Average Peak Plasma Concentration Research Articles

Pharmacokinetic and bioavailability study of lercanidipine hydrochloride fast disintegrating tablets in rabbits by high-performance liquid chromatography

In the present study, fast disintegrating tablets of Lercanidipine Hydrochloride (LFDT) were tested in vivo in the buccal cavity of the rabbits. Various pharmacokinetic parameters were analysed in the study, including maximum measured plasma concentration (Cmax), time of maximum measured plasma concentration (tmax) and area under the plasma concentration vs time curve (AUC). Also, the comparative study of the Lercanidipine Hydrochloride fast disintegrating tablets (LFDT) was performed with the marketed conventional tablets of the drug (LMKT). The technique selected for the bioanalytical analysis of the blood samples of the rabbits for pharmacokinetic data computation was High-Performance Liquid Chromatography. An already well-established and validated method was used to analyse the blood samples of the rabbits. The results revealed that the rate of absorption was improved for fast disintegrating tablets of Lercanidipine Hydrochloride (LFDT) as compared to the marketed conventional tablets of the drug (LMKT). This indicated that drug was rapidly absorbed from the fast disintegrating tablet and attained elevated plasma concentration in a short interval after dosing than the marketed formulation. However, the value of tmax was drastically shorter for LFDT than the LMKT. The average peak plasma concentration also designated a rise in the extent of absorption (AUC). From the present study, it was concluded that the fast disintegrating tablet batch (LFDT) had much more improved pharmacokinetic parameters as compared to its conventional marketed counterpart (LMKT).

Pharmacokinetics and Sedative Effects of Intranasal Dexmedetomidine in Ambulatory Pediatric Patients.

Our aim was to characterize the pharmacokinetics and sedative effects of intranasally (IN) administered dexmedetomidine used as an adjuvant in pediatric patients scheduled for magnetic resonance imaging (MRI) requiring sedation. This was an open-label, single-period study without randomization. Pediatric patients from 5 months to 11 years of age scheduled for MRI and receiving IN dexmedetomidine for premedication as part of their care were included in this clinical trial. Single doses of 2-3 µg·kg of dexmedetomidine were applied IN approximately 1 hour before MRI. Five or 6 venous blood samples were collected over 4 hours for dexmedetomidine concentration analysis. Sedation was monitored with Comfort-B scores, and vital signs were recorded. Pharmacokinetic variables were calculated with noncompartmental methods and compared between 3 age groups (between 1 and 24 months, from 24 months to 6 years, and over 6-11 years). We evaluated 187 consecutive patients for suitability, of which 132 were excluded. Remaining 55 patients were recruited, of which 5 were excluded before the analysis. Data from 50 patients were analyzed. The average (standard deviation [SD]) dose-corrected peak plasma concentration (Cmax) was 0.011 liter (0.0051), and the median (interquartile range [IQR]) time to reach peak concentration (tmax) was 37 minutes (30-45 minutes). There was negative correlation with Cmax versus age (r = -0.58; 95% confidence interval [CI], -0.74 to -0.37; P < .001), but not with tmax (r = -0.14; 95% CI, 0.14-0.39; P = .35). Dose-corrected areas under the concentration-time curve were negatively correlated with age (r = -0.53; 95% CI, 0.70 to -0.29; P < .001). Median (IQR) maximal reduction in Comfort-B sedation scores was 8 (6-9), which was achieved 45 minutes (40-48 minutes) after dosing. Median (IQR) decrease in heart rate was 15% (9%-23%) from the baseline. Dexmedetomidine is relatively rapidly absorbed after IN administration and provides clinically meaningful but short-lasting sedation in pediatric patients.

Pharmacokinetics of Intranasally Administered Dexmedetomidine in Chinese Children.

Background: Intranasal application is a comfortable, effective, nearly non-invasive, and easy route of administration in children. To date, there is, however, only one pharmacokinetic study on intranasal dexmedetomidine in pediatric populations and none in Chinese children available. Therefore, this study aimed to characterize the pharmacokinetics of intranasally administered dexmedetomidine in Chinese children. Methods: Thirteen children aged 4 to 10 years undergoing surgery received 1 µg/kg dexmedetomidine intranasally. Arterial blood samples were drawn at various time points until 180 min after dose. Dexmedetomidine plasma concentrations were measured with high performance liquid chromatography (HPLC) and mass spectrometry. Pharmacokinetic modeling was performed by population analysis using linear compartment models with first-order absorption. Results: An average peak plasma concentration of 748 ± 30 pg/ml was achieved after 49.6 ± 7.2 min. The pharmacokinetics of dexmedetomidine was best described by a two-compartment model with first-order absorption and an allometric scaling with estimates standardized to 70-kg body weight. The population estimates (SE) per 70 kg bodyweight of the apparent pharmacokinetic parameters were clearance CL/F = 0.32 (0.02) L/min, central volume of distribution V1/F = 34.2 (4.9) L, intercompartmental clearance Q2/F = 10.0 (2.2) L/min, and peripheral volume of distribution V2/F = 34.9 (2.3) L. The estimated absorption rate constant was Ka = 0.038 (0.004) min−1. Conclusions: When compared with studies in Caucasians, Chinese children showed a similar time to peak plasma concentration after intranasal administration, but the achieved plasma concentrations were about three times higher. Possible reasons are differences in age, ethnicity, and mode of administration.

Impact of a cystic fibrosis transmembrane conductance regulator (CFTR) modulator on high-dose ibuprofen therapy in pediatric cystic fibrosis patients.

This study was undertaken to determine if a clinically relevant drug-drug interaction occurred between ibuprofen and lumacaftor/ivacaftor. Peak ibuprofen plasma concentrations were measured prior to and after lumacaftor/ivacaftor initiation. A Wilcoxon signed rank sum test was used to compare the values. Nine patients were included in the final analysis. Peak ibuprofen plasma concentrations decreased an average of 36.4 mcg/mL after initiation of lumacaftor/ivacaftor with a relative reduction of 41.7%. The average peak plasma concentration was 84.2 mcg/mL (SD = 10.9) prior to lumacaftor/ivacaftor initiation and 47.9 mcg/mL (SD = 16.4) following initiation (P = 0.0039). Peak concentrations occurred at an average of 100 min (SD = 30) and 107 min (SD = 40) prior to and following lumacaftor/ivacaftor initiation, respectively. We suggest a clinically relevant drug-drug interaction exists between ibuprofen and lumacaftor/ivacaftor. Lumacaftor may cause subtherapeutic ibuprofen plasma concentrations due to the induction of CYP enzymes and increased metabolism of ibuprofen. Based on this analysis, we have modified our use of ibuprofen in several patients after evaluation of this drug-drug interaction.

Does intranasal dexmedetomidine provide adequate plasma concentrations for sedation in children: a pharmacokinetic study

BackgroundAtomised intranasal dexmedetomidine administration is an attractive option when sedation is required for paediatric diagnostic procedures, as vascular access is not required. The risk of haemodynamic instability caused by dexmedetomidine necessitates better understanding of its pharmacokinetics in young children. To date, intranasal dexmedetomidine pharmacokinetics has only been studied in adults. MethodsEighteen paediatric patients received dexmedetomidine 1 or 2 μg kg−1 intranasally or 1 μg kg−1 i.v. Plasma concentrations were determined by liquid chromatography/mass spectrometry. Non-compartmental analysis provided estimates of Cmax and Tmax. Volume of distribution, clearance, and bioavailability were estimated by simultaneous population PK analysis of data after intranasal and i.v. administration. Dexmedetomidine plasma concentration-time profiles were evaluated by simulation for intranasal and i.v. administration. ResultsAn average peak plasma concentration of 199 pg ml−1 was achieved 46 min after 1 μg kg−1 dosing and 355 pg ml−1 was achieved 47 min after 2 μg kg−1 dosing. A two-compartment pharmacokinetic model, with allometrically scaled parameters, adequately described the data. Typical bioavailability was 83.8% (95% confidence interval 69.5–98.1%). ConclusionMean arterial plasma concentrations of dexmedetomidine in infants and toddlers approached 100 pg ml−1, the low end reported for sedative efficacy, within 20 min of an atomised intranasal administration of 1 μg kg−1. Doubling the dose to 2 μg kg−1 reached this plasma concentration within 10 min and achieved almost twice the peak concentration. Peak plasma concentrations with both doses were reached within 47 min of intranasal administration, with an overall bioavailability of 84%.

A Low Concentration of ABL001 Potentiates In Vitro TKI-Induced Bcr-Abl Kinase Inhibition in CML Cells

▪Background ABL001 (Novartis) is an allosteric inhibitor that binds to the myristate binding pocket of Abl to hold Bcr-Abl in the inactive conformation. A Phase I multicentre trial of ABL001 in chronic myeloid leukemia (CML) is ongoing (Protocol CABL001X2101), and includes testing ABL001 in combination with the ATP-competitive Tyrosine Kinase Inhibitors (TKIs) imatinib (IM), nilotinib (NIL) and dasatinib (DAS) to determine if simultaneous targeting of the myristate and ATP binding pockets provides greater pharmacological inhibition of Bcr-Abl and promotes greater reduction in tumor burden. In vitro sensitivity to TKIs can be measured by assessing the phosphorylation status of the Bcr-Abl substrate CrkL. Using this method, high IM in vitro sensitivity at diagnosis (IC50IM <0.6 µM; White et al, Blood 2005) is predictive of molecular response for patients treated with 600 mg IM.Aim To investigate if the in vitro combination of ABL001 (at a pharmacologically-relevant concentration) with ATP-competitive inhibitors is more effective atBcr-Abl kinase blockade than IM, NIL or DAS as single agents.Methods Blood mononuclear cells (MNC) were isolated with informed consent either prior to TKI therapy (n=6 de novo chronic phase CML patients) or at TKI-switch (n=4 resistant, intolerant or non-compliant patients). For in vitro sensitivity, MNC were treated for 2 h with a pre-determined range of concentrations of IM, NIL and DAS -/+ 1.2 µM ABL001 (based on human PK parameters from Novartis, average peak plasma concentration on 40 mg BID = 578 ng/mL or 1.24 µM) or a much lower dose of 1.2 nM; or with ABL001 alone. Phosphorylated-Crkl (p-Crkl) levels were determined by western blot and the IC50 was calculated by densitometry.Results Kinase inhibition was markedly enhanced by addition of 1.2 µM ABL001 as compared to TKIs alone with mean IC50s without and with ABL001 of 1.52 µM ± 0.46 µM vs. 0.019 µM ± 0.012 µM (p=0.014), 79.1 nM ± 8.8 nM vs. 0.26 nM ± 0.22 nM (p<0.0001) and 2.3 nM ± 0.3 nM vs. 0.014 nM ± 0.007 nM (p=0.002) for IM, NIL and DAS respectively (Fig 1A-C). Since NIL and DAS IC50 values were reduced to picomolar levels in the presence of 1.2 µM ABL001 we then tested a 1000-fold lower ABL001 concentration of 1.2 nM. Similar results were obtained: the observed reductions in IC50s with 1.2 nM ABL001 were 86% (n=8, p=0.013), 72% (n=9, p<0.0001) and 90% (n=3, p=0.0024) for IM, NIL and DAS respectively (Fig 1A-D). In contrast, ABL001 alone was unable to completely inhibit phosphorylation of Crkl in 2 h, thus IC50 calculation was not possible. Collectively, 8 patients of various disease status were tested with IM and all had high IC50IM >0.6 µM, however, with the addition of just 1.2 nM ABL001, the IC50IM was reduced in all cases to <0.6 µM (Fig 1D, p=0.0078), a level that predicts excellent outcomes with IM therapy. The ABL001-induced reductions in TKI IC50s were of similar magnitudes in previously untreated patients as well as those switching TKIs for resistance or intolerance.Conclusions These data suggest that (1) in vitro kinase inhibition achieved with ABL001 in combination with IM, NIL or DAS is greater than that achieved with TKIs alone, even at a concentration 1000-fold lower than achievable on the current ABL001 dosing regimen; and (2) patients with high IC50IM who would be predicted to respond poorly to 600 mg IM have dramatically increased kinase inhibition with the addition of just 1.2nM ABL001. These results suggest that simultaneous targeting of themyristate and ATP binding pockets ofBcr-Abl may be more effective than targeting either site alone and provides a strong rationale for combining IM and ABL001, particularly in patients with low intrinsic sensitivity to IM. [Display omitted] DisclosuresYeung:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Research Funding. White:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Australasian Leukaemia and Lymphoma Group (ALLG): Other: Chair of the CML/MPN Disease Group; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Formulation and Evaluation of Dexibuprofen Transdermal Films in Rabbits

Dexibuprofen is a practically water-insoluble nonsterodial anti-inflammatory drug. Following previous experience on enhancing the solubility of the drug, a mixed hydrotropic solubilization technique was here applied in order to improve the aqueous solubility of the drug so that a soluble form of dexibuprofen was prepared and then could be used as a main active ingredient in transdermal films. Nine formulae were prepared applying 32 full factorial design using different amounts of hydroxypropylmethylcellulose (HPMC) and polyvinylpyrrolidone K30 (PVP K30). The prepared formulae were evaluated for their physical properties, loading efficacy and In-vitro dissolution studies adopting the USP XXII dissolution method type V paddle over disk apparatus method. Permeation studies were done for best three films showing higher dissolution rate using Franz cell apparatus and also bioavailability study was carried out on the best formula to compare the absorption of dexibuprofen from the prepared film (treatment A) to commercial tablets (treatment B) following administration of a single dose to rabbits. The prepared films were off-white color, opaque, smooth, moist and non-sticky. Increasing the amounts of HPMC and PVP K30 lead to increasing weight, folding endurance, tensile strength, moisture content and moisture absorption. Transdermal films containing higher concentrations of PVP K30 and lower concentration of HPMC showed higher rate and amount of dexibuprofen released from dissolution medium and Franz cell. The bioavailability study showed that (Tmax) in treatments A and B is 3 hours and 2 hours respectively. The average peak plasma concentration values (Cmax) were 28.98±3.36 and 34.67±0.61 ug/mL, respectively and the AUC0-∞ values were 145.82±13.09 and 117.44±3.15 µg·h/mL, respectively. There were significant differences between treatments A and B in Cmax, t(1/2)ab, Kel, t(1/2)el, TCR, AUC0-8, AUC0-∞, AUMC0-8, AUMC0-∞, and MRT. While the difference was insignificant in Kab.

Small Molecule Inhibitors of Plasminogen Activator Inhibitor-1 Elicit Anti-Tumorigenic and Anti-Angiogenic Activity.

Numerous studies have shown a paradoxical positive correlation between elevated levels of plasminogen activator inhibitior-1 (PAI-1) in tumors and blood of cancer patients with poor clinical outcome, suggesting that PAI-1 could be a therapeutic target. Here we tested two orally bioavailable small molecule inhibitors of PAI-1 (TM5275 and TM5441) for their efficacy in pre-clinical models of cancer. We demonstrated that these inhibitors decreased cell viability in several human cancer cell lines with an IC50 in the 9.7 to 60.3 μM range and induced intrinsic apoptosis at concentrations of 50 μM. In vivo, oral administration of TM5441 (20 mg/kg daily) to HT1080 and HCT116 xenotransplanted mice increased tumor cell apoptosis and had a significant disruptive effect on the tumor vasculature that was associated with a decrease in tumor growth and an increase in survival that, however, were not statistically significant. Pharmacokinetics studies indicated an average peak plasma concentration of 11.4 μM one hour after oral administration and undetectable levels 23 hours after administration. The effect on tumor vasculature in vivo was further examined in endothelial cells (EC) in vitro and this analysis indicated that both TM5275 and TM5441 inhibited EC branching in a 3D Matrigel assay at concentrations where they had little effect on EC apoptosis. These studies bring novel insight on the activity of PAI-1 inhibitors and provide important information for the future design of inhibitors targeting PAI-1 as therapeutic agents in cancer.

Vitamin K absorption and kinetics in human subjects after consumption of13C-labelled phylloquinone from kale

The absorption and plasma disappearance of vitamin K were investigated by uniformly labelling phylloquinone in kale with carbon-13, and by feeding the kale to study subjects. Seven healthy volunteers ingested a single 400 g serving of kale with 30 g vegetable oil. The kale provided 156 nmol of phylloquinone. Serial plasma samples were collected and analysed for the appearance of 13C-phylloquinone by HPLC-MS. Six of the subjects showed significant amounts of labelled phylloquinone in plasma, though one subject's plasma was not consistently enriched above the detection limit, and this subject's baseline plasma phylloquinone level was the lowest in the group. After ingestion of the labelled kale, plasma 13C-phylloquinone concentration increased rapidly to a peak between 6 and 10 h, and then rapidly decreased. Average peak plasma concentration for the six subjects with detectable 13C-phylloquinone was 2.1 nmol/l. Plasma concentration-time data were analysed by compartmental modelling. Modelling results demonstrated a mean (n 6) bioavailability of phylloquinone from kale to be 4.7%. Plasma and tissue half-times for phylloquinone were found to be 8.8 and 215 h, respectively.

Anticholinergic Activity of 107 Medications Commonly Used by Older Adults

The objective of this study was to measure the anticholinergic activity (AA) of medications commonly used by older adults. A radioreceptor assay was used to investigate the AA of 107 medications. Six clinically relevant concentrations were assessed for each medication. Rodent forebrain and striatum homogenate was used with tritiated quinuclidinyl benzilate. Drug-free serum was added to medication and atropine standard-curve samples. For medications that showed detectable AA, average steady-state peak plasma and serum concentrations (C(max)) in older adults were used to estimate relationships between in vitro dose and AA. All results are reported in pmol/mL of atropine equivalents. At typical doses administered to older adults, amitriptyline, atropine, clozapine, dicyclomine, doxepin, L-hyoscyamine, thioridazine, and tolterodine demonstrated AA exceeding 15 pmol/mL. Chlorpromazine, diphenhydramine, nortriptyline, olanzapine, oxybutynin, and paroxetine had AA values of 5 to 15 pmol/mL. Citalopram, escitalopram, fluoxetine, lithium, mirtazapine, quetiapine, ranitidine, and temazepam had values less than 5 pmol/mL. Amoxicillin, celecoxib, cephalexin, diazepam, digoxin, diphenoxylate, donepezil, duloxetine, fentanyl, furosemide, hydrocodone, lansoprazole, levofloxacin, metformin, phenytoin, propoxyphene, and topiramate demonstrated AA only at the highest concentrations tested (patients with above-average C(max) values, who receive higher doses, or are frail may show AA). The remainder of the medications investigated did not demonstrate any AA at the concentrations examined. Psychotropic medications were particularly likely to demonstrate AA. Each of the drug classifications investigated (e.g., antipsychotic, cardiovascular) had at least one medication that demonstrated AA at therapeutic doses. Clinicians can use this information when choosing between equally efficacious medications, as well as in assessing overall anticholinergic burden.

Vitamin K kinetics in humans after consumption of 13C‐labeled phylloquinone from kale

The absorption and plasma elimination of vitamin K was investigated by uniformly labeling phylloquinone in kale with carbon‐13 and feeding the kale in a clinical study. Seven healthy volunteers ingested a single 400 g serving of kale with 30 g vegetable oil. The kale provided 156 nmol of phylloquinone. Serial plasma samples were collected and analyzed for the appearance of 13C‐phylloquinone by HPLC‐MS. Six of the subjects showed significant amounts of labeled phylloquinone in plasma, with labeled phylloquinone detectable for between 7 and 28 days following the dose. One subject's plasma was not consistently enriched above the detection limit, and this subject's baseline plasma was the lowest of the group. Average peak plasma concentration for the 6 subjects with detectable 13C‐phylloquinone was 2.1 nmolar. At the peak plasma concentration, the 13C‐phylloquinone was elevated between 5% and 34% above baseline (14% on average). The peak plasma 13C‐phylloquinone concentration represented 5±4% of the 13C‐phylloquinone in the kale dose. Carbon‐13 labeling of leafy vegetables for use in clinical nutrition studies is a feasible method for studying the absorption and metabolism of phylloquinone. Funded by USDA/ARS.

Pharmacokinetic and phase II study of heated intraoperative intraperitoneal melphalan

Peritoneal surface malignancy resulting from local dissemination is a common manifestation of treatment failure of gastrointestinal cancers. Although the management of carcinomatosis has been improved with an aggressive surgical approach of extensive cytoreduction followed by heated intraoperative intraperitoneal chemotherapy, no patients are cured when there is residual disease after surgery. Melphalan (L-phenylalanine mustard) is a well-known antineoplastic alkylating agent which has markedly increased pharmacological activity with heat. The use of heated intraoperative intraperitoneal melphalan may provide a pharmacokinetic and clinical advantage in this group of gastrointestinal cancer patients who cannot be made cancer-free with cytoreductive surgery. Thirteen patients with residual disease following cytoreductive surgery for peritoneal carcinomatosis were included in this study. After surgical resection and prior to anastomotic reconstruction, patients received intraperitoneal melphalan (70 mg/m2) in 3 l of 1.5% dextrose peritoneal dialysis solution at 41-42 degrees C for 90 min. Concentrations of melphalan were assessed in the peritoneal fluid, blood, urine and tumor nodules using high-performance liquid chromatography. During the 90 min of treatment 87.2 +/- 4.3% of the drug was absorbed from the perfusate/peritoneal fluid and 11.9 +/- 2.1% was excreted in the urine. The area-under-the-curve ratio of peritoneal fluid to plasma was 33.3 +/- 11.8 with an average peak plasma concentration of 0.82 +/- 0.24 microg/ml occurring at 28.5 +/- 13.1 min. Concentrations of melphalan in tumor nodules on the peritoneal surface were approximately ten times higher than in plasma with an average peak concentration of 7.2 +/- 4.2 microg/gm. The grade III/IV morbidity was 38%; there was no mortality. Approximately 90% of the drug was absorbed during the 90-minute procedure with a 30 times greater exposure of drug at the peritoneal surfaces than in the blood. Concentrations of the drug in peritoneal surface tumor nodules were approximately ten times greater than concentrations in the blood. These data demonstrate that heated intraoperative intraperitoneal melphalan could have a significant impact on the treatment of peritoneal surface malignancies.

Plasma appearance of labeled β-carotene, lutein, and retinol in humans after consumption of isotopically labeled kale

The bioavailability of carotenoids from kale was investigated by labeling nutrients in kale with 13C, feeding the kale to seven adult volunteers, and analyzing serial plasma samples for labeled lutein, beta-carotene, and retinol. Ingested doses of labeled carotenoids were 34 micromol for beta-carotene and 33 micromol for lutein. Peak plasma concentrations, areas under the plasma concentration-time curves (AUCs), and percentages of dose recovered at peak plasma concentrations were calculated. Average peak plasma concentrations were 0.38, 0.068, and 0.079 microM for [13C]lutein, [13C]beta-carotene, and [13C]retinol, respectively. Average AUC values (over 28 days) were 42.8, 13.6, 13.2 microM h for [13C]lutein, [13C]beta-carotene, and [13C]retinol, respectively. Percentages of dose recovered at peak plasma concentrations were 3.6, 0.7, and 0.7% for [13C]lutein, [13C]beta-carotene, and [13C]retinol, respectively. A positive relationship was observed between baseline plasma retinol levels and [13C]retinol plasma response. It is possible that this relationship was mediated either through some aspect of beta-carotene absorption or via the common pathways of metabolism for postdose and endogenous retinoid.

Effect of Peritoneal Dialysis on Plasma and Peritoneal Fluid Concentrations of Isoniazid, Pyrazinamide, and Rifampin

♦ Objective This study was performed to elucidate the pharmacokinetic profiles of antimycobacterial regimens for peritoneal dialysis patients. ♦ Patients Nine patients on maintenance continuous ambulatory peritoneal dialysis (CAPD) were included in this study. ♦ Methods After administering a conventional oral dose of antituberculosis medications, we measured plasma and peritoneal fluid concentrations of isoniazid by fluorometry, and rifampin and pyrazinamide by high performance liquid chromatography. The assay data were subjected to pharmacokinetic analysis. ♦ Results Average peak plasma concentrations of isoniazid, rifampin, and pyrazinamide were 3.3 mg/L, 6.5 mg/L, and 30.9 mg/L, respectively, all of which much exceed the minimum inhibitory concentration (MIC) for Mycobacterium tuberculosis. Peritoneal fluid concentrations of isoniazid and pyrazinamide were maintained well above the MICs for M. tuberculosis; however, peritoneal fluid concentration of rifampin was below the therapeutic range most of the time. ♦ Conclusion For the treatment of systemic or pulmonary tuberculosis in CAPD patients, no dose adjustments are required for isoniazid, rifampin, or pyrazinamide. On the contrary, for the treatment of tuberculous peritonitis, oral rifampin therapy is not expected to be effective because of its low peritoneal fluid concentration.

Pharmacokinetics and safety of oral levofloxacin in human immunodeficiency virus-infected individuals receiving concomitant zidovudine

This phase I, double-blind, randomized, placebo-controlled, parallel-design study was conducted to evaluate the safety and pharmacokinetics of levofloxacin in human immunodeficiency virus (HIV)-infected subjects concomitantly receiving a stable regimen of zidovudine (AZT). Sixteen HIV-infected males with CD4-cell counts ranging from 100 to 550 and not experiencing significant AZT intolerance were enrolled. Subjects received levofloxacin (350 mg of levofloxacin hemihydrate) or a placebo (eight subjects per treatment group) as a single oral dose on day 1, multiple doses every 8 h from days 3 to 9, and a single dose on day 10. On days 1 and 10, an AZT dose (100 mg) was administered concurrently with the study drug. In between these doses, AZT was administered according to the regimen used by the subject prior to entering the study up to a maximum of 500 mg/day. Plasma levofloxacin concentrations were monitored for 36 h after levofloxacin dosing on day 1, immediately prior to the morning doses on days 3 to 9, and for 72 h after dosing on day 10. Plasma AZT concentrations were monitored on day 0 for baseline (for 6 h after the AZT dose) and for 4 h after the AZT doses on days 1 and 10. Levofloxacin was rapidly absorbed (time to maximum plasma concentration, approximately 1.0 h) and extensively distributed in the body with an apparent volume of distribution of approximately 104 liters (approximately 1.34 liters/kg). Steady-state conditions on day 10 were confirmed. Pharmacokinetic profiles of levofloxacin from single doses and multiple (three-times-daily) doses were similar, with a moderate accumulation (observed day 10-to-day 1 ratio of the maximum plasma concentration, approximately 185% versus expected 169%; for the corresponding ratio of the area under the concentration-time curve from 0 to 8 h [AUC(0-8)], the values were observed 217% versus expected 169%) at steady state. Mean average steady-state peak plasma concentration, plasma levofloxacin concentration at the end of the dosing interval, AUC(0-8), terminal half-life, and total body clearance were 7.06 microg/ml, 3.62 microg/ml, 37.4 microg x h/ml, 7.2 h, and 9.4 liters/h (0.12 liters/h/kg), respectively. Pharmacokinetic profiles of levofloxacin in HIV-infected patients did not appear to be affected by the concomitant administration of AZT; nor were AZT pharmacokinetics altered by levofloxacin. Oral administration of 350 mg of levofloxacin hemihydrate every 8 h appeared to be well tolerated by the subjects. There were no apparent differences in adverse events between the two treatment groups. There were no clinically significant changes from baseline in any laboratory parameter or vital sign following treatments observed in this study. The study results suggest that there is no need for levofloxacin dosage adjustment in HIV-seropositive subjects who concomitantly receive AZT.

Comparative Uptake of Orally Administered Difloxacin in Atlantic Salmon in Freshwater and Seawater

Abstract Fluoroquinolones are synthetic antibacterials with potential use for treatment of fish diseases. This study examined the comparative uptake of difloxacin, administered as a single oral gavage, by juvenile Atlantic salmon Salmo salar in freshwater and in seawater. In separate freshwater and seawater experiments with fish of the same spawning cohort, the concentration of difloxacin in plasma and fillets was determined at 1, 2, 4, 8, 12, 18, 24, and 48 h after the fish received the dose. Although plasma difloxacin concentration began to plateau in the freshwater fish at about 24 h, the highest average, 1,195 ng/mL, was in fish sampled at 48 h; thus, the plasma levels continued to rise through the end of the test. A similar pattern was observed in fillets from fish held in freshwater, but the peak average fillet concentration at 48 h was 4,737 ng/g. Contrastingly, in the seawater study, the average peak plasma concentration of 678 ng/mL was observed at 8 h after gavage and the peak average fillet con...

A New Extended‐Release Formulation of Diltiazem HCl for the Treatment of Mild‐to‐Moderate Hypertension

Calcium-channel blockers are a safe and effective treatment modality and have been used extensively in the treatment of angina and hypertension. Dilacor XR capsules, a new extended-release formulation of diltiazem, has been developed for the treatment of hypertension. Dilacor XR (Rhône-Poulenc Rorer Pharmaceuticals Inc., Collegeville, PA) uses a novel drug delivery system, the Geomatrix (JAGO Research AG, Zollikon, Switzerland) controlled-release system, to deliver diltiazem at a constant rate for 24 hours. The rate of absorption is also slower. As doses of Dilacor XR were increased from 120 mg to 540 mg/day, there were disproportionate increases observed in area under the curve, maximum peak plasma concentration, minimum peak plasma concentration, and average peak plasma concentration. The efficacy data from two clinical trials have confirmed the established efficacy of diltiazem and the 24-hour efficacy of Dilacor XR in the control of mild-to-moderate hypertension. The incidence of adverse effects with Dilacor XR in doses as high as 540 mg/day was generally comparable to that of placebo. This new extended-release formulation of diltiazem should significantly facilitate blood pressure control because of better patient compliance with a once daily regimen.

Nicotinamide pharmacokinetics in humans and mice: a comparative assessment and the implications for radiotherapy

Healthy human volunteers orally ingested escalating doses of up to 6 g nicotinamide in capsule form on an empty stomach. Some side-effects were seen although these were mild and transient. HPLC analysis of blood samples showed peak plasma levels, typically within 45 min after ingestion, which were linearly dependent on dose ingested. The elimination half-life and AUC were also found to increase with drug dose, although these increases were non-linear. Pharmacokinetic studies were also performed in female CDF1 mice with OH mammary carcinomas grown in the right rear foot. Analysis of blood and tumour samples taken from mice injected i.p. with nicotinamide doses between 100–1000 mg/kg showed similar characteristics as the human data, although the elimination half-lives were not dose-dependent. The average peak plasma concentration of 160 μg/ml measured in humans after taking 6 g of nicotinamide was equivalent to that seen in mice after injecting 171 mg/kg. Using a regrowth delay assay the enhancement of radiation damage by nicotinamide in this mouse tumour was found to be independent of drug dose from 100–1000 mg/kg, resulting in a constant 1.3-fold increase in radiation response. Doses of nicotinamide that can be tolerated clinically should therefore produce adequate enhancements of radiation damage in human tumours.

Pharmacokinetics of Ritanserin in Patients Undergoing Hemodialysis

The pharmacokinetics of ritanserin were studied in five patients with chronic renal insufficiency and who were undergoing periodic hemodialysis. Immediately after breakfast, a single 10-mg ritanserin tablet was administered to each patient on a day that they did not undergo dialysis. Plasma ritanserin levels were measured by a specific high-performance liquid chromatographic assay sensitive to 2 ng/mL plasma. After the oral 10-mg dose, the average time to reach the peak plasma concentration, Tmax, was 4.4 +/- 2.2 hours in these uremic patients, with a range of 2 to 8 hours. The average peak plasma concentration was 73.6 +/- 26.9 ng/mL (range: 54.6-120.0 ng/mL). Compared with a previous study in healthy volunteers, the uremic patients had a slower absorption profile, with a 39% reduction in peak plasma concentration and mean delay of 2.5 hours in Tmax. The mean area under the plasma concentration-time curve for ritanserin (2031 +/- 636 ng.hr/mL) was 47% lower compared with that in healthy volunteers (3867 +/- 1413 ng.hr/mL). The observed delayed and lower ritanserin absorption in these uremic patients may be caused by the chronic use of antacids such as aluminum hydroxide and calcium carbonate in all patients and/or by concurrent pathologic changes in the gastrointestinal mucosa of these patients. The regular hemodialysis sessions every 2-3 days did not affect the elimination rate of ritanserin, as the terminal half-life in these patients (39 +/- 23 hr) is similar to that in healthy volunteers (41 +/- 14 hr).

A Review of the Pharmacokinetics of Cefpodoxime Proxetil

Cefpodoxime proxetil is an orally absorbed broad spectrum third generation cephalosporin antibacterial. It is a prodrug that is de-esterified in vivo to its active metabolite, cefpodoxime. After single- and multiple-dose (12-hourly) administration of cefpodoxime proxetil in the therapeutic dose range of 100 to 400mg of cefpodoxime equivalents, average peak plasma concentrations of cefpodoxime range from 1.0 to 4.5 mg/L and occur between 1.9 and 3.1 hours after administration. The half-life of cefpodoxime ranges from 1.9 to 2.8 hours. The absolute bio-availability of cefpodoxime proxetil tablets is 50%, and absorption is enhanced by concomitant administration of food. Raising gastric pH by pretreatment with antacids or H2-receptor antagonists results in reduced absorption. Binding of cefpodoxime to human plasma or serum protein is low (18 to 23%), suggesting that cefpodoxime should readily transfer across the capillary lining into tissues. Cefpodoxime undergoes minimal metabolism in humans. Drug not absorbed is degraded in the gastrointestinal tract and excreted in the faeces. As expected for a drug eliminated primarily by renal excretion, the disposition of cefpodoxime is altered in patients with impaired renal function; the half-life increases, while apparent plasma clearance and renal clearance decrease. The pharmacokinetics of cefpodoxime after oral administration of cefpodoxime proxetil are not affected by age.