Plasma Pharmacokinetic Properties Research Articles

Exploiting the Receptor-Binding Domains of R-Spondin 1 to Target Leucine-Rich Repeat-Containin G-Coupled Protein Receptor 5-Expressing Stem Cells in Ovarian Cancer.

Leucine-rich repeat-containing G-protein-coupled receptor (LGR5) and LGR6 mark epithelial stem cells in normal tissues and tumors. They are expressed by stem cells in the ovarian surface and fallopian tube epithelia from which ovarian cancer arises. High-grade serous ovarian cancer is unique in expressing unusually high levels of LGR5 and LGR6 mRNA. R-spondins are the natural ligands for LGR5 and LGR6 to which they bind with nanomolar affinity. To target stem cells in ovarian cancer, we used the sortase reaction to site-specifically conjugate the potent cytotoxin monomethyl auristatin E (MMAE) via a protease sensitive linker to the two furin-like domains of RSPO1 (Fu1-Fu2) that mediate its binding to LGR5 and LGR6 and their co-receptors Zinc And Ring Finger 3 and Ring Finger Protein 43 via a protease-cleavable linker. An immunoglobulin Fc domain added to the N-terminal end served to dimerize the receptor-binding domains so that each molecule carries two MMAE. The resulting molecule, FcF2-MMAE, demonstrated: 1) selective LGR5-dependent low nanomolar cytotoxicity against ovarian cancer cells in vitro; 2) selectivity that was dependent on binding to both the LGR receptors and ubiquitin ligase co-receptors; 3) favorable stability and plasma pharmacokinetic properties when administered intravenously with an elimination half-life of 29.7 hours; 4) selective inhibition of LGR5-rich as opposed to isogenic LGR5-poor tumors in vivo; and, 5) therapeutic efficacy in three aggressive wild-type human ovarian cancer xenograft models. These results demonstrate the successful use of the Fu1-Fu2 domain of RSPO1 as a drug carrier and the ability of FcF2-MMAE to target cells in tumors that express stem cell markers. SIGNIFICANCE STATEMENT: FcF2-MMAE is a novel cancer therapeutic that exploits the high-affinity binding domains of RSPO1 to target monomethyl auristatin E to tumor stem cells that express LGR5. FcF2-MMAE has low nanomolar LGR5-dependent cytotoxicity in vitro, favorable pharmacokinetics, and differential efficacy in an isogenic LGR5-poor versus LGR5-rich ovarian cancer xenograft model when given on a weekly schedule.

Therapeutic Targeting of Tumor Cells Rich in LGR Stem Cell Receptors.

LGR5 and LGR6 mark epithelial stem cells in many niches including the ovarian surface and fallopian tube epithelia from which ovarian cancer arises. Human ovarian cancers express these receptors at high levels and express one of their ligands, RSPO1, at levels uniquely higher than all other tumor types except mesothelioma. Reasoning that these receptors are also important to tumor stem cells, arming the LGR binding domain of RSPO1 with a cytotoxin may permit depletion of the tumor stem cells. The Fu1-Fu2 receptor binding domain of RSPO1 (R1FF), containing a sortase recognition sequence at the C-terminal end, was produced in bacteria and a single molecule of MMAE was attached to each R1FF through a val-cit-PAB linker using the sortase reaction, thus producing a homogeneous population of armed molecules. R1FF-MMAE demonstrated (1) selective LGR-dependent binding, uptake, and cytotoxicity; (2) low nM cytotoxicity to multiple types of human tumor cell lines in vitro; (3) favorable plasma pharmacokinetic properties when administered iv with an elimination half-life of 27.8 h; (4) favorable absorption from the peritoneal cavity; and (5) therapeutic activity in aggressive xenograft models of ovarian cancer in the absence of any weight loss or other adverse events. These results demonstrate that the Fu1-Fu2 domain of RSPO1 can be exploited to deliver a potent cytotoxin to tumor cells that express the LGR4-6 family of stem cell receptors.

A Phase I Study to Assess the Effect of Speed of Injection on Pain, Tolerability, and Pharmacokinetics After High-volume Subcutaneous Administration of Gantenerumab in Healthy Volunteers

PurposeGantenerumab, a fully human anti–amyloid-β IgG1 monoclonal antibody that binds to aggregated forms of amyloid-β, is being investigated as a potential disease-modifying treatment for early (prodromal to mild) Alzheimer disease (AD). Our study compared the pain associated with 5- and 15-s subcutaneous injections of gantenerumab and evaluated the tolerability and pharmacokinetic properties of subcutaneous gantenerumab. MethodsThis randomized, open-label, single-active-dose, placebo-controlled crossover study was conducted in 50 healthy volunteers aged 40–80 years with no history of clinically significant disorders, drug or alcohol abuse, familial history of early-onset AD, or prior gantenerumab exposure. Eligible participants were randomized to a sequence of one 300-mg SC gantenerumab injection into the abdomen and 2 SC placebo injections (1 into the abdomen and 1 into the thigh) during 5 or 15 s. All injections were administered at least 90 min apart. Participants were assessed for local pain by visual analog scale (VAS) and verbal rating scale; safety profiles were assessed by recording adverse events (AEs), and plasma pharmacokinetic properties were also evaluated. FindingsImmediately after the subcutaneous gantenerumab injection, the pain VAS score was numerically higher without reaching statistical significance in the 5-s versus 15-s injection group (VAS least-squares mean difference, 7.492 mm; 95% CI, −4.439–19.423 mm). In both injection speed groups, the mean pain VAS score was comparable after subcutaneous gantenerumab and placebo injections into the abdomen. Pain was reported after needle insertion and immediately after dosing, subsiding within 5 min after the dose. The pain VAS score was numerically higher after SC placebo injection into the thigh versus abdomen (5-s injection group: mean [SD] VAS score, 26.68 [27.83] vs 19.20 [25.60] mm; 15-s injection group: mean [SD] VAS score, 14.16 [20.62] vs 9.48 [12.04] mm). No serious AEs were reported; no participants withdrew because of an AE. All AEs were of mild intensity, were transient, and had resolved without sequelae at follow-up. The most common AEs were injection site reactions; redness was the most frequently observed skin reactivity event after subcutaneous gantenerumab administration (5-s injection group: 36%; 15-s injection group: 32%). After subcutaneous administration, gantenerumab reached a peak plasma concentration at a median time of 119 h (approximately 5 days); plasma concentrations declined in a monoexponential manner. Comparable pharmacokinetic profiles were observed between the injection speed groups. ImplicationsSubcutaneous gantenerumab injections at speeds of 5 and 15 s were well tolerated in healthy volunteers and could enable at-home administration by patients with AD or their caregivers. ClinicalTrials.gov identifier: NCT02882009.

Double PEGylation Significantly Improves Pharmacokinetic Properties of Irinotecan Containing Nanoparticles in a Zebrafish Model

Background: Plasma pharmacokinetic (PK) properties of oral or injectable drugs dictate whether the drug is clinically viable or not. Poor PK properties often result in termination of the development of the drug. Optimizing PK properties of drugs is a major challenge in the pharmaceutical industry. Ideally, sufficient circulating time of the drug in the plasma is required, so that it has adequate opportunity to reach the target tissue. Methods: We have used irinotecan, a known drug with poor PK properties, as a prototype to apply our idea of improving PK in plasma by PEGylation. We compared the PK profile of free irinotecan, irinotecan packaged in nanoparticles (NPs) with single polyethylene glycol (PEG) layer and irinotecan packaged in NPs with double PEG layer. PK properties of these formulations were compared in a zebrafish model when given intraperitoneally. Results: Dramatic differences in the PK properties of the three formulations were observed. The AUC, Cmax and T1/2 of irinotecan in each of these formulations differed from each other significantly. Approx. 4.5 - fold higher peak concentration (Cmax) and ~3 - fold higher exposure (AUC0-t) were observed for double PEGylated NPs as compared to free irinotecan and single PEGylated NPs. Conclusion: In summary, our data suggest that double PEGylation of NPs could be a very effective way to improve PK properties of drugs such as irinotecan.

Effect of Cefiderocol, a Siderophore Cephalosporin, on QT/QTc Interval in Healthy Adult Subjects

PurposeCefiderocol is a novel siderophore cephalosporin with potent activity against gram-negative bacteria, including multidrug-resistant strains. This Phase I study was conducted to assess the tolerability of single-ascending doses of cefiderocol (part 1) and the effect of cefiderocol on cardiac repolarization, assessed using the electrocardiographic corrected QT interval (QTcF) and other ECG parameters (part 2), in healthy adult subjects. MethodsPart 1 was a randomized, double-blind, placebo-controlled, single-ascending dose study in healthy adult male and female subjects. Part 2 was a 4-period crossover study in which subjects received a single 2-g dose of cefiderocol (therapeutic dose), a single 4-g dose of cefiderocol (supratherapeutic dose), or saline (placebo), each infused over 3 hours, and a single oral 400-mg dose of moxifloxacin. In each treatment period, continuous cardiac monitoring was used to assess the effects of cefiderocol on ECG parameters. The QT interval corrected using the Fridericia formula (QTcF) was the primary ECG parameter; the time-matched placebo- and baseline-adjusted (dd)-QTcF interval was the primary end point. The plasma pharmacokinetic properties of cefiderocol were calculated on the basis of concentration–time profiles in all evaluable subjects. FindingsAll point estimates for the ddQTcF interval were <5 ms and the upper bound of the 90% CIs were <10 ms at each timepoint after the initiation of the cefiderocol 3-hour infusion. Concentration-effect modeling showed a slightly negative slope and predicted modestly negative values of the ddQTcF interval at the Cmax of cefiderocol. Both doses of cefiderocol were well tolerated. All adverse events were mild in severity, with no deaths or serious adverse events reported. ImplicationsOverall, therapeutic and supratherapeutic doses of cefiderocol had no apparent clinically significant effect on the QTcF.

Pharmacokinetic study of single- and multiple-dosing with metolazone tablets in healthy Chinese population

BackgroundMetolazone is a diuretic, saluretic and antihypertensive chemical compound from the quinazoline category that possesses medicinal features similar to those of other thiazide diuretic drugs. However, the pharmacokinetics of metolazone in the Chinese population has rarely been studied.This study aimed to examine the pharmacokinetic characteristics, safety characteristic, and tolerability of metolazone in healthy Chinese subjects after single and multiple doses taken orally as well as the effects that food and gender have on oral metolazone pharmacokinetic parameters.MethodsAn open-label, randomized, and single- and multiple-dosing investigation was performed in healthy Chinese subjects. The investigation included 3 study groups: the 0.5 mg, 1 mg and 2 mg dose groups were the single-dose study groups in the first stage. Eligible volunteers were randomly and orally administered a single 0.5 mg, 1 mg, or 2 mg metolazone tablet. The 0.5 mg dose group was also part of the multiple-dose study group, and the 1 mg dose group was the food-effect study group in the second stage. Human plasma samples were gathered pre-dosing and up to 48 h after dosing. The human plasma sample concentration of metolazone was quantified using a validated liquid chromatography tandem mass spectrometry method. Pharmacokinetic data were calculated by a noncompartmental analysis method using WinNonlin version 6.4. Tolerability was evaluated based on adverse events, medical examination, 12-lead ECG, and other clinical laboratory exams.ResultsThirty eligible subjects (15 men and 15 women) were registered in our investigation and completed all of the study stages. The AUC and Cmax showed dose proportionality after a single dose based on the linear-regression analysis. A comparison of the pharmacokinetic data revealed that the differences between the male and female groups were not statistically significant. The tmax of metolazone was increased by approximately 100% in the fed condition. Metolazone was well tolerated at the tested dose, and no adverse effects were observed.ConclusionsSingle dosing with 0.5 mg, 1 mg, or 2 mg metolazone yielded linear plasma pharmacokinetic properties in healthy Chinese subjects. Multiple oral doses of metolazone did not display significantly different distributions or elimination characteristics from those observed for a single dose. Gender factors did not appear to influence the pharmacokinetic parameter variation of metolazone. The tmax of metolazone increased in the fed condition. Metolazone was well tolerated at the tested dose in this study.Trial registrationThis investigation is retrospectively registered at chictr.org.cn (ChiCTR-IIR-17012929, October 09 2017).

Pharmacokinetic Properties of Single- and Multiple-Dose Pitavastatin Calcium Tablets in Healthy Chinese Volunteers

BackgroundPitavastatin is a newly developed 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor approved for the treatment of hyperlipidemia. Pharmacokinetic properties of pitavastatin have been studied previously. ObjectiveTo investigate the pharmacokinetic properties of pitavastatin in healthy Chinese volunteers after single-dose and multiple-dose administration. MethodsAn open-label, randomized, single-dose and multiple-dose study was conducted in healthy Chinese volunteers. The study included 4 stages, each separated with a 5-day washout period. A randomized, 3-way crossover design was carried out in Stages 1 to 3 for the single-dose study. Eligible subjects were randomized to receive a single 1 mg, 2 mg, or 4 mg pitavastatin calcium tablet. Blood samples were obtained predose and up to 36 hours following dosing. In Stage 4 the subjects received a 2-mg pitavastatin calcium tablet once daily for 6 days. At the last day of multiple dosing, blood samples were collected predose and up to 48 hours following dosing. Plasma pitavastatin was quantified by a validated liquid chromatography tandem mass spectrometry method. Tolerability was assessed by the adverse events, physical examination, 12-lead ECG, and laboratory tests. ResultsTwelve volunteers (6 male and 6 female) were enrolled in the study and 11 of them completed all 4 study stages. Following a single dose of 1 mg, 2 mg, and 4 mg, the mean (SD) Tmax values were 0.63 (0.17) hours, 0.65 (0.17) hours, and 0.79 (0.36) hours, respectively; the corresponding Cmax values were 66.80 (16.32) ng/mL, 106.09 (31.59) ng/mL, and 232.91 (66.42) ng/mL, respectively. AUC0−36 values were 190.04 (38.97) ng/mL/h, 307.87 (57.94) ng/mL/h, and 785.10 (166.08) ng/mL/h, respectively, whereas t1/2 values were 10.99 (2.70) hours, 9.52 (2.58) hours, and 10.38 (4.28) hours, respectively. The AUC and Cmax showed dose proportionality after single dosing according to linear-regression analysis. In the multiple-dose study, a rapid absorption (Tmax of 0.68 [0.20] hours) and marked peak concentration of 90.99 (36.88) ng/mL were observed. AUC0−48 and AUCss were 306.28 (130.02) ng/mL/h and 256.16 (116.34) ng/mL/h, respectively. The elimination half-life after multiple dosing was significantly prolonged, which amounted to 13.31 (2.58) hours. Comparison of the pharmacokinetic parameters between the male and female groups revealed no significant differences. ConclusionsIn healthy Chinese volunteers, single dosing of 1 mg, 2 mg, and 4 mg pitavastatin resulted in linear plasma pharmacokinetic properties. Compared with single dosing, multiple dosing of pitavastatin showed different distribution and elimination characteristics. Sex did not appear to affect the pharmacokinetic properties of pitavastatin. Chictr.org identifier: ChiCTR-OO-13004294.

Renal tubular secretion of tanshinol: molecular mechanisms, impact on its systemic exposure, and propensity for dose-related nephrotoxicity and for renal herb-drug interactions.

Tanshinol has desirable antianginal and pharmacokinetic properties and is a key compound of Salvia miltiorrhiza roots (Danshen). It is extensively cleared by renal excretion. This study was designed to elucidate the mechanism underlying renal tubular secretion of tanshinol and to compare different ways to manipulate systemic exposure to the compound. Cellular uptake of tanshinol was mediated by human organic anion transporter 1 (OAT1) (Km, 121 μM), OAT2 (859 μM), OAT3 (1888 μM), and OAT4 (1880 μM) and rat Oat1 (117 µM), Oat2 (1207 μM), and Oat3 (1498 μM). Other renal transporters (human organic anion-transporting polypeptide 4C1 [OATP4C1], organic cation transporter 2 [OCT2], carnitine/organic cation transporter 1 [OCTN1], multidrug and toxin extrusion protein 1 [MATE1], MATE2-K, multidrug resistance-associated protein 2 [MRP2], MRP4, and breast cancer resistance protein [BCRP], and rat Oct1, Oct2, Octn1, Octn2, Mate1, Mrp2, Mrp4, and Bcrp) showed either ambiguous ability to transport tanshinol or no transport activity. Rats may be a useful model, to investigate the contribution of the renal transporters on the systemic and renal exposure to tanshinol. Probenecid-induced impairment of tubular secretion resulted in a 3- to 5-fold increase in the rat plasma area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) of tanshinol. Tanshinol exhibited linear plasma pharmacokinetic properties over a large intravenous dose range (2-200 mg/kg) in rats. The dosage adjustment could result in increases in the plasma AUC0-∞ of tanshinol of about 100-fold. Tanshinol exhibited very little dose-related nephrotoxicity. In summary, renal tubular secretion of tanshinol consists of uptake from blood, primarily by OAT1/Oat1, and the subsequent luminal efflux into urine mainly by passive diffusion. Dosage adjustment appears to be an efficient and safe way to manipulate systemic exposure to tanshinol. Tanshinol shows low propensity to cause renal transporter-mediated herb-drug interactions.

Effects of Moderate Hepatic Impairment on the Pharmacokinetic Properties and Tolerability of Umeclidinium and Vilanterol in Inhalational Umeclidinium Monotherapy and Umeclidinium/Vilanterol Combination Therapy: An Open-Label, Nonrandomized Study

BackgroundThe long-acting muscarinic antagonist umeclidinium (UMEC) is approved as a monotherapy, and in combination with the long-acting β2-agonist vilanterol (VI), as a once-daily inhaled maintenance bronchodilator therapy for chronic obstructive pulmonary disease in the US and EU; they are not indicated for the treatment of asthma. Preclinical and clinical data suggest that UMEC and VI are predominantly eliminated by the liver. ObjectivesThe objectives of the study were to evaluate the effects of moderate hepatic impairment on the plasma and urinary pharmacokinetic properties of each drug, and on the tolerability of inhalational UMEC/VI 125/25 µg and UMEC 125 µg. MethodsThis open-label, nonrandomized study was conducted in patients with moderate hepatic impairment (Child-Pugh score, 7–9) and in healthy volunteers (control). Patients and volunteers were administered a single dose of UMEC/VI 125/25 µg, and, after a 7- to 14-day washout period, repeat-dose UMEC 125 µg once daily for 7 days. Primary end points were the plasma pharmacokinetic properties of single- and repeat-dose UMEC and VI. Secondary end points were the urinary pharmacokinetic properties of UMEC, and the tolerability of each treatment. ResultsAll 18 enrolled patients and volunteers (12 men, 6 women; mean age, 53.6 years) completed the study. Mean systemic exposures of UMEC and VI were similar or numerically lower in patients with moderate hepatic impairment compared with those in healthy volunteers, but the differences were not clinically significant. UMEC accumulations with 7-day dosing of UMEC were similar between patients with moderate hepatic impairment and healthy volunteers. UMEC/VI 125/25 µg and UMEC 125 µg were well-tolerated, with no safety concerns identified. ConclusionsThe administration of UMEC/VI 125/25 µg or UMEC 125 µg in patients with moderate hepatic impairment did not result in clinically relevant increases in UMEC or VI exposures compared with those in healthy volunteers. Based on these findings, no dose adjustment for UMEC/VI or UMEC is warranted in patients with moderate hepatic impairment.

Prediction of Human Pharmacokinetics from Preclinical Information of Rhein, an Antidiabetic Nephropathy Drug, Using a Physiologically Based Pharmacokinetic Model

The aim of the study was to develop a physiologically based pharmacokinetic (PBPK) model of rhein to predict human pharmacokinetics before dosing for the first time in human beings. After oral administration of rhein at the doses of 35, 70 and 140 mg/kg in rat, rhein had the following mean plasma pharmacokinetic properties: t1/2 of 3.2, 3.6 and 4.3 hr, AUC∞ of 69.5, 164.3 and 237.8 μg/h/ml and CL/F of 503.4, 426.1 and 588.8 ml/hr/kg, respectively. In vitro, the intrinsic clearance (Clint ) of rhein in cytochrome P450 (CYP450), UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) metabolism of rat was 0.6, 7.8, and 5.5 μl/min/mg protein, respectively. The Clint of rhein in CYP450, UGT and SULT of human beings was 0.10, 1.36 and 0.68 μl/min/mg protein. The rat pharmacokinetics and the metabolism data in vitro were used to construct the PBPK model of rhein, and the observed plasma drug concentration profiles of rhein in rat were validated by a PBPK model. Subsequently, the plasma drug concentration profiles of human beings by the present PBPK model were validated by experimental data in human beings accurately.

Parenteral nanosuspension of a novel synthesized antitumor candidate: Investigation of tissue biodistributions and plasma pharmacokinetics

Previously, nanosuspension of a novel synthesized p-terphenyl derivative (H2, ) with a mean particle size of 201.7±5.87nm was prepared using precipitation–microfluidization method. Enhanced saturation solubility and accelerated dissolution velocity were achieved. The objectives of this current study were to investigate the tissue biodistribution and plasma pharmacokinetic properties of H2 nanosuspension comparing with that of H2 solution after intravenously administration to mice. In an attempt to ensure the drug content accuracy during the animal tests, chemical stability of H2 nanosuspension was also monitored over a 1 month period. As shown in the plasma concentration–time profiles, drug nanosuspensions were effective in increasing the plasma level of H2 compared to drug solution. In particular, the initial concentration of H2 administered as nanosuspension and solution were 13.05μg/mL and 5.54μg/mL, respectively. What's more, compared with H2 solution, nanosuspension significantly changed drug biodistribution features in tissues, relatively increased drug concentration in liver and lung, and decreased that in other tissues.

Relationships between pharmacokinetics and efficacy of Xie-xin decoction in rats with experimental ulcerative colitis

Ethnopharmacological relevanceXie-xin decoction (XXD) has been used as a classic formula in China for the treatment of gastrointestinal dysfunction such as ulcerative colitis (UC). However, no potential action mechanisms and active compounds had been systematically investigated. Aim of the studyTo explore the effectiveness and the material basis of XXD in trinitrobenzene sulfonic acid (TNBS)-induced UC rats. Materials and methodsXXD was administered orally for 8 days at a dosage of 2 or 4g/kg/day. Plasma pharmacokinetic properties and colon tissue concentrations of multiple compounds from XXD were detected. Tissue damage scores, production of interleukin (IL)-10 and myeloperoxidase (MPO), expression of tumor necrosis factor-alpha (TNF-α) and nuclear factor-kappa Bp65 (NF-κBp65) in colon tissues were examined. Canonical correlation analysis was performed to evaluate the relationships between pharmacokinetics and efficacy to elucidate significantly active compounds of XXD. ResultsXXD promoted the recovery of colitis and inhibited the colonic inflammation damage in UC rats by reducing the level of MPO and the expression of TNF-α and NF-κBp65, and increasing the production of IL-10 in colon tissues. Efficacy of XXD was positively related with AUC of five plasma compounds (baicalin, berberine, wogonoside, wogonin, and rhein) and concentrations of six colon tissue compounds (coptisine, jatrorrhizine, palmatine, berberine, baicalein and emodin), respectively. ConclusionsThe multiple compounds in plasma and colon tissues from XXD might be the main material basis for therapeutic potentials in UC rats.

Pharmacokinetic study of inosiplex tablets in healthy Chinese volunteers by hyphenated HPLC and tandem MS techniques

Inosiplex is a compound formulation composed of inosine and p-acetaminobenzoic acid (PABA) salt of N,N-dimethylamino-2-propanol (DIP). This study was to investigate the clinical plasma pharmacokinetic properties of DIP and PABA after single and multiple oral doses of inosiplex tablets in healthy Chinese volunteers. The established LC/MS/MS method for plasma DIP determination had a linear range of 0.02–10µg/mL, and the HPLC method for plasma PABA determination had a linear range of 0.05–40µg/mL. Linear pharmacokinetic characteristics were found with single oral doses of 0.5, 1.0 and 2.0g. No obvious accumulation effects were observed for DIP and PABA.

Randomized, Open-Label, Single-Dose, Crossover, Relative Bioavailability Study in Healthy Adults, Comparing the Pharmacokinetics of Rabeprazole Granules Administered Using Soft Food or Infant Formula as Dosing Vehicle Versus Suspension

BackgroundA sprinkle capsule formulation containing enteric-coated, delayed-release rabeprazole granules is being developed for the treatment of children with gastrointestinal reflux disease. The granules are designed to be mixed with vehicles that facilitate delivery to children, who may be unable to swallow solid formulations. ObjectiveThe primary objective of this study—conducted on the sponsor's initiative—was to compare the bioavailability of rabeprazole granules when mixed with various dosing vehicles (small amount of soft food or infant formula) with that of a rabeprazole suspension with inactive vehicle granules (reference), to determine which dosing vehicle can be used to deliver rabeprazole in children. Tolerability was also assessed. MethodsThis single-center, single-dose, randomized, open-label, 5-period crossover study was conducted in 35 healthy adult subjects. In a randomized sequence, fasting subjects received a single dose of 10-mg rabeprazole granules per treatment period, mixed with small amounts of 1 of 5 dosing vehicles (a strawberry-flavored suspension of rabeprazole granules with inactive vehicle granules reconstituted with water, yogurt [1 tablespoon], applesauce [1 tablespoon], or infant formula [5 mL], or a suspension of rabeprazole granules with inactive vehicle tablet reconstituted with water). Full plasma pharmacokinetic (PK) profiles of rabeprazole and its thioether metabolite were collected; concentrations were estimated via LC-MS/MS. PK properties were estimated using noncompartmental methods; 90% CIs around least squares mean test-to-reference ratios were calculated for Cmax and AUC values. All treatment-emergent adverse events (TEAEs) were recorded and assessed for severity (mild, moderate, or severe) and relationship to study drug. ResultsA total of 35 subjects were enrolled (mean age, 38 years; 54.3% female; 100% white; mean weight, 71.4 kg). Thirty-four subjects completed the study. Rabeprazole and rabeprazole thioether plasma PK properties were comparable between all of the dosing vehicles tested. Median Tmax was 2.5 to 3.0 hours, and mean elimination half-life was 1.27 to 1.43 hours. The 90%CIs for the least squares mean ratios for rabeprazole and rabeprazole thioether exposure were within the 80% to 125% bioequivalence limits for all relevant comparisons. All TEAEs were of mild or moderate intensity, with headache being the most commonly reported; 21 subjects (60%) experienced TEAEs during the study. No deaths or serious AEs were reported during the study; 1 subject experienced a TEAE (urinary tract infection) that led to the discontinuation of treatment. ConclusionIn these healthy adult subjects, the bioavailability of rabeprazole granules was comparable between all of the dosing vehicles tested, and rabeprazole was well tolerated. Soft food suitable for young children or infant formula may be appropriate for use as dosing vehicles for rabeprazole granules. ClinicalTrials.gov identifier: NCT01186497.

BEHAVIOURAL AND PHARMACOKINETIC STUDIES IN THE MONKEY (Macaca mulatta) WITH DIAZEPAM, NORDIAZEPAM AND RELATED 1,4‐BENZODIAZEPINES

1. Behavioural activity (delayed differentiation and spatial delayed alternation) and pharmacokinetics of diazepam and its metabolites, N-desmethyldiazepam (nordiazepam), 3-hydroxydiazepam (temazepam) and 3-hydroxy-N-desmethyldiazepam (oxazepam), and of dipotassium clorazepate (clorazepate), were studied in the monkey (Macaca mulatta). Diazepam and its metabolites (1.8 and 3.0 mg/kg) and clorazepate (2.6 and 4.3 mg/kg) were given by intraperitoneal injection. 2. Hydroxylation of diazepam (temazepam and oxazepam) led to a loss of, or a considerable reduction in, behavioural activity, whereas activity was preserved, though modified, by demethylation (nordiazepam). It was not possible to establish change in behaviour at specific time intervals after clorazepate, but combined performance data revealed an effect. 3. The maximum mean plasma concentrations of diazepam, temazepam, oxazepam and clorazepate were observed at 0.5 h, and the maximum mean plasma concentration of nordiazepam was observed at 1 hour. Plasma concentrations of nordiazepam were the highest and decreased monoexponentially. Plasma concenqrations of the other drugs declined rapidly at first but more slowly later, and these data were analysed as biexponential models. In the analysis for metabolites, nordiazepam reached measurable levels after the injection of diazepam and clorazepate. 4. It is suggested that differences in the effects of closely related benzodiazepines may not be due solely to their plasma pharmacokinetic properties, but may arise from differences in their intrinsic activity.