Josephine Lim

Pharmacokinetics, safety, and tolerability of oral posaconazole administered in single and multiple doses in healthy adults.

ABSTRACT The pharmacokinetics, safety, and tolerability of posaconazole, an investigational triazole antifungal, were evaluated following the administration of rising single and multiple oral doses. A total of 103 healthy adults were enrolled in two phase I trials. Each study had a double-blind, placebo-controlled, parallel-group design with a rising single-dose (RSD) or rising multiple-dose (RMD) scheme. In the RSD study, subjects received single doses of posaconazole oral tablets (50 to 1,200 mg) or placebo. In the RMD study, subjects received posaconazole oral tablets (50 to 400 mg) or placebo twice daily for 14 days. By using model-independent methods, the area under the plasma concentration-time curve and the maximum concentration in plasma were determined and used to assess dose proportionality. In the RSD study, the levels of posaconazole in plasma increased proportionally between the 50- and 800-mg dose range, with saturation of absorption occurring above 800 mg. Dose proportionality was also observed in the RMD study. In both studies, the apparent volume of distribution was large (range, 343 to 1,341 liters) and the terminal-phase half-life was long (range, 25 to 31 h). Posaconazole was well tolerated at all dose levels, and the adverse events were not dose dependent. No clinically significant changes in clinical laboratory test values or electrocardiograms were observed. Following the administration of single and twice-daily rising doses, the level of posaconazole exposure increased in a dose-proportional manner. The long elimination-phase half-life of posaconazole supports once- or twice-daily dosing in clinical trials; however, additional studies are required to determine if further division of the dose will enhance exposure.

Oral bioavailability of posaconazole in fasted healthy subjects: comparison between three regimens and basis for clinical dosage recommendations.

Background and objectivePosaconazole is a potent, extended-spectrum triazole antifungal agent currently in clinical development for the treatment of invasive fungal infections. This study was conducted to compare the bioavailability and resulting serum concentrations of posaconazole 800mg following administration of three different dose regimens to fasting adults.Study designThis was a randomised, open-label, three-way crossover study.MethodsSubjects fasted 12 hours before and 48 hours after the administration of posaconazole oral suspension (800mg) given as a single dose (regimen A), 400mg every 12 hours (regimen B) or 200mg every 6 hours (regimen C). Plasma posaconazole concentrations were determined for 48 hours after the initial dose and subjects completed a 1-week washout period between treatment regimens. A one-compartment oral model with first-order rate of absorption and first-order rate of elimination was fitted to the plasma concentration-time data. Differences in exposure were investigated by allowing the bioavailability fraction to vary among regimens.Study participantsA total of 18 healthy men were enrolled in and completed the study.Main outcome measures and resultsPosaconazole relative bioavailability was estimated to be significantly different among regimens (p < 0.0001) and increased with the number of doses, such that regimen B/regimen A = 1.98 ± 0.35, representing a 98% increase, and regimen C/regimen A = 3.20 ± 0.69, or a 220% increase. With use of the one-compartment model, the population steady-state values for area under the concentration-time curve over 24 hours were predicted to be 3900, 7700 and 12 400 μg · h/L, with average plasma concentrations of 162, 320 and 517 μg/L for regimens and C, respectively.ConclusionThese data suggest that divided daily dose administration (every 12 or 6 hours) significantly increases posaconazole exposure under fasted conditions.

Pharmacokinetics of Posaconazole Coadministered with Antacid in Fasting or Nonfasting Healthy Men

ABSTRACT Posaconazole is a potent broad-spectrum azole antifungal agent in clinical development for the treatment of invasive fungal infections. This study evaluated the potential for a pH-dependent pharmacokinetic interaction between posaconazole and an antacid (Mylanta), under fasting and nonfasting conditions. Twelve men completed this randomized, four-period crossover, single-dose study. Subjects received 200 mg of posaconazole following a 10-h fast, with 20 ml of Mylanta and a 10-h fast, with 20 ml of Mylanta and a high-fat breakfast, and with a high-fat breakfast alone. Antacid coadministration had no statistically significant effects on posaconazole bioavailability under fasting or nonfasting conditions. In the fasting state, antacid slightly increased the relative oral bioavailability of posaconazole by 15% (P = 0.296); in the nonfasting state, antacid decreased the relative bioavailability of posaconazole by 12% (P = 0.352). Food increased the relative oral bioavailability of posaconazole by 400% (P = 0.001). In conclusion, the effect of antacid on posaconazole exposure in the fasting or nonfasting state was small and is not considered clinically significant.

Bioavailability and Metabolism of Mometasone Furoate following Administration by Metered‐Dose and Dry‐Powder Inhalers in Healthy Human Volunteers

These studies were conducted to assess the systemic bioavailability of mometasone furoate (MF) administered by both the dry‐powder inhaler (DPI) and the metered‐dose inhaler with an alternate propellant (MDI‐AP). The pharmacokinetics of single doses (400 μg) of MF administered by intravenous (IV) and inhalation routes was assessed in a randomized, three‐way crossover study involving 24 healthy volunteers. In a separate study, 6 healthy subjects were administered a single dose of tritiated (3H‐) MF by DPI, and the radioactivity in blood, urine, feces, and expired air was determined. Following IV administration, MF was detected in all subjects for at least 8 hours postdose. The half‐life (t1/2) following IV administration was 4.5 hours. In contrast, following DPI administration, plasma MF concentrations were below the limit of quantification (LOQ, 50 pg/mL) for many subjects (10 of 24), and the systemic bioavailability by this route was estimated to be less than 1%. Only two plasma samples following MDI‐AP administration had plasma concentrations of MF above the LOQ, indicating no detectable systemic bioavailability in 92% of the subjects. A separate study with 6 healthy male subjects administered a single dose of3H‐MF (200 μCi) by DPI revealed that much of the dose (∼ 41%) was excreted unchanged in the feces (0–72 hours), while that which was absorbed was extensively metabolized. These results indicate that inhaled MF has negligible systemic bioavailability and is extensively metabolized and should therefore be well tolerated in the chronic treatment of asthma.

Grapefruit Juice Reduces the Oral Bioavailability of Fexofenadine But Not Desloratadine

BackgroundCertain foods, such as grapefruit juice, are known to substantially alter the bioavailability of some drugs. These effects may be mediated by interactions with enzyme systems, such as cytochrome P450, or with active transporter systems, such as P-glycoprotein and organic anion transporting polypeptides.ObjectiveTo assess the effect of consumption of grapefruit juice on the oral bioavailability of two nonsedating antihistamines, fexofenadine and desloratadine.DesignNon-blinded, randomised, single-dose, four-way crossover study.ParticipantsTwenty-four healthy adult volunteers.InterventionsSingle oral doses of desloratadine 5mg and fexofenadine 60mg taken without and with grapefruit juice (pretreatment with 240ml of double-strength juice three times daily for 2 days prior to administration of study drug, plus the same amount simultaneously with, and 2 hours after, the drug dose). Each treatment was separated by at least 10 days.Main Outcome MeasuresLog-transformed pharmacokinetic parameters [peak plasma concentration (Cmax) and area under the curve (AUC)], time to maximum concentration, elimination half-life and electrocardiographic (ECG) parameters.ResultsComparing the ratio of the pharmacokinetic parameter means (Cmax and AUC) with and without grapefruit juice (expressed as a percentage), the rate (Cmax) and extent (AUC) of absorption of fexofenadine were reduced by 30% by consumption of grapefruit juice. In contrast, the bioavailability of desloratadine was unaffected by grapefruit juice. No clinically significant changes in ECG parameters were observed following coadministration of grapefruit juice with desloratadine or fexofenadine compared with either antihistamine given alone.ConclusionThe bioavailability of drugs that do not undergo significant intestinal or hepatic metabolism, such as fexofenadine, may be altered when administered with agents that influence drug transport mechanisms.

High-performance liquid chromatographic determination and stability of 5-(3-methyltriazen-1-yl)-imidazo-4-carboximide, the biologically active product of the antitumor agent temozolomide, in human plasma

5-(3-Methyltriazen-1-yl)-imidazo-4-carboximide (MTIC) is a highly unstable compound which is believed to be the biologically active degradation product of the antitumor agent temozolomide. An HPLC method has been developed and validated for the analysis of MTIC in human plasma. Because of the instability of MTIC, sample processing was kept to minimal. The method involved precipitation of plasma protein with methanol followed by analysis of the supernatant using reversed-phase column and UV detection at 316 nm. The linearity (r>0.99), precision (C.V.<9%) and accuracy (bias<5%) were satisfactory. The lower limit of quantitation (LOQ) was 10 ng/ml. The recovery of MTIC and internal standard was > or = 86.7%. MTIC was stable in plasma though three freeze-thaw cycles, and was stable at 4 degrees C for 1 h and at -80 degrees C for at least 70 days. MTIC may be unstable at 10 degrees C in processed samples; therefore, samples were placed in the autosampler (10 degrees C) immediately prior to injection. By using this analytical method, MTIC was quantified in plasma of cancer patients (n=12) within 0.25-12 h after oral administration of temozolomide at 150 mg/m2. The mean maximum plasma concentration (Cmax) was 211 ng/ml which was observed at a mean Tmax of 1.88 h post dose. MTIC disappeared rapidly from plasma with an apparent in vivo half-life (t1/2) of 1.9 h similar to that of temozolomide. Following in vitro incubation of MTIC in human plasma at 25 degrees C, MTIC disappearance was bioexponential with estimated t1/2 values of 25 and 60 min for the first and second phases, respectively. Therefore, the elimination t1/2 of MTIC in human in vivo (1.9 h) was controlled by the rate of its formation from temozolomide.

Use of high-performance liquid chromatographic and microbiological analyses for evaluating the presence or absence of active metabolites of the antifungal posaconazole in human plasma.

Posaconazole (SCH 56592) is a novel broad spectrum triazole antifungal agent that is currently in phase III clinical trials for the treatment of systemic fungal infections. This study was initiated to determine if orally administered posaconazole to humans would result in the formation of active metabolite(s). Plasma samples from a multiple-rising dose study in healthy volunteers were analyzed by validated HPLC and microbiological methods. The HPLC analysis involved extraction with a mixture of organic solvent (methylene chloride-hexane) followed by separation on a C18 column and quantification by UV absorbance at 262 nm. The microbiological assay was performed utilizing an agar diffusion method using Candida pseudorropicalis ATCC 46764 as the test organism. Potency was determined by comparing the growth inhibition zones produced by the test sample to those produced by standard concentrations prepared in plasma. Individual and mean plasma concentration-time profiles were similar for both HPLC and microbiological assays. The area under the plasma concentration-time curves of the microbiological and HPLC results were similar with a mean (RSD) ratio of 105.5% 15.3%), indicating that there was no relevant biologically active metabolite of posaconazole in human plasma.

Pharmacokinetics of loratadine and pseudoephedrine following single and multiple doses of once- versus twice-daily combination tablet formulations in healthy adult males.

The pharmacokinetic profiles of single and multiple doses of loratadine, descarboethoxyloratadine (DCL) (the major active metabolite of loratadine), and pseudoephedrine were determined in a randomized, open-label, two-way crossover study in 24 healthy men. Subjects received a single dose (day 1) and multiple doses (days 3 to 10) of a once-daily (QD) formulation of loratadine 10 mg in an immediate-release coating and pseudoephedrine sulfate 240 mg in an extended-release core (CLAR-ITIN-D 24 HOUR tablets), and a twice-daily (BID) formulation of loratadine 5 mg in an immediate-release coating and pseudoephedrine sulfate 120 mg, with 60 mg in an immediate-release coating and 60 mg in the barrier-protected core (CLARITIN-D 12 HOUR tablets) in study sessions, each separated by a 10-day washout period. Both regimens were safe and well tolerated. On day 1, plasma loratadine, DCL, and pseudoephedrine concentrations were higher following the QD formulation than following the BID formulation, as expected. On day 10, loratadine and DCL maximum plasma concentration (Cmax) values were, on average, 87% and 35% higher, respectively, for the QD formulation than for the BID formulation; however, the values of the area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24) for loratadine and DCL were equivalent (90% confidence interval [CI]: 83% to 110% for loratadine; 90% to 107% for DCL). On day 10, pseudoephedrine Cmax and AUC0-24 values were equivalent (90% CI for Cmax: 94% to 109%; for AUC: 91% to 106%) for the two formulations, and lower pseudoephedrine concentrations were observed from 16 to 24 hours with the QD formulation. Both loratadine/pseudoephedrine formulations produced equivalent loratadine and DCL AUC0-24 values and equivalent pseudoephedrine Cmax and AUC0-24 values following multiple dosing. The lower pseudoephedrine concentrations in the evening with the QD formulation may minimize the potential for insomnia in patients when compared with the BID formulation.

Effect of Felbamate on the Pharmacokinetics of Lamotrigine

To assess the possible interaction between lamotrigine and felbamate, a double‐blind, randomized, placebo‐controlled, two‐way crossover study was conducted in 21 healthy male volunteers. Volunteers were given lamotrigine (100 mg every 12 hours) and felbamate (1,200 mg every 12 hours) or matching placebo for 10 days during each period of the crossover. After morning administration on day 10, blood samples were obtained over 12 hours for measurement of lamotrigine. Felbamate increased the maximum concentration (Cmax) and and area under the concentration‐time curve from time 0 to 12 hours (AUC0–12) of lamotrigine by 13% and 14%, respectively, compared with placebo. The 90% confidence intervals of the log‐transformed pharmacokinetic parameters were within the 80–125% bioequivalence limits, however. Felbamate had no significant effect on the urinary excretion of lamotrigine (total), unconjugated lamotrigine, or the N‐glucuronide. One volunteer discontinued the study after developing a rash while taking lamotrigine and placebo. All other adverse events were primarily related to the central nervous system and gastrointestinal tract, with a higher incidence reported during coadministration of lamotrigine and felbamate than with placebo. Overall, felbamate appears to have no clinically relevant effects on the pharmacokinetics of lamotrigine.

Liquid chromatographic determination of ceftibuten, a new oral cephalosporin, in human plasma and urine

Two liquid chromatographic methods with UV detection were developed for the determination of ceftibuten in human plasma and urine. Diluted plasma samples were directly injected onto a reversed-phase column without prior protein precipitation while diluted urine samples were processed through an automated on-line sample clean-up procedure using column-switching. Both methods were linear over clinically relevant concentration ranges in plasma (from 0.1 to 50 micrograms ml-1) and urine (from 0.5 to 60 micrograms ml-1). The methods showed acceptable precision (RSD < 20%) and accuracy (bias < 15%) at the limit of quantitation (LOQ) for ceftibuten in plasma and urine. These LOQs represented the lowest concentrations of ceftibuten in plasma (0.1 micrograms ml-1) and urine (0.5 micrograms ml-1) that could be measured with acceptable precision and accuracy. RSDs for both within-day and between-day analyses were < or = 12% for plasma and < 7% for urine. These methods have been used successfully for the analysis of ceftibuten in plasma and urine following single oral doses of 200, 400 and 800 mg in man.