Pharmacokinetics and tolerability of extended-release clarithromycin.

BACKGROUND: Clarithromycin is a semisynthetic macrolide that exhibits broad-spectrum activity against gram-positive, gram-negative, and atypical respiratory tract and skin/skin structure pathogens, Mycobacterium species, and Helicobacter pylori. It is indicated for the treatment of a wide variety of respiratory and dermatologic infections in children and adults as well as prophylaxis and treatment of Mycobacterium avium complex infection and peptic ulcers due to H. pylori. OBJECTIVE: In this article, we review the results of 3 studies of the steady-state pharmacokinetic profiles of clarithromycin and 14(R)-hydroxy-clarithromycin after multiple oral once-daily doses of 500-mg extended-release (ER) clarithromycin tablets. We also review the drug tolerability in 2 phase III comparative clinical trials of immediate-release (IR) and ER clarithromycin conducted in adults with acute maxillary sinusitis (AMS) and acute exacerbation of chronic bronchitis (AECB). METHODS: In the 3 pharmacokinetic studies, multiple-dose regimens of clarithromycin IR (one 250-mg or 500-mg tablet twice daily) and clarithromycin ER (one or two 500-mg tablets once daily), administered to healthy male and female volunteers, were evaluated. The effect of administration in nonfasting versus fasting conditions was assessed as well. Tolerability information was collected from each adult patient enrolled in phase III efficacy studies conducted to support the application for US Food and Drug Administration approval for the treatment of AMS and AECB. Regimens evaluated were 500 mg IR clarithromycin tablets twice daily or 1000 mg (2 x 500 mg) ER clarithromycin tablets once daily for 7 days (AECB) or 14 days (AMS). RESULTS: Bioavailability of the ER clarithromyin tablet administered with food was equivalent to that of the reference IR tablet, based on area under the plasma concentration-time curve (AUC) for both parent compound and active metabolite. The bioavailability of the ER tablet was 30% lower (based on clarithromycin AUC) when administered under fasting versus nonfasting conditions. Compared with the IR tablet, administration of the ER tablet resulted in significantly lower (P < 0.05) clarithromycin peak plasma concentration (Cmax), delayed time to Cmax, and lower degree of concentration fluctuation, confirming its in vivo extended-release characteristics. The most frequently reported adverse events (AEs) in the phase III clinical trials were diarrhea, abnormal taste, and nausea and were generally mild or moderate. The incidence of AEs was comparable for the 2 formulations. The severity of gastrointestinal AEs was significantly less for the ER formulation than for the IR formulation (P = 0.018), as was the frequency of premature study discontinuation due to gastrointestinal AEs or abnormal taste (P = 0.004). CONCLUSIONS: The results from the 3 pharmacokinetic studies reviewed demonstrate the bioequivalence of the ER and IR formulations and support the use of this clarithromycin ER formulation in a once-daily dosing regimen in phase III clinical trials. The ER tablet should be taken with food to maximize bioavailability. The results of 2 phase III comparative clinical efficacy and safety trials of clarithromycin ER tablets versus IR tablets in AMS and AECB confirm the good tolerability of the ER formulation.

Lack of a clinically significant pharmacokinetic interaction between fenofibrate and pravastatin in healthy volunteers.

This study was conducted to evaluate the potential pharmacokinetic interaction between fenofibrate and pravastatin. A total of 23 healthy adult volunteers received single-dose 201 mg fenofibrate alone, 201 mg fenofibrate + 40 mg pravastatin, and 40 mg pravastatin alone in a three-period crossover experiment. Plasma samples were collected at predetermined times and were analyzed with validated methods for the quantitation of fenofibric acid, pravastatin, and 3 alpha-hydroxy-isopravastatin (3 alpha-iso-PV). Pharmacokinetic parameters of these three compounds were calculated using noncompartmental methods and compared by analyses of variance and bioavailability assessments. Concomitant administration of fenofibrate and pravastatin did not affect the pharmacokinetics of either fenofibric acid or pravastatin. However, the AUC0-infinity and Cmax of 3 alpha-iso-PV were increased by 26% and 29%, respectively. The moderate increase in the formation of this pravastatin metabolite should not raise any clinical concerns due to its much lower pharmacological potency compared to pravastatin and lack of toxicity.

Population analysis of the pharmacokinetics of tiagabine in patients with epilepsy.

PURPOSE: In two open-label long-term safety studies, we determined tiagabine (TGB) pharmacokinetics in patients with epilepsy. METHODS: In all, 2,147 plasma samples from 511 patients who participated in the studies were available. The total daily dose ranged from 2 mg administered once daily to 80 mg administered in four doses. A one-compartment model with first-order absorption and elimination was used to fit the TGB plasma concentration-time data, with a population pharmacokinetic approach. RESULTS: The patients' average (+/-SD) weight and age were 73.8+/-20.7 kg and 32.1+/-12.3 years. The most significantly factor affecting TGB pharmacokinetics was concomitant administration of other antiepileptic drugs (AEDs). The central clearance value in patients receiving AEDs known to induce hepatic drug metabolism was 21.4 L/h, a value 67% higher than the central clearance estimate obtained for the patients receiving AEDs not known to affect hepatic drug metabolism (12.8 L/h). There was no evidence of any dose or time effect, indicating that TGB pharmacokinetics are linear. TGB pharmacokinetics were not different in white, black, or Hispanic patients, although our ability to explore racial effects was limited since 90% of the patients were white. No other demographic variables (including age and smoking) or any clinical chemistry measurements (including bilirubin, SGOT, and SGPT) were important in explaining the variability in the clearance estimates. CONCLUSIONS: TGB pharmacokinetics are linear, influenced by enzyme-inducing AEDs, and largely unaffected by other demographic variables.

Steady-state pharmacokinetics and electrocardiographic pharmacodynamics of clarithromycin and loratadine after individual or concomitant administration.

To evaluate the potential for an interaction between clarithromycin and loratadine, healthy male volunteers (n = 24) received each of the following regimens according to a randomized crossover design: 500 mg of clarithromycin orally every 12 h (q12h) for 10 days, 10 mg of loratadine orally q24h for 10 days, and the combination of clarithromycin and loratadine. A washout interval of 14 days separated regimens. The addition of loratadine did not statistically significantly affect the steady-state pharmacokinetics of clarithromycin or its active metabolite, 14(R)-hydroxy-clarithromycin. However, the addition of clarithromycin statistically significantly altered the steady-state maximum observed plasma concentration and the area under the plasma concentration-time curve over a dosing interval for loratadine (+36 and +76%, respectively) and for descarboethoxyloratadine (DCL), the active metabolite of loratadine (+69 and +49%, respectively). Clarithromycin probably inhibits the oxidative metabolism of loratadine and DCL by the cytochrome P-450 3A subfamily. Electrocardiograms (n = 12) were obtained over 24-h periods at baseline and steady state (day 10). The mean maximum QTc interval and area under the QTc interval-time curve on day 10 were modestly increased (<3%) from baseline for all three regimens, but no QTc interval exceeded 439 ms for any subject. Elevated steady-state concentrations of loratadine and DCL do not appear to be associated with adverse cardiovascular effects related to prolongation of the QTc interval. Loratadine and clarithromycin were well tolerated, alone and in combination.

Effect of renal impairment on the pharmacokinetics and tolerability of tiagabine.

PURPOSE: We wished to determine the effect of renal impairment on the pharmacokinetics and tolerability of the new antiepileptic drug tiagabine (TGB). METHODS: We assessed TGB pharmacokinetics and tolerability in 25 subjects with various degrees of renal function (based on creatinine clearance, n = 4-6 per group) from healthy (group I) to requiring hemodialysis (group V) in a single and multiple dose (every 12 h), one-period (groups I-IV) or a single dose, two-period (group V) study (4-mg oral doses of TGB x HCl). Blood samples were collected after the first dose (both periods for group V) and after the last dose on day 5 (groups I-IV). TGB plasma concentrations and plasma protein binding were determined by high-performance liquid chromatography (HPLC) and ultrafiltration, respectively. RESULTS: TGB was well tolerated by all study subjects. The pharmacokinetics of TGB were similar in all subjects; no pharmacokinetic parameter (based on either total or unbound concentrations) was statistically correlated with creatinine clearance. For total TGB in plasma, single-dose mean values of the maximum plasma concentration, clearance, and half-life (t(1/2)) ranged from 52 to 108 ng/ml, from 7.14 to 11.02 l/h, and from 6.4 to 8.4 h, respectively. CONCLUSIONS: TGB pharmacokinetics and tolerability were independent of renal function; therefore, dosage adjustment is unnecessary for epilepsy patients with renal impairment.

Lack of pharmacokinetic drug interactions between tiagabine and carbamazepine or phenytoin.

Two single-center, open-label studies examined the potential effects of tiagabine on the pharmacokinetics and safety of carbamazepine and phenytoin at steady state. Twelve adult patients with seizures controlled by an individualized fixed dosage of antiepilepsy medication (carbamazepine or phenytoin) participated in each study. On day 1, the pharmacokinetics of the baseline antiepilepsy drug were determined. On days 2 through 18, tiagabine was titrated from 8 to 48 mg/d (or the maximum tolerated dose up to 48 mg/d), and the usual fixed dosage of carbamazepine or phenytoin was continued. The pharmacokinetic assessment was repeated on day 18. There were no statistically significant differences in carbamazepine, carbamazepine epoxide, and phenytoin pharmacokinetic parameters when either drug was administered alone or in combination with tiagabine. In each study, 11 of 12 patients (92%) experienced treatment-emergent adverse events after tiagabine was added. The most frequent adverse events were dizziness, headache, difficulty concentrating, drowsiness, and tremor. Most symptoms were mild or moderate in severity and resolved without further treatment, although tiagabine dosage reductions were required by 4 patients in the carbamazepine study and by 3 patients in the phenytoin study. There were no clinically important effects on physical examination or neurologic test results, laboratory values, or vital signs. The results suggest that addition of tiagabine to a fixed regimen of either carbamazepine or phenytoin is generally well tolerated and that carbamazepine and phenytoin steady-state pharmacokinetics are unaffected by the addition of tiagabine.

Lack of a clinically significant pharmacokinetic drug interaction between tiagabine and valproate.

This single-center, open-label study examined the safety and potential effect of tiagabine on valproate pharmacokinetics under steady-state conditions. Twelve adult patients with seizures controlled by an individualized fixed dosage of valproate participated in the study. On day 1, the pharmacokinetics of valproic acid were determined. On days 2 through 14, tiagabine was titrated from 8 to 24 mg/d (or the maximum tolerated dose up to 24 mg/d), and the patients continued to take their usual fixed dosage of valproate. Valproic acid pharmacokinetics were assessed again on day 14. The mean maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve from time zero to the end of the dosing interval (AUC0-tau ) for valproic acid were reduced approximately 10% and 12%, respectively (p < or = 0.05), when valproate and tiagabine were administered concomitantly, compared with the mean values when valproate was administered alone. The concomitant administration of these drugs was generally well tolerated. Ten patients reported treatment-emergent adverse events during the study, the most common of which was dizziness(n = 8). Only one patient experienced events that were considered to be severe. There were no clinically important effects on laboratory values, vital signs, or physical exam findings. The small decreases in mean valproic acid Cmax and AUC0-tau observed during the concomitant administration of tiagabine and valproate are probably of limited clinical importance, given the broad therapeutic range of valproate (50-100 microg/mL).

A single-dose study to define tiagabine pharmacokinetics in pediatric patients with complex partial seizures.

We report an open-label study of 25 children with complex partial seizures that assessed the pharmacokinetics and safety of a single dose of approximately 0.1 mg/kg tiagabine. The children received their usual individualized regimen of one concomitant antiepilepsy drug (AED) throughout the study. Seventeen children were receiving an inducing AED (carbamazepine or phenytoin); eight were receiving valproate. Tiagabine was well tolerated. Dose-normalized Cmax was higher in children taking valproate (18.2 +/- 5.0 ng/mL/mg) than in the induced children (14.8 +/- 6.9 ng/mL/mg), but the difference was not statistically significant. Dose-normalized area under the plasma concentration-time curve from time zero to infinite time was significantly higher (p = 0.002) in children taking valproate (176.5 +/- 54.7 ng.hr/mL/mg) than in induced children (92.4 +/- 56.7 ng.hr/mL/mg). Similarly, oral clearance in the children taking valproate (96 +/- 39 mL/min) was half that of the induced children (207 +/- 91 mL/min). Half-life in children taking valproate (5.7 hr) was almost twice that for the induced children (3.2 hr), and the elimination rate constant was significantly lower (p < 0.02) for the children taking valproate than for the induced children. Volume of distribution was similar in the children taking valproate (52 +/- 9 L) and the induced children (59 +/- 29 L). This is consistent with observations in adults taking tiagabine with inducing AEDs or valproate. Exploratory regressions on these data in children and previous data in adults showed fairly strong relationships between body size and tiagabine clearance and volume of distribution, with body size explaining about 40 to 50% of the variability. When adjusted per kg body weight, clearance and volume were greater in children than adults. When adjusted per m2 body surface area, clearance and volume were more similar in adults and children.

Pharmacokinetics and safety of tiagabine in subjects with various degrees of hepatic function.

PURPOSE: To evaluate the pharmacokinetics and safety of multiple oral doses of tiagabine HCl in subjects with different degrees of hepatic impairment. METHODS: Four subjects with mild hepatic impairment, three subjects with moderate hepatic impairment, and six matched normal subjects received twice daily oral tiagabine HCl for 5.5 days. Serial blood specimens were obtained for 48 h after the final dose. Total and unbound tiagabine plasma concentrations were determined by high-performance liquid chromatography (HPLC) and ultrafiltration, respectively. Pharmacokinetic parameters were compared between the groups by analysis of covariance. RESULTS: For total tiagabine concentrations in normal subjects and subjects with mild and moderate hepatic impairment, C(max) values (mean +/- SD) were 117 +/- 54, 172 +/- 40, and 172 +/- 28 ng/ml; C(min) values were 13 +/- 4, 27 +/- 4, and 28 +/- 6 ng/ml; areas under the plasma concentration-time curve were 396 +/- 59, 633 +/- 16, and 675 +/- 32 ng x h/ml, and elimination half-lives (harmonic means) were 7, 12, and 16 h, respectively. Unbound tiagabine concentrations, area under the unbound plasma concentration-time curve, and the free fractions were increased in the hepatically impaired subjects. Reduced serum albumin and alpha1-acid glycoprotein concentrations may have contributed to increases in the unbound fraction. Adverse events observed included dizziness, tremor, nausea, somnolence, incoordination, and unsteady gait. The frequency of these events was increased in the subjects with liver impairment. CONCLUSIONS: Because of the decreased drug elimination caused by liver function impairment, reduced doses or increased dosing interval or both may be needed to attain therapeutic plasma drug concentrations. Time to reach steady state also may be prolonged. The patients should be monitored closely for potential neurologic adverse events.

Pharmacokinetics of tiagabine as add-on therapy in patients taking enzyme-inducing antiepilepsy drugs.

The effect of hepatic enzyme-inducing antiepilepsy drugs (AEDs) on the clinical pharmacokinetics of tiagabine, a new AED, was studied in the steady-state condition. Patients with epilepsy entered this two-day study on a previously stable regimen of one to three enzyme-inducing drugs (phenytoin, phenobarbital, carbamazepine, and/or primidone) and tiagabine.HCl (24, 40, 56, or 80 mg daily). Patients were confined on both days, and serial blood samples were collected. Plasma tiagabine concentrations were determined by high-performance liquid chromatography; pharmacokinetic parameters were calculated using noncompartmental methods. Tiagabine pharmacokinetics were linear at all doses, as substantiated by the lack of significant differences among groups for dose-adjusted Cmax, Cmin, and AUC0-6. Some diurnal variation occurred, as evidenced by a statistically significant time effect for dose-adjusted AUC0-6. The effect was small, however, and possibly not clinically relevant. The harmonic mean half-lives of 3.8 to 4.9 h were remarkably constant across dosages and shorter than those of historical control subjects not taking enzyme-inducing AEDs suggesting that epilepsy patients not taking enzyme-inducing AEDs may require lower tiagabine.HCl doses to achieve the plasma levels observed in patients taking these drugs.

Effect of omeprazole on concentrations of clarithromycin in plasma and gastric tissue at steady state.

This study was conducted to determine (i) the effect of omeprazole on steady-state concentrations of clarithromycin and 14-(R)-hydroxyclarithromycin in plasma and gastric mucosa, (ii) the effect of clarithromycin on steady-state concentrations of omeprazole in plasma, and (iii) the effect of clarithromycin on the suppression of gastric acid secretion by omeprazole. Twenty healthy, Helicobacter pylori-negative male subjects completed this three-period, double-blind, randomized crossover study. In period 1, all subjects received 40 mg of omeprazole each morning for 6 days. Twenty-four-hour gastric pH monitoring took place on days -1 and 6. Pharmacokinetic sampling took place on day 6. In periods 2 and 3, subjects were randomly assigned to receive either 40 mg of omeprazole or omeprazole placebo daily for 6 days plus clarithromycin (500 mg) every 8 h for 5 days with a single 500-mg dose on day 6. Gastric tissue and mucus samples were obtained via endoscopy on day 5. Gastric pH monitoring and pharmacokinetic sampling took place on day 6. Two-week washout intervals separated the three study periods. Clarithromycin increased mean omeprazole area under the concentration-time curve from 0 to 24 h from 3.3 +/- 2.0 to 6.3 +/- 4.5 micrograms.h/ml (P < 0.05) and harmonic mean half-life from 1.2 to 1.6 h (P < 0.05) but did not significantly alter the effect of omeprazole on gastric pH. Mean clarithromycin area under the concentration-time curve from 0 to 8 h increased from 22.9 +/- 5.5 (placebo) to 26.4 +/- 5.7 micrograms.h/ml (omeprazole) (P < 0.05) when clarithromycin was administered with omeprazole. Analysis of variance revealed that mean concentrations of clarithromycin in tissue and mucus were statistically significantly higher when clarithromycin was given with omeprazole than when clarithromycin was given with placebo (P <0.001). Mean maximum observed concentrations of clarithromycin in the gastric fundus increased from 20.8 +/- 7.6 (placebo) to 24.3 +/- 6.4 micrograms/g (omeprazole), and those in the gastric mucous from 4.2 +/- 7.7 placebo to 39.3 +/- 32.8 micrograms/g (omeprazole). Similar increases were observed for the 14-(R)-hydroxyclarithromycin. These results show that omeprazole increases concentrations of clarithromycin in gastric tissue and mucus and may provide a mechanism for synergy between clarithromycin ad omeprazole that explains the excellent eradication of H. pylori seen in clinical trials.

Pharmacokinetics of tiagabine, a gamma-aminobutyric acid-uptake inhibitor, in healthy subjects after single and multiple doses.

Tiagabine (TGB) HCl, a new antiepileptic compound, is a potent and specific inhibitor of gamma-aminobutyric acid (GABA) uptake. In conjunction with three phase I studies, the pharmacokinetics of TGB were examined in 58 healthy male volunteers. Study I involved single increasing doses (2-24 mg TGB HCl); study II involved doses of 2-10 mg given once daily for 5 days; study III explored one dose daily (6 or 12 mg) for 14 consecutive days. Plasma TGB concentrations were measured by high-performance liquid chromatography (HPLC). Pharmacokinetic parameters were calculated by standard noncompartmental methods. Pharmacokinetic profiles were similar in all three studies and indicated that the processes of absorption and elimination of TGB were linear. The drug was rapidly absorbed, and half-life (t1/2) averaged 5-8 h. The accumulation ratio was fairly low: < 1.4 in most subjects. Secondary peaks in plasma concentration-time profiles suggested enterohepatic recycling. Lack of significant effects on antipyrine clearance indicated that TGB does not induce or inhibit hepatic microsomal enzyme systems.

Menopause: pharmacodynamics and pharmacokinetics.

Effects of menopause on pharmacokinetics and pharmacodynamics remain largely uninvestigated. We described decreased clearance of prednisolone in postmenopausal (POM) vs. premenopausal (PRM) women. Decreased clearance may be related to greater age in POM women, or to hormonal differences between PRM and POM women, independent of age. Estrogen replacement therapy (ERT) did not restore POM pharmacokinetic parameters to PRM values. However, in a single POM woman taking estrogen and progestin, clearance was similar to PRM values, suggesting that estrogen and progestin replacement may restore PRM prednisolone elimination. Lemmens and coworkers reported a significant negative correlation between age and alfentanil clearance in women, but not men, concluding that effects of age on alfentanil clearance were gender dependent. An alternative conclusion based on these same data was proposed by Rubio and Cox, who found that 67.5% of the variation in alfentanil clearance in women was explained when clearance values were divided into groups by menopausal status. Alfentanil clearance may exhibit hormonal dependence, independent of age. These data are consistent with an enzyme system that becomes less active after menopause. Gennari and coworkers examined calcium absorption before and after oophorectomy in women who received ERT or placebo therapy for 6 months after surgery. Placebo women showed significant decreases in vertebral bone density (VBD) and calcium absorption. ERT women maintained presurgical VBD and calcium absorption. The placebo group displayed intestinal resistance to normal 1,25-dihydroxyvitamin D3 stimulation of calcium absorption, whereas ERT preserved normal intestinal responsiveness.

High-performance liquid chromatographic procedure for the determination of tiagabine concentrations in human plasma using electrochemical detection.

A sensitive and precise high-performance liquid chromatographic procedure has been developed for the measurement of tiagabine concentrations in human plasma. Isolation of tiagabine and the internal standard was achieved using solid-phase extraction on disposable C8 columns. Separation was performed on a C18 analytical column using a mobile phase containing sodium octanesulfonate. The effluent was monitored with coulometric electrochemical detection at ca. + 0.76 V. The workup procedure recovered more than 95% of tiagabine from plasma. Standard curves were linear over the concentration range 0-500 ng/ml. The precision of the method was good: coefficients of variation were typically less than 5% for concentrations as low as 8 ng/ml and although they were higher at concentrations less than 8 ng/ml, they remained within acceptable limits (less than 17%) for concentrations as low as the limit of quantitation (2 ng/ml using a l-ml plasma sample). The stability of tiagabine in plasma was excellent, with no evidence of degradation after 23 h at room temperature or 2 months at -20 degrees C.

The clinical pharmacokinetics of single doses of estazolam.

The pharmacokinetics of estazolam were examined in 17 healthy male subjects. Plasma concentration-time profiles were compared following the oral administration of one 1-mg tablet, two 1-mg tablets, and one 2-mg tablet. No statistically significant differences were detected among the mean time of maximal plasma concentration (Tmax), maximal plasma concentration (Cmax), area under the plasma concentration-time curve from zero to 72 hours (AUC), or half-life values for the 2-mg doses. Mean Cmax was 97.7 and 98.6 ng/ml and mean Tmax was 1.9 and 1.6 hours for two 1-mg tablets and one 2-mg tablet, respectively. Proportionately decreased Cmax and AUC were observed following the 1-mg dose. Mean Cmax was 54.7 ng/ml for the 1-mg dose. Mean Tmax and elimination half-life values were similar to those observed after the 2-mg doses. The overall harmonic mean half-life was 14.4 hours.

A pilot study of the bioavailability and pharmacokinetics of 2',3'-dideoxycytidine in patients with AIDS or AIDS-related complex.

Eight patients with AIDS or ARC received four single doses of 2',3'-dideoxycytidine (ddC). The treatments included 0.5 and 5 mg oral tablets, a 0.5 mg oral solution, and a 0.5 mg intravenous infusion. Blood samples were collected for 4 to 6 h after each dose. Plasma concentrations of ddC were determined by a specific gas chromatographic-mass spectrometric (GC-MS) assay. A combination of the low dose and the assay sensitivity of 2 ng/ml limited data treatment and comparison. Mean Cmax of 8.5, 7.6, and 79.0 ng/ml occurred at mean tmax of 1.1, 1.3, and 0.9 h for the 0.5 mg oral solution, the 0.5 mg tablet, and the 5 mg tablet, respectively. A mean clearance of 5.57 ml/min/kg and volume of distribution of 0.64 L/kg were determined from the 0.5 mg intravenous infusion. Half-life values ranged between 0.95 and 2.0 h and appeared to be independent of the dose and route of administration. The bioavailability values calculated for the oral tablets were variable, ranging from 54 to 127%. Single doses of ddC were well tolerated in this population. The results of this pilot study indicate that ddC is rapidly and extensively absorbed when administered as an oral tablet or solution to fasting AIDS or ARC patients. It is also rapidly eliminated with a half-life of 1-2 h. There are no apparent differences in the absorption or elimination of ddC between 0.5 and 5 mg oral doses.

Pharmacokinetics of teceleukin (recombinant human interleukin-2) after intravenous or subcutaneous administration to patients with cancer.

Single doses of teceleukin ranging from 0.1 to 30 x 10(6) units were administered to cancer patients as intravenous infusions or subcutaneous injections. Serum samples were analyzed using a bioassay. In general, teceleukin was rapidly eliminated after intravenous administration, with half-lives ranging from 0.24 to 3.3 h. Teceleukin disappeared from serum more slowly following subcutaneous administration, with half-lives of 2.7 to 12.2 h. This finding may be a result of slow absorption from the subcutaneous injection site. Serum concentrations of teceleukin increased in an apparently dose-proportional manner following intravenous administration. When administered subcutaneously, serum concentrations increased with increasing dose but in a manner that was less than dose-proportional, possibly due to dose-dependent bioavailability for subcutaneously administered teceleukin.

Multiple-dose pharmacokinetics of rimantadine in elderly adults.

To assess the possible effect of aging on rimantadine hydrochloride pharmacokinetics, single- and multiple-dose kinetics were determined in 18 healthy adults with ages between 51 and 79 years. Subjects ingested single 100-mg oral doses of rimantadine after an overnight fast, followed after 5 days by a dosage of 100 mg twice a day for 9.5 days. No differences were observed among the age-stratified groups in measured or derived pharmacokinetic parameters. Peak concentrations in plasma (mean +/- standard deviation) following the single- and multiple-dose regimens, respectively, were 89 +/- 25 and 417 +/- 129 ng/ml for subjects who were 50 to 60 years of age (group 1), 92 +/- 24 and 401 +/- 84 ng/ml for those 61 to 70 years of age (group 2), and 100 +/- 14 and 538 +/- 51 for those 71 to 79 years of age (group 3). The elimination half-life in plasma following multiple doses averaged 33.5 h for group 1, 32.5 h for group 2, and 38.6 h for group 3. Steady-state concentrations in nasal mucus developed by day 5 of dosing (1.5-fold higher than concentrations in plasma), and rimantadine remained detectable in secretions for 5 days after the last dose in 65% of subjects. Stepwise regression analysis suggested that changes in maximum concentration in plasma and area under the concentration-time curve at steady state may be related to creatinine clearance. The results indicate that no important differences in rimantadine multiple-dose pharmacokinetics exist among healthy elderly adults with ages between 51 and 79 years.

Impairment of prednisolone disposition in women taking oral contraceptives or conjugated estrogens.

Companion studies were designed to determine the effects of oral contraceptives and conjugated estrogens on the pharmacokinetics of prednisolone. Twenty-four normal women entered the studies, including six young women taking oral contraceptives and six age-matched control women, and six postmenopausal women receiving conjugated estrogens and six age-matched postmenopausal women. All received 0.53 mg/kg prednisolone phosphate, iv. Significant decreases (P less than 0.05) in the clearance and volume of distribution and significant increases in the half-life were found for both total and unbound prednisolone in the women taking oral contraceptives compared to values in the young control women. A significant decrease in the unbound clearance and increases in the total and unbound half-lives of prednisolone were found in the women receiving conjugated estrogens compared to values in the postmenopausal control women. Total clearance and volume of distribution were unchanged by conjugated estrogen therapy. Administration of prednisolone to women receiving estrogen-containing oral contraceptives or conjugated estrogens results in exposure of these women to increased concentrations of unbound prednisolone for increased periods of time. Increases in the pharmacological and toxic effects of prednisolone might be expected in these women.