Pascale Reidenberg

Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for refractory or relapsing malignancies.

SummaryTemozolomide, an oral cytotoxic agent with approximately 100% bioavailability after one administration, has demonstrated schedule-dependent clinical activity against highly resistant cancers. Thirty patients with minimal prior chemotherapy were enrolled in this phase I trial to characterize the drug’s safety, pharmacokinetics and anti-tumour activity, as well as to assess how food affects oral bioavailability. To determine dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD), temozolomide 100–250 mg m–2 was administered once daily for 5 days every 28 days. The DLT was thrombocytopenia, and the MTD was 200 mg m–2 day–1. Subsequently, patients received the MTD to study how food affects the oral bioavailability of temozolomide. When given orally once daily for 5 days, temozolomide was well tolerated and produced a non-cumulative, transient myelosuppression. The most common non-haematological toxicities were mild to moderate nausea and vomiting. Clinical activity was observed against several advanced cancers, including malignant glioma and metastatic melanoma. Temozolomide demonstrated linear and reproducible pharmacokinetics and was rapidly absorbed (mean Tmax ~1 h) and eliminated (mean t1/2 = 1.8 h). Food produced a slight reduction (9%) in absorption of temozolomide. Temozolomide 200 mg m–2 day–1 for 5 days, every 28 days, is recommended for phase II studies.

Phase I and Pharmacokinetic Study of Temozolomide on a Daily-for-5-Days Schedule in Patients With Advanced Solid Malignancies

PURPOSE To determine the principal toxicities, characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of temozolomide (TMZ) on a daily-for-5-days schedule, and recommend a dose for subsequent disease-directed studies in both minimally pretreated (MP) and heavily pretreated (HP) patients. PATIENTS AND METHODS Patients received TMZ as a single oral dose daily for 5 consecutive days every 28 days. TMZ doses were escalated from 100 to 150, and 150 to 200 mg/m(2)/d in separate cohorts of MP and HP patients. PK plasma was sampled on days 1 and 5. TMZ concentrations were analyzed and pertinent PK parameters were related to the principal toxicities of TMZ in PD analyses. RESULTS Twenty-four patients were treated with 85 courses of TMZ. Thrombocytopenia and neutropenia were the principal dose-limiting toxicities (DLTs) of TMZ on this schedule. The cumulative rate of severe myelosuppressive effects was unacceptably high at TMZ doses exceeding 150 mg/m(2)/d in both MP and HP patients. TMZ was absorbed rapidly with maximum concentrations achieved in 0.90 hours, on average, and elimination was rapid, with a half-life and systemic clearance rate (Cl(S/F)) averaging 1.8 hours and 115 mL/min/m(2), respectively. When clearance was normalized to body-surface area (BSA), interpatient variability in Cl(S/F) was reduced from 20% to 13% on day 1 and from 16% to 10% on day 5. Patients who experienced DLT had significantly higher maximum drug concentration( )(median 16 v 9.5 microg/mL, P =. 0084) and area under the concentration-time curve (median 36 v 23 microg-h/mL, P =.0019) values on day 5. CONCLUSION Prior myelosuppressive therapy was not a determinant of toxicity. TMZ 150 mg/m(2)/d administered as a single oral dose daily for 5 days every 4 weeks is well tolerated by MP and HP patients, with higher doses resulting in unacceptably high rates of severe hematologic toxicity. TMZ doses should be individualized according to BSA rather than use of a prespecified oral dose for all individuals. TMZ is an optimal agent to develop in combination with other cytotoxic, biologic, and targeted therapeutics for patients with relevant malignancies.

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.

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.

Lack of hypothalamic-pituitary-adrenal axis suppression with once-daily or twice-daily beclomethasone dipropionate aqueous nasal spray administered to patients with allergic rhinitis

The potential for a newly developed, double-strength (0.084%) beclomethasone dipropionate (BDP) aqueous (AQ) nasal suspension to produce effects associated with exposure to systemic corticosteroids was assessed by the plasma cortisol response to cosyntropin stimulation induced by a 6-hour intravenous infusion of 250 micrograms of cosyntropin in 500 mL of normal saline. Sixty-four patients with allergic rhinitis were enrolled in this study. Patients were randomly assigned to one of the following four treatment groups: (1) BDP AQ Forte (0.084%) nasal spray 336 micrograms once daily; (2) BDP AQ (0.042%) nasal spray 168 micrograms twice daily; (3) placebo nasal spray twice daily; or (4) oral prednisone 10 mg once daily in the morning. After 36 consecutive days of treatment, there was a significant (P < 0.01) difference in the plasma cortisol response to cosyntropin stimulation between the prednisone and placebo groups; however, there were no significant differences between the BDP AQ Forte or the BDP AQ groups compared with the placebo group. Secondary analyses comparing BDP AQ Forte administered as 336 micrograms once daily with BDP AQ administered as 168 micrograms twice daily showed no significant differences in plasma cortisol responses to cosyntropin stimulation. No serious adverse events were reported. Adverse events consisted of headache, pharyngitis, or nasal irritation, with headache being reported most frequently. These adverse events were similarly distributed among active treatment groups and were similar to placebo. No clinically relevant changes were observed in any treatment group in findings on clinical laboratory tests, physical examination, or electrocardiography. Vital signs, obtained daily, were consistent with values observed in healthy individuals. No patient exhibited signs of oral candidiasis. All patients met the plasma cortisol concentration criteria for discharge relative to expected hypothalamic-pituitary-adrenal axis function. In conclusion, there were no significant differences in plasma cortisol responses to cosyntropin stimulation between groups of patients with allergic rhinitis treated with either BDP AQ Forte (0.084%) nasal spray 336 micrograms once daily or BDP AQ (0.042%) nasal spray 168 micrograms twice daily compared with the placebo group. These results indicate that the dosing regimens of BDP AQ nasal suspensions used in this study lack systemic effects and are safe and well tolerated.

Effect of gastric pH on the relative oral bioavailability and pharmacokinetics of temozolomide.

Purpose: Temozolomide is an imidazotetrazine alkylating agent which undergoes chemical conversion at physiological pH to the active species 5-(3-methyltriazene-1-yl)imidazole-4-carboxamide (MTIC) but is stable at acid pH. This study evaluated the effect of an increase in gastric pH, through the use of ranitidine, on the oral bioavailability and plasma pharmacokinetics of temozolomide and MTIC. Methods: Fifteen patients with advanced cancer were enrolled of which 12 were evaluable, all of whom had pharmacokinetic blood sampling. Each patient received temozolomide 150 mg m−2 day−1 for 5 days in cycle 1 and also received ranitidine 150 mg every 12 h either on days 1 and 2 or days 4 and 5. Gastric pH was monitored by the use of the Heidelberg capsule system. Results: Following the administration of ranitidine there was a rise in gastric pH by 1–2 pH units over the duration of the study period (pH range 2.2–5.2 without ranitidine and 3.5–6.0 with ranitidine). There was no difference in the pharmacokinetic parameters of temozolomide or MTIC with or without the concomitant administration of ranitidine. There was however, a lower Cmax for temozolomide and MTIC for patients receiving ranitidine on day 1 and 2 versus day 4 and 5. Temozolomide was rapidly absorbed [time to maximum plasma concentration (tmax) 1.8 h] and eliminated [elimination half-life (t1/2) 1.8 h] and MTIC followed a similar pattern with a tmax of 1.9 h and a t1/2 of 1.9 h. Overall, the AUC of the MTIC represented about 2–4% of the AUC for temozolomide.

Comparative Pharmacokinetics of Oral Ceftibuten, Cefixime, Cefaclor, and Cefuroxime Axetil in Healthy Volunteers

Study Objective. To compare the pharmacokinetics of ceftibuten, cefixime, cefuroxime axetil, and cefaclor after oral administration.

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.

Effects of felbamate on the pharmacokinetics of the monohydroxy and dihydroxy metabolites of oxcarbazepine

The effects of felbamate on the multiple dose pharmacokinetics of the monohydroxy and dihydroxy metabolites of oxcarbazepine were assessed in a placebo‐controlled, randomized, double‐blind crossover study in 18 healthy male volunteers. Oxcarbazepine, 1200 mg/day, was administered on an open basis in combination with double‐blind placebo or 2400 mg/day felbamate for two 10‐day treatment periods separated by a 14‐day washout period. Pharmacokinetic parameters of monohydroxyoxcarbazepine and dihydroxyoxcarbazepine were determined from plasma and urine samples obtained on the tenth day of each treatment period. Felbamate had no effect on monohydroxyoxcarbazepine plasma or urine pharmacokinetics compared with placebo, but it significantly increased values for dihydroxyoxcarbazepine maximum concentration and area under the curve from 0 to 12 hours, as well as urinary excretion of free and total dihydroxyoxcarbazepine. The mechanism that may account for the observations is the induction of oxidative metabolism of monohydroxyoxcarbazepine. Despite these changes, the relative amount of dihydroxyoxcarbazepine is small in comparison to monohydroxyoxcarbazepine, and antiepileptic activity is associated with monohydroxyoxcarbazepine rather than dihydroxyoxcarbazepine. Therefore we conclude that felbamate has no clinically relevant effects on the pharmacokinetics of oxcarbazepine in humans.