Elaine Radwanski

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.

Pharmacokinetics and Dose Proportionality of Loratadine

The dose proportionality and pharmacokinetics of loratadine, a new nonsedating antihistamine, were studied in 12 normal volunteers. In a three‐way cross‐over, each volunteer received a single 10‐, 20‐, or 40‐mg loratadine capsule. Blood was collected up to 96 hours after dosing. Plasma loratadine concentrations were determined by radioimmunoassay (RIA), and those of a minor, but active metabolite, descarboethoxyloratadine, by high performance liquid chromatography (HPLC). Concentrations in the disposition phase were fitted to a biexponential equation for pharmacokinetic analysis. For dose proportionality, AUC‐ and Cmax‐dose relationships were evaluated by linear regression. Also, pharmacokinetic parameters and dose‐adjusted AUCs were compared by analysis of variance. Loratadine was rapidly absorbed, reaching Cmax values (4.7, 10.8, and 26.1 ng/mL) at 1.5, 1.0 and 1.2 hours for the 10‐, 20‐, and 40‐mg doses, respectively. The loratadine t1/2β ranged from 7.8 to 11.0 hours. Descarboethoxyloratadine reached Cmax values (4.0, 9.9, and 16.0 ng/mL) at 3.7, 1.5, and 2.0 hours for the 10‐, 20‐, and 40‐mg doses, respectively. Its t1/2β ranged from 17 to 24 hours. For both compounds, AUC‐ and Cmax‐dose relationships were linear and there were no differences in the t1/2β, CL/F, or dose‐adjusted AUC values among the treatments. Loratadine and descarboethoxyloratadine plasma concentrations and pharmacokinetics were not dose dependent.

Clinical, hematologic, and immunologic effects of interleukin-10 in humans.

We conducted a double-blind, placebo-controlled study to investigate the safety, pharmacokinetics, and immunological properties of interleukin-10 (IL-10) administration in healthy humans. Volunteers received a single intravenous bolus injection of recombinant human IL-10 (1, 10, or 25μg/kg) or placebo. Cytokine production in whole blood and peripheral blood mononuclear cells (PBMC) was assessed before and 3, 6, 24, and 48 hr after the injection. Peak serum concentrations of IL-10 (15±1.1, 208±20.1, and 505±22.3 ng/ml) occurred after 2–5 min for 1, 10, and 25μg/kg IL-10, respectively. The terminal-phase half-life was 3.18 hr. A transient leukocytosis (24–63% above baseline) was observed 6 hr after injection, which coincided with a dose-dependent decrease (12–24%) in neutrophil superoxide generation. There was a marked inhibition (60–95%) of endotoxin-induced IL-6 production from whole blood in each group receiving IL-10. Production of IL-8 in endotoxin-stimulated blood was reduced in the 10μg/kg group. In PBMC stimulated with phytohemagglutinin and phorbol ester, there was a decrease (72–87%) in interferon-γ (IFNγ) production 6 hr after IL-10 with a return to pre-IL-10 levels after 24 hr. This reduction was only partially associated with a decrease in the number of CD2-bearing cells. We conclude that IL-10 administration into humans is without significant side effects, and a single injection reducesex vivo production of IL-6, IL-8, and IFNγ.

Effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive

The effects of felbamate on the pharmacokinetics of a low‐dose combination oral contraceptive containing 30 μg ethinyl estradiol and 75 μg gestodene were assessed in a randomized, double‐blind, placebo‐controlled parallel‐group study in healthy premenopausal female volunteers established in a regimen of oral contraceptive use. They received either placebo or 2400 mg/day felbamate from midcycle (day 15) to midcycle (day 14) of two consecutive oral contraceptive cycles (months 1 and 2). Pharmacokinetic assessments of ethinyl estradiol and gestodene were performed on day 14 of both cycles. To determine whether ovulation occurred, plasma progesterone and urinary luteinizing hormone levels were measured, and diaries recording vaginal bleeding were kept. Felbamate treatment resulted in a significant 42% decrease in gestodene area under the plasma concentration‐time curve (0 to 24 hours) (p = 0.018) compared with baseline, whereas a minor but not clinically relevant effect was observed on the pharmacokinetic parameters of ethinyl estradiol. There were no changes in the pharmacokinetics of ethinyl estradiol or gestodene after placebo treatment. No volunteer showed hormonal evidence of ovulation; however, one volunteer reported the onset of intermenstrual bleeding during felbamate treatment. Because of the effect of felbamate on the pharmacokinetics of gestodene and the report of intermenstrual bleeding, it is possible that the contraceptive efficacy of low‐dose combination oral contraceptives may be adversely affected during felbamate treatment.

Loratadine administered concomitantly with erythromycin: Pharmacokinetic and electrocardiographic evaluations

To evaluate the effects of coadministration of loratadine and erythromycin on the pharmacokinetics and electrocardiographic repolarization (QTc) pharmacodynamics of loratadine and its metabolite descarboethoxyloratadine in healthy volunteers.

Pharmacokinetics of Interferon α-2b in Healthy Volunteers

In a three‐way crossover design, 12 healthy male volunteers received 5 × 106 IU/m2 body surface area interferon α‐2b(IFN α‐2b) by intravenous (IV) infusion over 30 minutes, intramuscular (IM) injections, and subcutaneous (SC) injections. Blood and urine samples were collected at specified times, and analysis of IFN α‐2b concentrations was performed by immunoradiometric assay. “Flulike” symptoms were the most frequently reported adverse experiences and were independent of the route of administration. After a 30‐minute IV infusion, IFN α‐2b disappeared rapidly from serum, with distribution and elimination phase half‐lives of 0.1 hour and 1.7 hours, respectively. Interferon α‐2b was absorbed slowly after IM and SC administration, with similar absorption half‐lives of 5.8 and 5.5 hours, respectively. The observed maximal concentrations after IM and SC administration were 42.1 IU/mL at six hours and 45.8 IU/mL at eight hours, respectively. Interferon α‐2b was eliminated with half‐lives of 2.2 hours after IM administration and 2.9 hours after SC administration. The areas under the serum concentration‐time curves for the SC and IM doses were higher than those obtained for the IV infusion. Measurable amounts of IFN α‐2b were not found in urine regardless of the route of administration.

Pharmacokinetics and Leukocyte Responses of Recombinant Human Interleukin-10

AbstractPurpose. To study the pharmacokinetics and ex vivo leukocyte responses of recombinant human IL-10 (rHuIL-10) following single SC and IV dosing. Methods. A randomized two-way cross-over study was undertaken in 17 healthy volunteers in which rHuIL-10 was administered as 25 μg/ kg SC and IV doses. Blood samples were collected for 48 hr after dosing to determine serum IL-10 concentrations. Inhibitory activity of IL-10 on ex vivo production of inflammatory cytokines (TNF-α and IL-1β) by LPS-treated peripheral blood cells were measured over 96 hr. Results. A physiologically-relevant modeling approach was developed to determine the pharmacokinetics for two routes of administration (SC and IV). The IV dose showed polyexponential disposition with CL of 65 mL/kg/hr, Vss of 70 mL/kg, and t1/2 of 1.94 hr. Absolute bioavailability averaged 42% for SC dosing which produced lower but sustained concentrations. Substantial and prolonged suppression of TNF-α and IL-1β production was achieved during IL-10 treatment. The Hill Function was used to account for the joint concentration-dependent immunosuppressive action of rHuIL-10 after both IV and SC doses. The IC50 values were about 0.03 ng/mL and Imax values were about 0.85 for both TNF-α and IL-lβ suppression. The degree of change as well as the duration of leukocyte response was greater after SC administration than after IV administration. Conclusions. rHuIL-10 shows favorable PK/PD characteristics especially by theSC route of administration which produced prolonged suppression of cytokine production (ex vivo) which may be applicable in various immune-related disorders.

Excretion of Loratadine in Human Breast Milk

The excretion of loratadine, a new nonsedating antihistamine, into human breast milk was studied in six lactating nonpregnant volunteers. Each volunteer received one 40‐mg loratadine capsule. Milk and blood were collected before and at specified times (to 48 hours) after dosing. Plasma and milk loratadine concentrations were determined by a specific radioimmunoassay, and those of an active but minor metabolite, descarboethoxyloratadine, by high performance liquid chromatography (HPLC). Breast milk concentration‐time curves of both loratadine and descarboethoxyloratadine paralleled the plasma concentration‐time curves. For loratadine, the plasma Cmax was 30.5 ng/mL at 1.0 hour after dosing and the milk Cmax was 29.2 ng/mL in the 0 to 2 hour collection interval. Through 48 hours, the loratadine milk‐plasma AUC ratio was 1.2 and 4.2 μg of loratadine was excreted in breast milk, which was 0.010% of the administered dose. For descarboethoxyloratadine, the plasma Cmax was 18.6 ng/mL at 2.2 hours after dosing, whereas the milk Cmax was 16.0 ng/mL, which was in the 4 to 8‐hour collection interval. Through 48 hours, the mean milk‐plasma descarboethoxyloratadine AUC ratio was 0.8 and a mean of 6.0 μg of descarboethoxyloratadine (7.5 μg loratadine equivalents) were excreted in the breast milk, or 0.019% of the administered loratadine dose. Thus, a total of 11.7 μg loratadine equivalents or 0.029% of the administered dose were excreted as loratadine and its active metabolite. A 4‐kg infant ingesting the loratadine and descarboethoxyloratadine excreted would receive a dose equivalent to 0.46% of the loratadine dose received by the mother on a mg/kg basis. An estimated “worst‐case” dose (i.e., the maximum dose that could be expected under any circumstances) of loratadine and descarboethoxyloratadine to an infant was calculated to be only 1.1% of the adult loratadine dose on a mg/kg basis. The adult dose has been reported to be safe and well tolerated, so it is unlikely that this dose presents a hazard to infants.

Effects of felbamate on the pharmacokinetics of phenobarbital

The effects of felbamate on the pharmacokinetics of phenobarbital and one of its main metabolites, parahydroxyphenobarbital, were assessed in a parallel‐group, placebo‐controlled, double‐blind study, in 24 healthy volunteers. Pharmacokinetic parameters of phenobarbital and parahydroxyphenobarbital were determined from plasma and urine samples obtained after 28 days of daily administration of 100 mg phenobarbital and after a further 9 days of phenobarbital plus 2400 mg/day felbamate or placebo. Felbamate increased phenobarbital values for area under the plasma concentration‐time curve from 0 to 24 hours and maximum concentration by 22% and 24%, respectively, whereas placebo had no effect. This increase was caused by a reduction in parahydroxylation of phenobarbital and possibly through effects on other metabolic pathways. Because felbamate inhibits the S‐mephenytoin hydroxylase (CYP2C19) isozyme in vitro, it appears that phenobarbital hydroxylation is mediated in part by this isozyme.

Loratadine: multiple-dose pharmacokinetics

The steady‐state pharmacokinetics of loratadine (L), a new long‐acting antihistamine devoid of CNS activity, was investigated in 12 healthy male volunteers. Each volunteer received 40‐mg L capsules q24h for ten days. Blood samples were collected at various times on day 1, 5, 7, and 10 and assayed for L by radioimmunoassay (RIA) and for descarboethoxyloratadine (DCL), a known active metabolite, by high‐performance liquid chromatography (HPLC). The plasma L and DCL concentration‐time data in the disposition phases were fitted to a biexponential equation for pharmacokinetic analysis. Steady‐state plasma L Cmax concentrations were reached at 1.5 hour (Tmax) after each dose. DCL steady‐state Cmax values ranged 26 to 29 ng/mL at a Tmax ranging from 1.8 to 3 hours. The AUC at steady state, AUCτ, was 80 to 96 and 349 to 421 h × ng/mL for L and DCL, respectively. The accumulation indexes (Ra) based on AUCτ ratios, did not change for either compound after day 5. Ra values for L and DCL after the fifth dose were 1.4 and 1.9, respectively, indicating that there is little accumulation of either L or DCL after a multiple (once‐a‐day) dosage regimen. The t1/2β at steady state were 14.4 and 18.7 hours for L and DCL, respectively, which were similar to those reported following a single‐dose L administration. Observed plasma drug concentrations were in good agreement with predicted values derived for pharmacokinetic parameters.