Pharmacokinetics and tolerability of a novel progesterone intravaginal ring in sheep.

The objectives of this work were to evaluate the in vitro release and in vivo pharmacokinetics and local tolerability of a novel, segmented ethylene-vinyl acetate (EVA) intravaginal ring (IVR) delivering progesterone (P) in drug-naïve ovariectomized female Dorset crossbred sheep. Following preparation and assessment of in vitro release of P, animals were randomized into one of six treatment groups: group 1 Crinone® 8% gel (90 mg); group 2 Prometrium® 200-mg capsules; group 3 placebo IVR; group 4 progesterone (P) IVR 4 mg/day; group 5 P IVR 8 mg/day; or group 6 P IVR 12 mg/day. Crinone 8% gel and Prometrium capsules were administered once daily for 28 days. IVRs were inserted vaginally on day 1 and remained in place through day 14; a new ring was administered on day 15 and was removed at day 28. Animals underwent daily examinations to confirm ring placement, and vaginal irritation was scored from 0 (none) to 4 (severe). Blood samples were taken at scheduled times for pharmacokinetic analysis. Postmortem examinations performed on all IVR groups included vaginal irritation, macroscopic, and microscopic evaluations, including irritation scoring and histopathology. Intravaginal rings were retained over 28 days in all animals. Clinical observations showed no significant abnormal findings in any group. Pharmacokinetic analysis in animals showed sustained release of P over from days 0 through 14 of ring use. Irritation scores and microscopic assessments were consistent with the IVRs being well tolerated. These results will guide future human clinical studies to ultimately develop an IVR for use in women for the prevention of preterm birth.

Pharmacokinetics and Tolerability of a Novel 17ß-Estradiol and Progesterone Intravaginal Ring in Sheep.

This study reports the preparation, in vitro release, pharmacokinetics, and local tolerability of novel ethylene-vinyl acetate intravaginal rings (IVRs) delivering 17ß-estradiol (E2) and progesterone (P), in drug-naïve ovariectomized female Dorset crossbred sheep. After preparation and assessment of in vitro release of E2 and P, animals were randomized to treatment groups 1 or 2 (comparator rings releasing 50 or 100 µg/d E2, respectively), groups 3 or 4 (ethylene-vinyl acetate IVRs, 160 µg/d E2 with 4 [160/4 IVR] or 8 mg/d P [160/8 IVR], respectively), or group 5 (160 µg E2 and 10 mg P administered intravenously). IVRs were placed on day 1 and remained in place through day 29. Animals underwent daily examinations to confirm ring placement, and vaginal irritation was scored from 0 (none) to 4 (severe). Blood samples were taken at scheduled times for pharmacokinetic analysis. Postmortem examinations performed on groups 1-4 were macroscopic and microscopic evaluations, including irritation scoring and histopathology. IVRs were retained over 28 days in all but 1 animal (group 4). In all animal groups, clinical observations showed no significant abnormal findings. Pharmacokinetic analysis in the animals showed sustained release of E2 and P over a 28-day period. Irritation scores and microscopic assessments were consistent with foreign object placement. A novel 2-drug IVR delivery system was well tolerated in a sheep model and pharmacokinetic release was as expected over a 28-day release period. These results will guide future human clinical studies.

Pharmacokinetics of Lidocaine and Its Metabolites Following Vaginal Administration of Lidocaine Gel to Healthy Female Subjects.

Lidocaine vaginal bioadhesive gel is being developed as a local anesthetic for use in minimally invasive outpatient gynecological procedures and was investigated in single-dose and multiple-dose studies in healthy young adult women. Lidocaine doses of 2.5%, 5%, and 10% (w/w) were administered, and parent drug and metabolites monoethylglycinexylidide and glycinexylidide were measured in plasma. Lidocaine was absorbed through vaginal tissue and into the systemic circulation in a dose-proportional manner, and there was little systemic accumulation. Plasma concentrations were 10- to 20-fold lower than concentrations obtained after administration of intravenous lidocaine used to treat arrhythmic activity, thus demonstrating a wide safety margin for a vaginal lidocaine product.

TX-004HR vaginal estradiol has negligible to very low systemic absorption of estradiol.

OBJECTIVE: To evaluate the pharmacokinetics of TX-004HR vaginal estradiol softgel capsules when used for treating moderate-to-severe dyspareunia in postmenopausal women with vulvar and vaginal atrophy. METHODS: A substudy of the REJOICE trial (multicenter, double-blind, placebo-controlled, phase 3) evaluated the pharmacokinetics of 4, 10, and 25-µg TX-004HR doses once/d for 2 weeks, followed by twice/wk for 10 weeks. Serum samples obtained at 2, 4, 6, 10, and 24 hours postdose on days 1 and 14, and once on day 84, were analyzed for area under the serum concentration-time curve, tmax, Cmin, Cavg, and Cmax for estradiol, estrone, and estrone conjugates. RESULTS: Seventy-two women (mean 59 y) participated. TX-004HR 4 µg showed no statistical differences from placebo in estradiol pharmacokinetic (PK) parameters. At 10 µg, estradiol Cmax was statistically higher than placebo on day 1, but was not different from placebo on day 14. With 25 µg, estradiol PK parameters were statistically higher than placebo. Estradiol Cavg values for 25 µg were 9.1 pg/mL on day 1 and 7.1 pg/mL on day 14. Estrone and estrone conjugate PK parameters with TX-004HR were lower than or similar to placebo across all doses. No drug accumulation was observed. CONCLUSIONS: Vaginal TX-004HR resulted in negligible to very low systemic absorption of estradiol. No statistical differences in estradiol PK parameters were observed on day 14 with 4 and 10 µg, and only minor increases were observed with 25 µg (within the normal postmenopausal range). This PK substudy, in conjunction with the primary efficacy results, demonstrated that TX-004HR provided local benefits of estradiol with limited systemic exposure.

A Cluster of Proteins Implicated in Kidney Disease Is Increased in High-Density Lipoprotein Isolated from Hemodialysis Subjects.

Cardiovascular disease is the leading cause of death in end-stage renal disease (ESRD) patients treated with hemodialysis. An important contributor might be a decline in the cardioprotective effects of high-density lipoprotein (HDL). One important factor affecting HDL's cardioprotective properties may involve the alterations of protein composition in HDL. In the current study, we used complementary proteomics approaches to detect and quantify relative levels of proteins in HDL isolated from control and ESRD subjects. Shotgun proteomics analysis of HDL isolated from 20 control and 40 ESRD subjects identified 63 proteins in HDL. Targeted quantitative proteomics by isotope-dilution selective reaction monitoring revealed that 22 proteins were significantly enriched and 6 proteins were significantly decreased in ESRD patients. Strikingly, six proteins implicated in renal disease, including B2M, CST3, and PTGDS, were markedly increased in HDL of uremic subjects. Moreover, several of these proteins (SAA1, apoC-III, PON1, etc.) have been associated with atherosclerosis. Our observations indicate that the HDL proteome is extensively remodeled in uremic subjects. Alterations of the protein cargo of HDL might impact HDL's proposed cardioprotective properties. Quantifying proteins in HDL may be useful in the assessment of cardiovascular risk in patients with ESRD and in assessing response to therapeutic interventions.

Comparative bioavailability study of single-dose film-coated and sugar-coated ethionamide tablets in healthy volunteers.

BACKGROUND: Ethionamide sugar-coated tablets have been reformulated to film-coated tablets to improve dissolution and stability. OBJECTIVE: The study objective was to compare the bioavailability of the film-coated (test) and sugar-coated (reference) formulations of ethionamide. METHODS: After providing informed consent and undergoing screening procedures, 40 healthy subjects were assigned to receive a single dose of ethionamide 250-mg film- or sugar-coated tablets, in randomized order, in the fasted state. Serial blood samples were collected before and from 0.5 to 24 hours after dosing. After a 7-day washout, procedures were repeated for the other formulation. The blood samples were processed to provide plasma samples, which were frozen until assay. Plasma ethionamide concentrations were measured using a validated LC-MS/MS method, with a lower limit of quantitation of 20 ng/mL. Pharmacokinetic parameters were determined using noncompartmental methods, with subsequent evaluation for bioequivalence. RESULTS: All 40 subjects (37 men, 3 women; mean age, 28 years; mean weight, 74 kg) completed the study. Seven subjects reported a total of 10 adverse events (5 with each formulation), all of which were mild and considered possibly related to drug treatment. None of the events resulted in discontinuation from the study. Mean (SD) pharmacokinetic properties observed with the film- and sugar-coated tablets, respectively, were as follows: Cmax, 2160 (614) and 1484 (636) ng/mL; Tmax, 1.0 (0.5) and 1.5 (0.9) hours; ke, 0.369 (0.053) and 0.232 (0.114) h(-1); t½, 1.92 (0.27) and 4.06 (2.52) hours; and AUC, 7668 (1688) and 6594 (1764) ng · h/mL. CONCLUSIONS: Comparing AUC values, the formulations were bioequivalent. The maximum concentrations observed with the film-coated product were higher but were more consistent (%CV, 28%) compared with those of the sugar-coated formulation (%CV, 43%).

Humans with atherosclerosis have impaired ABCA1 cholesterol efflux and enhanced high-density lipoprotein oxidation by myeloperoxidase.

RATIONALE: The efflux capacity of high-density lipoprotein (HDL) with cultured macrophages associates strongly and negatively with coronary artery disease status, indicating that impaired sterol efflux capacity might be a marker-and perhaps mediator-of atherosclerotic burden. However, the mechanisms that contribute to impaired sterol efflux capacity remain poorly understood. OBJECTIVE: Our aim was to determine the relationship between myeloperoxidase-mediated oxidative damage to apolipoprotein A-I, the major HDL protein, and the ability of HDL to remove cellular cholesterol by the ATP-binding cassette transporter A1 (ABCA1) pathway. METHODS AND RESULTS: We quantified both site-specific oxidation of apolipoprotein A-I and HDL's ABCA1 cholesterol efflux capacity in control subjects and subjects with stable coronary artery disease or acute coronary syndrome. Subjects with coronary artery disease and acute coronary syndrome had higher levels of chlorinated tyrosine 192 and oxidized methionine 148 compared with control subjects. In contrast, plasma levels of myeloperoxidase did not differ between the groups. HDL from the subjects with coronary artery disease and acute coronary syndrome was less able to accept cholesterol from cells expressing ABCA1 compared with HDL from control subjects. Levels of chlorinated tyrosine and oxidized methionine associated inversely with ABCA1 efflux capacity and positively with atherosclerotic disease status. These differences remained significant after adjusting for HDL-cholesterol levels. CONCLUSIONS: Our observations indicate that myeloperoxidase may contribute to the generation of dysfunctional HDL with impaired ABCA1 efflux capacity in humans with atherosclerosis. Quantification of chlorotyrosine and oxidized methionine in circulating HDL might be useful indicators of the risk of cardiovascular disease that are independent of HDL-cholesterol.

Multiple-reaction monitoring-mass spectrometric assays can accurately measure the relative protein abundance in complex mixtures.

BACKGROUND: Mass spectrometric assays could potentially replace protein immunoassays in many applications. Previous studies have demonstrated the utility of liquid chromatography-multiple-reaction monitoring-mass spectrometry (LC-MRM/MS) for the quantification of proteins in biological samples, and many examples of the accuracy of these approaches to quantify supplemented analytes have been reported. However, a direct comparison of multiplexed assays that use LC-MRM/MS with established immunoassays to measure endogenous proteins has not been reported. METHODS: We purified HDL from the plasma of 30 human donors and used label-free shotgun proteomics approaches to analyze each sample. We then developed 2 different isotope-dilution LC-MRM/MS 6-plex assays (for apoliporoteins A-I, C-II, C-III, E, B, and J): 1 assay used stable isotope-labeled peptides and the other used stable isotope-labeled apolipoprotein A-I (an abundant HDL protein) as an internal standard to control for matrix effects and mass spectrometer performance. The shotgun and LC-MRM/MS assays were then compared with commercially available immunoassays for each of the 6 analytes. RESULTS: Relative quantification by shotgun proteomics approaches correlated poorly with the 6 protein immunoassays. In contrast, the isotope dilution LC-MRM/MS approaches showed correlations with immunoassays of r = 0.61-0.96. The LC-MRM/MS approaches had acceptable reproducibility (<13% CV) and linearity (r ≥0.99). Strikingly, a single protein internal standard applied to all proteins performed as well as multiple protein-specific peptide internal standards. CONCLUSIONS: Because peak area ratios measured in multiplexed LC-MRM/MS assays correlate well with immunochemical measurements and have acceptable operating characteristics, we propose that LC-MRM/MS could be used to replace immunoassays in a variety of settings.

Relative Bioavailability of Liquid and Tablet Formulations of the Antiparasitic Moxidectin.

The antiparasitic agent moxidectin is under development for the treatment of onchocerciasis. As the first-in-human study of moxidectin used a liquid formulation but other trials used tablets, a study was performed to determine the relative bioavailability of the 2 formulations and to gain more information about the pharmacokinetics of moxidectin. Fifty-eight healthy male participants were randomized to receive open-label moxidectin (10 mg) as a tablet (n = 29) or liquid (n = 29) formulation. The mean ± SD pharmacokinetic parameters observed following administration of the tablet were peak concentration (Cmax) 67.1 ± 27.4 ng/mL, time to peak concentration (tmax) 3.2 ± 1.4 hours, area under the concentration time curve (AUC) 4403 ± 2360 ng·h/mL, apparent volume of distribution 3635 ± 1720 L, oral clearance 2.83 ± 1.25 L/h, and elimination half-life 1032 ± 502 hours. The Cmax and AUC observed following administration of the liquid formulation were 28.6% and 28.8% higher, respectively, and tmax 0.9 hours shorter compared with tablets. No serious adverse events (AEs) were observed. The most commonly reported AEs were headache, infection, diarrhea, asthenia, myalgia, and dizziness during the inpatient phase and flu syndrome, headache, and infection during the 6-month outpatient phase. There was no difference in reporting of these AEs between formulations.

Plasma estrogen concentrations after oral and vaginal estrogen administration in women with atrophic vaginitis.

In this open-label, randomized, multiple-dose, two-treatment crossover study, 24 postmenopausal women with moderate to severe atrophic vaginitis received 0.3 mg conjugated estrogens daily for 14 days: 7 days orally (0.3 mg tablet) and 7 days vaginally (0.5 g cream). Steady-state plasma concentrations of E2 and estrone were one-third lower after vaginal versus oral administration of conjugated estrogens.

HDL in humans with cardiovascular disease exhibits a proteomic signature.

BACKGROUND: Alterations in protein composition and oxidative damage of high density lipoprotein (HDL) have been proposed to impair the cardioprotective properties of HDL. We tested whether relative levels of proteins in HDL(2) could be used as biomarkers for coronary artery disease (CAD). METHODS: Twenty control and eighteen CAD subjects matched for HDL-cholesterol, age, and sex were studied. HDL(2) isolated from plasma was digested with trypsin and analyzed by high-resolution matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) and pattern recognition analysis. RESULTS: Partial least squares discriminant analysis (PLS-DA) of mass spectra clearly differentiated CAD from control subjects with area under the receiver operating characteristic curve (ROC(AUC)) of 0.94. Targeted tandem mass spectrometric analysis of the model's significant features revealed that HDL(2) of CAD subjects contained oxidized methionine residues of apolipoprotein A-I and elevated levels of apolipoprotein C-III. A proteomic signature composed of MALDI-MS signals from apoA-I, apoC-III, Lp(a) and apoC-I accurately classified CAD and control subjects (ROC(AUC)=0.82). CONCLUSIONS: HDL(2) of CAD subjects carries a distinct protein cargo and that protein oxidation helps generate dysfunctional HDL. Moreover, models based on selected identified peptides in MALDI-TOF mass spectra of the HDL may have diagnostic potential.

Relationship between Tomm performance and PAI validity scales in a mixed clinical sample.

This study addressed the relationship between Personality Assessment Inventory (PAI) validity indicators and cognitive effort measures on the Test of Memory Malingering (TOMM). Significant correlations were found between TOMM and some PAI validity scales. Factor analysis results found separate cognitive and personality components, but the Negative Impression Management (NIM) scale, a measure of response bias, had factor loadings on both the cognitive and the personality components. Follow-up hierarchical multiple regression and t-test analysis generally confirmed this result, and found that NIM and the Infrequency (INF) scale have significant relationships with the TOMM. The results indicate that individuals with elevations on the PAI's INF and NIM scales often display decreased cognitive effort on the TOMM. The current results support the hypothesis that personality assessment validity indicators have a modest but significant relationship with poor cognitive effort.

Steady-state pharmacokinetics of conjugated equine estrogens in healthy, postmenopausal women.

OBJECTIVE: To determine the steady-state exposure of conjugated and unconjugated estrogen components following oral administration of conjugated equine estrogens (2 0.625-mg tablets). STUDY DESIGN: A prospective, open-label, single-treatment study conducted at 1 clinical site with 12 healthy, postmenopausal women. Each subject received 7 daily doses of 2 conjugated equine estrogen (0.625-mg) tablets, and blood samples were taken on the last day of dosing for pharmacokinetic analysis of estrogen components. RESULTS: The major estrogen components after estrogen dosing (as determined by steady-state plasma concentration-time curves) were estrone (100 ng x h/mL), equilin (43.1 ng x h/mL) and delta8,9-dehydroestrone (13.6 ng x h/mL). Several 17beta-reduced forms of estrogen also had consistent plasma concentrations during a steady-state dosing interval. Mean t(max) values ranged from 6.2 to 9.0 hours after dosing, and the 24-hour profiles of the various plasma estrogen concentrations at steady state showed limited fluctuations. CONCLUSION: Oral dosing of conjugated equine estrogen at steady state resulted in consistent concentrations of estrogen components during a dosing interval.

Preparative separation of a multicomponent peptide mixture by mass spectrometry.

We report on the first multiplex preparative separation by mass spectrometry of bio-organic molecules in the 200-350 Da mass range that is typical for synthetic drugs. A five-component mixture consisting of two di- and three tripeptides has been separated by mass using a specially designed mass spectrometer. The instrument for preparative separations consists of an electrospray ionization (ESI) source, ion transfer optics, an electrostatic sector, and an inhomogeneous-field magnetic mass analyzer that achieves linear mass dispersion of ion beams. Protonated peptides produced by electrospray were separated, nondestructively landed on a 16-channel array of dry collector plates, and reconstituted in solution. The preparation procedures and the instrumental conditions have been optimized to maximize the ion currents. The significant features of the special mass spectrometer are high ion currents and simultaneous separation and collection of mixture components.

Preparative separation of mixtures by mass spectrometry.

A specially designed mass spectrometer which allows for preparative separation of mixtures is described. This mass spectrometer allows for large ion currents, on the order of nanoamperes, to be produced by electrospray and transmitted into a high vacuum. Accumulation of nanomole quantities of collected and recovered material in several hours is demonstrated. The use of high-velocity ions reduces space charge effects at high ion currents. Separation of mass occurs simultaneously for all ions, providing a 100% duty cycle. The use of a linear dispersion magnet avoids compression at higher m/z ratios. A deceleration lens slows the ions to allow for soft landing at low kinetic energy. The ions are neutralized by ion pairing on an oxidized metal surface. Retractable landing plates allow for easy removal of the separated components.

Excretion of pantoprazole in human breast.

OBJECTIVE: To measure the amount of pantoprazole in human milk following its oral administration to a breast-feeding mother and to estimate human exposure. STUDY DESIGN: One woman was studied over a 24-hour interval after oral administration of 40-mg pantoprazole. Serial plasma and milk samples were collected over 24 hours, and pantoprazole concentrations were measured by high-performance liquid chromatography. A milk/plasma ratio of 0.022 was observed at tmax, 2 hours after dose administration. Infant exposure was measured as maximum concentration in milk multiplied by an estimated maximum consumption of 200 mL at this time. RESULTS: The relative infant dose was estimated to be 7.3 microg of pantoprazole, which is equivalent to 0.14% of the weight-normalized dose received by the mother. Because pantoprazole is unstable in acidic pH, the systemic dose received by the infant is expected to be lower if the ingested pantoprazole is exposed to acid in the infant's stomach. The mother detected no adverse events in the infant. CONCLUSION: These limited data show that pantoprazole is minimally excreted into breast milk. While it is not known if pantoprazole affects breast milk production, women who are breast-feeding do not have to stop breastfeeding when taking pantoprazole chronically.

Unaltered etanercept pharmacokinetics with concurrent methotrexate in patients with rheumatoid arthritis.

The purpose of this study was to evaluate the potential impact of concurrent weekly oral methotrexate administration on the pharmacokinetics of etanercept in patients with rheumatoid arthritis (RA) in a phase 3B trial. As part of a double-blind randomized trial of 682 patients with rheumatoid arthritis who received etanercept (25 mg subcutaneously twice weekly), methotrexate (weekly oral dose, median weekly dose: 20 mg), or etanercept (25 mg subcutaneously twice weekly) plus methotrexate (weekly oral dose, median weekly dose: 20 mg), serum etanercept concentrations were measured in a subset of patients. Serum samples for 98 randomly selected patients (48 receiving etanercept-alone treatment, 50 receiving etanercept plus methotrexate combination treatment) were analyzed to assess the pharmacokinetics of etanercept. A single blood sample was drawn from each patient at baseline and at the week 24 visit. Given the variable sampling time for patients in both groups, a population pharmacokinetic analysis using NONMEM was conducted for etanercept. A final covariate population pharmacokinetic model was constructed based on previously obtained etanercept data from both healthy subjects (n = 53) and patients with RA (n = 212) in 10 prior clinical trials. The predictive performance of the final model was assessed by both bootstrap and data-splitting validation approaches. The final model was then used to estimate Bayesian pharmacokinetic parameters for the patients in both treatments in the current trial. The potential effect of the concurrent administration of methotrexate on the pharmacokinetics of etanercept was examined by comparing the clearance values between 2 treatments using statistical criteria. A population 2-compartment model with first-order elimination from the central compartment and with either zero-order (intravenous administration) or first-order (subcutaneous administration) input was selected based on the data from the prior 10 etanercept clinical studies. The following pharmacokinetic parameters (typical value +/- standard error) were estimated: clearance (CL: 0.072 +/- 0.005 L/h), volume of distribution in the central compartment (V(c): 5.97 +/- 0.45 L), volume of distribution in the peripheral compartment (V(p): 2.05 +/- 0.32 L), intercompartment clearance (Q: 0.0645 +/- 0.0093 L/h), first-order absorption rate constant (k(a): 0.0282 +/- 0.0039 1/h), and absolute bioavailability for subcutaneous administration (F: 0.626 +/- 0.056). Interindividual variability of the pharmacokinetic parameters was quantified for CL (25.1%), V(c) (41.7%), k(a) (53.1%), and F (24.2%). Residual variability consisted of combined additive (11.4 ng/mL) and proportional error (49.9%). Both age (< 17 years) and body weight (< 60 kg) were found to be important covariates on CL. The results of both validation tests indicated the adequate predictive performance of the population model. Based on the bioequivalence criteria, the Bayesian-estimated clearance for patients receiving etanercept alone (mean: 0.070 L/h) was comparable to that for patients receiving a combination of etanercept and methotrexate (mean = 0.066 L/h). The pharmacokinetics of etanercept were not altered by the concurrent administration of methotrexate in patients with rheumatoid arthritis. Thus, no etanercept dose adjustment is needed for patients taking concurrent methotrexate.

Pharmacokinetics of gemtuzumab ozogamicin as a single-agent treatment of pediatric patients with refractory or relapsed acute myeloid leukemia.

Gemtuzumab ozogamicin is currently approved to treat CD33-positive acute myeloid leukemia (AML) in first relapse in patients older than age 60 years. The objective of this study was to characterize the pharmacokinetics of gemtuzumab ozogamicin in pediatric patients with relapsed or refractory AML. The study population comprised 29 subjects younger than age 18 with AML in first relapse. Dosages of 6, 7.5, and 9 mg/m(2) were administered during the study. Pharmacokinetic parameters were determined following each dose for hP67.6, total calicheamicin derivatives, and unconjugated calicheamicin derivatives. hP67.6 pharmacokinetic parameters had a consistent and statistically significant change between the first and second doses. Increases in AUC and decreases in both CL and V(ss) from the first dose to the second dose were consistent with those of the adult population. Changes between dose periods for total calicheamicin derivatives and unconjugated calicheamicin derivatives were consistent with those of hP67.6. Changes in pharmacokinetic parameters between dose periods are attributed to saturation of CD33 binding sites and diminished clearance resulting from a lower peripheral blast burden and antigen. Children receiving 9 mg/m(2) had the following hP67.6 pharmacokinetic parameters: C(max), 3.47+/-1.04 mg/L; AUC, 136 +/- 107 mg x h/L; CL, 0.12 +/- 0.15 L/h/m(2); V(ss), 6.5 +/- 5.5 L; and t(1/2), 64 +/- 44 h after their first dose. Mean pharmacokinetic values are similar to values reported in adults. Individual children demonstrated large intersubject variability, similar to adults. The pharmacokinetics of gemtuzumab ozogamicin in pediatric patients closely follow the profile and variability of adult patients.

Oral bioavailability of pantoprazole suspended in sodium bicarbonate solution.

The bioavailability of pantoprazole when administered as a suspension in sodium bicarbonate solution and as the oral tablet was studied. In an open-label, randomized, two-period crossover study, healthy fasting subjects received either one enteric-coated 40-mg pantoprazole tablet by mouth with 240 mL of water or 20 mL of a suspension prepared from one crushed pantoprazole tablet and 840 mg of sodium bicarbonate solution and administered via a nasogastric tube. Treatments were separated by a 48-hour washout period. Blood samples were collected at intervals up to 24 hours after drug administration for measurement of pantoprazole concentration by high-performance liquid chromatography (HPLC) and estimation of pharmacokinetic values. A separate study was conducted to determine pantoprazole's stability in the suspension for up to three months at 25, 5, and -20 degrees C; concentrations were measured by HPLC. Twelve subjects completed the study. The suspension yielded pantoprazole Cmax values similar to those of the tablet formulation, but the drug was 25% less bioavailable. There was no lag time for the suspension. The suspension was stable for up to two weeks at 5 degrees C and up to three months at -20 degrees C. A suspension of pantoprazole in sodium bicarbonate solution yielded a Cmax similar to that of the tablet formulation, and the drug was quickly absorbed. However, bio-availability was slightly lower with the suspension than with the tablet.