), time to reach Cmax and bioavailability (p < 0.05). Conclusions and clinical relevanceMeloxicam showed long elimination half-life and high bioavailability following IM and oral administration. Meloxicam in Pekin ducks provided the effective therapeutic concentration indicated in other species for up to 48 hours. However, there is a need to determine the clinical efficacy of meloxicam in Pekin ducks.

Revamping Biopharmaceutics-Pharmacokinetics with Scientific and Regulatory Implications for Oral Drug Absorption.

The Wagner-Nelson and Loo-Riegelman methods developed in the 1960s and used since for the construction of percent of drug absorbed as a function of time as well as in in vitro in vivo correlations are re-considered in the light of the physiologically sound Finite Absorption Time (F.A.T.) concept developed recently. The classical equations for the percentage of drug absorption as a function of time were modified by taking into account the termination of drug absorption at F.A.T., replacing the parameters associated with the assumption of infinite drug absorption. Mathematical analysis using the relevant Physiologically Based Pharmacokinetic Finite Time (PBFTK) models assuming one- or two-compartment drug disposition, revealed that the modified %absorbed versus time curves are of bilinear type with an ascending limb intersecting the horizontal line at F.A.T. A computer-based methodology is described for the estimation of F.A.T. from experimental data. More than one linear ascending limb is found when more than one absorption phase is operating. Experimental data were analyzed and the estimates for F.A.T were found to be similar to those derived from nonlinear regression analysis using PBFTPK models. These results place an end to the routinely reported exponential %absorbed versus time curves prevailing in biopharmaceutics-pharmacokinetics since their inception in the'60s. These findings point to the use of the F.A.T. concept in drug absorption research and regulatory guidelines such as deconvolution techniques for the assessment of drug input rate, stochastic mean absorption time calculations, population analyses, in vitro in vivo correlations and bioequivalence guidelines.

Pharmacokinetics of meloxicam in pigeons after single intravenous, oral, and intramuscular administration

This study aimed to determine the pharmacokinetics of meloxicam in pigeons. Twenty-four 7-wk-old meat pigeons (Columba livia) were randomly divided into 3 groups (PO, IM, and IV) and given a single dose of 1 mg/kg body weight of meloxicam. Plasma samples were taken at predetermined times, which were then analyzed using a validated high-performance liquid chromatography (HPLC) method and subjected to noncompartmental analysis using Phoenix software. Results indicated that meloxicam was absorbed effectively and quickly after PO and IM dosing. Peak concentrations (0.83 ± 0.21 and 1.59 ± 0.49 μg/mL) were achieved at 2 and 0.26 h, respectively, with mean absorption times of 2.56 ± 1.50 and 1.47 ± 0.89 h. Bioavailability was high at 86.31 ± 43.45% and 81.57 ± 52.58%, respectively, and the area under the concentration-time curve (AUC0-∞) was 5.33 ± 2.68 and 5.03 ± 3.26 h·µg/mL. After IV administration, the elimination was faster with a total body clearance (CL) of 188.75 ± 83.23 mL/h/kg, an elimination half-life (t1/2λz) of 1.76 ± 0.56 h, and a volume of distribution at steady-state (VSS) of 427.50 ± 188.43 mL/kg. Considering the lack of a precise analgesic threshold of meloxicam in pigeons and the notable differences in its analgesic threshold among various animal species, formulating a dosing regimen in pigeons presented a significant challenge. Based on the previous analgesic threshold (3.5 μg/mL) in parrots, a higher dose (e.g., 2 mg/kg) or shorter dosing interval (e.g., every 6 h) is recommended for treating pain in pigeons. Nonetheless, further pharmacodynamic research is required to verify these recommendations.

Dependence of Bioavailability on Mean Absorption Time: What Does It Tell Us?

The extent and rate of bioavailability are fundamental measures to characterize the pharmacokinetics of drugs after oral administration. Together with bioavailability (F), the mean absorption time (MAT) can be used to define the rate of bioavailability, i.e., the rate of drug absorption. Previous results suggest that F may depend on MAT. Estimates of F and MAT were obtained from the input function (sum of two inverse Gaussian functions) used to model the oral absorption process. The estimation was performed by population analysis (nonlinear mixed-effects modeling) based on data from bioavailability studies in healthy volunteers. For trospium and ketamine, F decreased significantly with increasing MAT, while for propiverine, a significant increase was observed. Thus, the interindividual variability in F could be largely attributed to the interindividual variability in MAT. For trospium and propiverine, the relative dispersion (normalized variance) of the absorption time distribution increased significantly with MAT. For trospium and propiverine, the plot of F versus MAT provides information about the effect of gastrointestinal transit on drug absorption. In contrast, an increase in hepatic extraction with increasing MAT is responsible for the dependence of F on MAT. The F versus MAT plot is suggested as a simple diagnostic tool in evaluating the results of bioavailability studies.

Oral Pharmacokinetics of sulfadiazine and sulfamonomethoxine in female Holstein milking cows.

The efficacy of orally administered drugs in cattle is thought to be slow because of the anatomical and physiological features of their forestomach. Thus, parenteral routes are mainly preferred to administer drugs. However, the effect of some drugs with unique physicochemical properties was promptly obtained even after oral administration in clinically ill cattle. Therefore, the present study aimed to investigate pharmacokinetically the usefulness of the oral route in cattle by comparing the oral pharmacokinetic properties of two sulfonamides with different physicochemical properties. Sulfadiazine (SDZ) and sulfamonomethoxine (SMM) were administered by intravenous and oral route to four female Holstein cows with a 4-weeks washout period. Blood samples were collected over time, and SDZ and SMM concentrations in plasma were analyzed by HPLC. Data obtained from the same animal after intravenous and oral administration were simultaneously analyzed with the one compartment model, and kinetic parameters were calculated. The Tmax (mean ± SD) of SMM (2.75 ± 0.96 hr) was significantly achieved earlier than that of SDZ (5.00 ± 1.15 hr). Further, the mean absorption time of SMM (5.24 ± 0.69 hr) was significantly shorter than that of SDZ (5.92 ± 1.11 hr). Also, the half-life of absorption of SMM (3.91± 0.51 hr) was significantly shorter than that of SDZ (4.51 ± 0.82 hr). These data suggest that the absorption rates of highly unionized drugs (such as SMM) from the forestomach of cattle may be markedly higher than less unionized ones (such as SDZ).

Determination of Leuprolide-Fatty Acid Conjugate in Rat Plasma Using LC-MS/MS and Its Pharmacokinetics after Subcutaneous Administration in Rats.

Leuprolide is a synthetic nonapeptide drug (pyroGlu-His-Trp-Ser-Tyr-d-Leu-Leu-Arg-Pro-NHEt) that acts as a gonadotropin-releasing hormone agonist. The continuous administration of therapeutic doses of leuprolide inhibits gonadotropin secretion, which is used in androgen-deprivation therapy for the treatment of advanced prostate cancer, central precocious puberty, endometriosis, uterine fibroids, and other sex-hormone-related conditions. To improve the pharmacokinetic properties of peptide drugs, a fatty acid was conjugated with leuprolide for long-term action. In this study, we developed a simple ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous determination of leuprolide and leuprolide-oleic acid conjugate (LOC) levels. The developed method was validated in terms of linearity, precision, accuracy, recovery, matrix effect, and stability according to the US Food and Drug Administration guidelines, and the parameters were within acceptable limits. Subsequently, the pharmacokinetics of leuprolide and LOCs were evaluated. In vivo rat subcutaneous studies revealed that conjugation with fatty acids significantly altered the pharmacokinetics of leuprolide. After the subcutaneous administration of fatty-acid-conjugated leuprolide, the mean absorption time and half-life were prolonged. To the best of our knowledge, this is the first study showing the effects of fatty acid conjugates on the pharmacokinetics of leuprolide using a newly developed UPLC-MS/MS method for the simultaneous quantification of leuprolide and LOCs.

Pharmacokinetics of antitubercular drugs in patients hospitalized with HIV-associated tuberculosis: a population modeling analysis.

Early mortality among hospitalized HIV-associated tuberculosis (TB/HIV) patients is high despite treatment. The pharmacokinetics of rifampicin, isoniazid, and pyrazinamide were investigated in hospitalized TB/HIV patients and a cohort of outpatients with TB (with or without HIV) to determine whether drug exposures differed between groups. Standard first-line TB treatment was given daily as per national guidelines, which consisted of oral 4-drug fixed-dose combination tablets containing 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol. Plasma samples were drawn on the 3rd day of treatment over eight hours post-dose. Rifampicin, isoniazid, and pyrazinamide in plasma were quantified and NONMEM ® was used to analyze the data. Data from 60 hospitalized patients (11 of whom died within 12 weeks of starting treatment) and 48 outpatients were available. Median (range) weight and age were 56 (35 - 88) kg, and 37 (19 - 77) years, respectively. Bioavailability and clearance of the three drugs were similar between TB/HIV hospitalized and TB outpatients. However, rifampicin's absorption was slower in hospitalized patients than in outpatients; mean absorption time was 49.9% and 154% more in hospitalized survivors and hospitalized deaths, respectively, than in outpatients. Higher levels of conjugated bilirubin correlated with lower rifampicin clearance. Isoniazid's clearance estimates were 25.5 L/h for fast metabolizers and 9.76 L/h for slow metabolizers. Pyrazinamide's clearance was more variable among hospitalized patients. The variability in clearance among patients was 1.70 and 3.56 times more for hospitalized survivors and hospitalized deaths, respectively, than outpatients. Conclusion. We showed that the pharmacokinetics of first-line TB drugs are not substantially different between hospitalized TB/HIV patients and TB (with or without HIV) outpatients. Hospitalized patients do not seem to be underexposed compared to their outpatient counterparts,as well as hospitalized patients who survived vs who died within 12 weeks of hospitalization.

Involvement of Transporters in Intestinal Drug-Drug Interactions of Oral Targeted Anticancer Drugs Assessed by Changes in Drug Absorption Time.

(1) Background: Oral targeted anticancer drugs are victims of presystemic pharmacokinetic drug-drug interactions (DDI). Identification of the nature of these DDIs, i.e., enzyme-based or/and transporter-based, is challenging, since most of these drugs are substrates of intestinal and/or hepatic cytochrome P-450 enzymes and of intestinal membrane transporters. (2) Methods: Variations in mean absorption time (MAT) between DDIs and control period (MAT ratios &lt; 0.77 or &gt;1.30) have been proposed to implicate transporters in DDIs at the intestinal level. This methodology has been applied to a large set of oral targeted anticancer drugs (n = 54, involved in 77 DDI studies), from DDI studies available either in the international literature and/or in publicly accessible FDA files. (3) Results: Significant variations in MAT were evidenced in 33 DDI studies, 12 of which could be explained by modulation of an efflux transporter. In 21 DDI studies, modulation of efflux transporters could not explain the MAT variation, suggesting a possible relevant role of influx transporters in the intestinal absorption. (4) Conclusions: This methodology allows one to suggest the involvement of intestinal transporters in DDIs, and should be used in conjunction with in vitro methodologies to help understanding the origin of DDIs.

The pulmonary pharmacokinetics and anti-inflammatory effects after intratracheal and intravenous administration of Chuankezhi injection

BackgroundChuankezhi injection (CKZ) is a traditional Chinese medicine for the treatment of respiratory diseases and has been often used off-label as a nebulization therapy. However, little is known about the aerosolization performance and pulmonary fate of the inhaled CKZ. This study aimed to evaluate the aerodynamic characteristics of nebulizer generated aerosols and to compare the properties of pharmacokinetics, lung distribution and anti-inflammation effects of CKZ after intratracheal and intravenous administration. MethodsThe nebulization performance was evaluated in vitro based on the aerodynamic particle size distribution and aerosol output. The concentrations of epimedins A, B, C and icariin, the main active ingredients of CKZ, in plasma, bronchoalveolar lavage fluids (BALF) and lung tissues were measured by LC-MS/MS analysis. The pulmonary anti-inflammatory efficacy were tested using LPS-induced pulmonary inflammation mice model as indicated by the total cells counts, and the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in BALF. ResultsThe aerosols of CKZ generated by a commercial nebulizer showed excellent aerodynamic properties and delivery output. Following intratracheal instillation of CKZ, epidemins A, B and C, and icariin, were absorbed into the bloodstream with the mean absorption time varying from 101.8 min to 271.8 min, and their absolute bioavailabilities ranging from 26.4 % to 104 %. The instillation of CKZ increased the lung to plasma concentration ratios by 25.5–718 folds compared to intravenous administration, leading to improved and prolonged local anti-inflammatory effects. ConclusionNebulization therapy of CKZ could be a promising alternative to the injectable counterpart.

Pharmacokinetics of menbutone after intravenous and intramuscular administration to sheep.

Menbutone is a drug currently approved in several European Union (EU) countries to treat digestive disorders in different animal species. The objective of this study was to establish the pharmacokinetic parameters resulting from intravenous (IV) and intramuscular (IM) administration of this drug in sheep. Menbutone was administered to 12 animals at the dose of 10 mg/kg for both IV and IM routes. Plasma samples were collected up to 24 h (15 points, IV route; 14 points, IM route). Concentrations were determined using high-performance liquid chromatography with photodiode-array (PDA) detection, following a method validated according to the EMEA/CHMP/EWP/192217/2009 guideline. Pharmacokinetic data were analyzed by non-compartmental methods. After IV administration, a total clearance (Cl) of 63.6 ± 13.6 mL/h/kg, a volume of distribution at steady-state (Vss) of 259.6 ± 52.7 mL/kg, and an elimination half-life (t½λ) of 6.08 ± 2.48 h were calculated. After IM administration, menbutone peak plasma concentration (Cmax) was 18.8 ± 1.9 μg/mL, the time to reach Cmax (tmax) 3.75 ± 0.45 h, the mean absorption time (MAT) 3.31 ± 1.36 h, and the fraction of dose absorbed (F) 103.1 ± 23.0 %. The results obtained indicate that menbutone absorption after IM administration is quick and complete.

A simple extemporaneous oral suspension of aprepitant yields sufficient pharmacokinetic exposure in children.

Aprepitant is used for the treatment of chemotherapy induced nausea and vomiting. A liquid formulation is needed for treatment of young children. However, the commercial (powder for) suspension was not available worldwide for a prolonged period of time and, therefore, a 10 mg/mL aprepitant oral suspension was extemporarily prepared to prevent suboptimal antiemetic treatment. The current pharmacokinetic study was developed to investigate whether this extemporaneous oral suspension offers an appropriate treatment option. From 49 pediatric patients (0.7-17.9 years) 235 plasma concentrations were collected. Patients were either treated with our extemporaneous oral suspension (n = 26; 53%), commercially available capsules (n = 18; 37%), or the intravenous prodrug formulation of aprepitant (fosaprepitant, n = 5; 10%). Pharmacokinetic analyses were performed using nonlinear mixed effects modelling. A one-compartment model adequately described the pharmacokinetics of aprepitant in children. The bioavailability of the extemporaneous oral suspension was not significantly different to that of the capsules (P = 0.26). The observed bioavailability throughout the total population was 83% (95% CI 69%-97%). The absorption of the extemporaneous oral suspension was 39.4% (95%CI 19.5-57.4%) faster than that of capsules (mean absorption time of 1.78 h (95%CI 1.32-2.35), but was comparable to that of the commercial oral suspension. The median area under the curve after (fos)aprepitant was 22.2 mg/L*h (range 8.9-50.3 mg/L*h) on day 1. Our extemporaneous oral suspension is an adequate alternative for the commercially (un)available oral suspension in young children. An adequate exposure to aprepitant in children was yielded and the bioavailability of the extemporaneous suspension was comparable to capsules.

A comparison of the population pharmacokinetics of rifampicin, isoniazid and pyrazinamide between hospitalized and non-hospitalized tuberculosis patients with or without HIV.

Early mortality among hospitalized HIV-associated tuberculosis (TB/HIV) patients is high despite treatment. The pharmacokinetics of rifampicin, isoniazid, and pyrazinamide were investigated in hospitalized TB/HIV patients and a cohort of outpatients with TB (with or without HIV) to determine whether drug exposures differed between groups. Standard first-line TB treatment was given daily as per national guidelines, which consisted of oral 4-drug fixed-dose combination tablets containing 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol. Plasma samples were drawn on the 3rd day of treatment over eight hours post-dose. Rifampicin, isoniazid, and pyrazinamide in plasma were quantified and NONMEM ® was used to analyze the data. Data from 60 hospitalized patients (11 of whom died within 12 weeks of starting treatment) and 48 outpatients were available. Median (range) weight and age were 56 (35 - 88) kg, and 37 (19 - 77) years, respectively. Bioavailability and clearance of the three drugs were similar between TB/HIV hospitalized and TB outpatients. However, rifampicin's absorption was slower in hospitalized patients than in outpatients; mean absorption time was 49.9% and 154% more in hospitalized survivors and hospitalized deaths, respectively, than in outpatients. Higher levels of conjugated bilirubin correlated with lower rifampicin clearance. Isoniazid's clearance estimates were 25.5 L/h for fast metabolizers and 9.76 L/h for slow metabolizers. Pyrazinamide's clearance was more variable among hospitalized patients. The variability in clearance among patients was 1.70 and 3.56 times more for hospitalized survivors and hospitalized deaths, respectively, than outpatients. Conclusion. We showed that the pharmacokinetics of first-line TB drugs are not substantially different between hospitalized TB/HIV patients and TB (with or without HIV) outpatients. Hospitalized patients do not seem to be underexposed compared to their outpatient counterparts.

Absorbed driven diffusion can provide positive heat and work output

We investigate overdamped Brownian motion in a fluctuating potential on a one-dimensional interval bordered by absorbing boundaries. The potential switches randomly between the ∨-shaped and the ∧-shaped form and is symmetric with respect to the origin. We derive exact expressions describing the absorption process, dynamics and stochastic energetics of the particle. The mean absorption time can exhibit a pronounced minimum as the function of the potential switching rate. Moreover, there exists a parameter region where both the output work and the released heat are positive. We give a plausible explanation for this phenomenon based on typical statistical features of absorbed trajectories. The presented analytical method can be generalized to other models based on dichotomous switching between two potential shapes.