George Perentesis

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.

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.

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.

Single and Multiple Dose Pharmacokinetic Evaluation of Flutamide in Normal Geriatric Volunteers

Single dose and steady‐state pharmacokinetics of flutamide (F) and its active plasma metabolite, hydroxyflutamide (HF) were studied in twelve healthy geriatric volunteers administered 250 mg flutamide capsules on day 1 and 250 mg flutamide capsules three times a day on days 2 through 9. After oral administration, F was rapidly absorbed and metabolized. It was present in the plasma in small and variable concentrations, which precluded quantitative assessment of pharmacokinetic parameters for individual subjects. Steady‐state plasma concentrations were reached on or before Day 6. The mean steady state Cmax (Day 9), 112.7 ng/ml, occurred at 1.3 hr. Pharmacokinetic analysis of mean data at steady‐state gave a distribution and elimination half‐life of 0.8 hr and 7.8 hours, respectively. The plasma levels for HF were much higher and less variable than F. The mean Cmax for HF averaged 894 ng/ml at 2.7 hours after a single dose and 1719 ng/ml (Day 9) at 1.9 hr after multiple doses. The distribution and elimination half‐lives of HF at steady‐state were 1.9 and 9.6 hours, respectively. The steady‐state HF plasma concentrations were also achieved on or before Day 6 and were approximately twice those obtained after a single dose. From this study, it has been demonstrated that the pharmacokinetics of F and HF do not change appreciably upon multiple dosing of 250 mg F capsule given three times a day.

The Pharmacokinetics of Loratadine in Normal Geriatric Volunteers

The pharmacokinetics of loratadine, a non-sedating anti-histamine, were studied in 12 normal geriatric volunteers. In an open label fashion, each volunteer received one 40 mg loratadine capsule. Blood was collected prior to and at specified times (up to 120 h) after dosing. Plasma loratadine concentrations were determined by a specific radioimmunoassay and those of an active metabolite, descarboethoxyloratadine, by high performance liquid chromatography. Concentrations of loratadine in the disposition phase were fitted to a biexponential equation and those of descarboethoxyloratadine to either a monoexponential or biexponential equation for pharmacokinetic analysis. Loratadine was rapidly absorbed, reaching a maximum plasma concentration of 50.5 ng/ml at 1.5 h after dosing. The disposition half-lives of loratadine in the distribution and elimination phases were 1.5 and 18.2 h, respectively. The area under the plasma concentration–time curve, was 146.7 h·ng/ml. Descarboethoxyloratadine had a maximum plasma concentration of 28.0 ng/ml at 2.9 h post-dose and an area under the concentration–time curve of 394.9 h·ng/ml. Its disposition half-lives in the distribution and elimination phases were 2.8 and 17.4 h, respectively. Comparison of these data with those from a previous study of loratadine in young adults showed no clear differences in the disposition half-lives between the two groups. The clearance of loratadine tends to be lower in the elderly, but inter-individual variation within each age group appears greater than any age effect.

Pharmacokinetics of loratadine in patients with renal insufficiency

The disposition of loratadine, a new orally active histamine H1 receptor antagonist and its primary metabolite descarboethoxyloratadine were characterized in adult volunteers with normal renal function (group I), patients with chronic renal failure, i.e., creatinine clearances less than 30 mL/min (group II), as well as chronic hemodialysis patients (group III). The effect of hemodialysis on the disposition of loratadine and descarboethoxyloratadine was also assessed. Subjects in groups I and II were given a single oral 40 mg dose of loratadine while the patients in Group III received two single 40 mg doses of loratadine (during an interdialytic period and just prior to hemodialysis). Loratadine was rapidly absorbed and the decline of plasma concentrations after attainment of the Cmax was biexponential in all subjects. No significant differences in t1/2β were observed between the three groups (8.7 ± 5.9, 7.6 ± 6.9, 8.6 ± 1.6 hrs: in groups I, II, and III, respectively). The apparent total body clearance and apparent volume of distribution of loratadine also did not differ significantly among the three groups. No significant differences in the Cmax or tmax of the metabolite were observed. The metabolite AUC0∞ however was significantly greater in group II subjects: (212.4 ± 37.8, 469.5 ± 95.4, 325.2 ± 114.6 ng · hr/mL; groups I, II, and III, respectively). No significant relationship was observed between the terminal elimination half‐life of loratadine or descarboethoxyloratadine and creatinine clearance. Hemodialysis augmented endogenous clearance by less than 1%. The disposition of loratadine is not significantly altered in patients with severe renal insufficiency nor is hemodialysis an effective means of removing loratadine or descarboethoxyloratadine from the body.

The Effect of Antacid and Cimetidine on the Oral Absorption of the Antifungal Agent SCH 39304

The single‐dose pharmacokinetics of the antifungal agent SCH 39304 (Schering‐Plough Corp., Kenilworth, NJ) were assessed alone and in combination with antacid and cimetidine. On three separate occasions nine healthy men received a single oral 50 mg dose of SCH 39304 either alone, with 60 mL antacid, or with oral cimetidine 300 mg four times a day for 4 days. Concomitant antacid or cimetidine administration had no significant effect on any of the SCH 39304 pharmacokinetic parameters studied. The oral absorption of SCH 39304, as assessed by the area under the plasma concentration‐time curve (AUC) and the amount of drug recovered unchanged in the urine, was not affected by either antacid or cimetidine. The AUC0‐t for the drug given alone was 80.5 ± 15.8 μg · hr/mL, compared to 81.4 ± 12.7 and 79.7 ± 9.6 μg · hr/mL with concomitant antacid and cimetidine, respectively. The amount of drug excreted in the urine (Ae0‐t) was 22.7 ± 5.1, 24.2 ± 9.2, and 23.6 ± 7.6 mg when the drug was given alone, with antacid, and with cimetidine, respectively. Antacid coadministration delayed absorption as evidenced by an increase in the tmax in 7 out of 9 subjects, although this did not reach statistical significance (P = .082, Wilcoxon test). We conclude that concomitant antacid or cimetidine does not alter the oral absorption or pharmacokinetic disposition of single‐dose SCH 39304.

Secretion of Dilevalol in Breast Milk

The pharmacokinetics of unchanged and total (unchanged plus Glusulase [Biotechnology Systems, Boston, MA]) released dilevalol and secretion into human breast milk was studied in six healthy breast‐feeding female volunteers administered a single 400‐mg dilevalol hydrochloride capsule. In plasma, the mean Cmax for unchanged dilevalol, 485 ng/mL was reached at 0.8 hour (tmax) and the AUC(48 hours) was 1435 hr × ng/mL. Pharmacokinetic analysis of unchanged dilevalol in plasma showed that dilevalol was distributed and eliminated with half‐lives of 0.9 and 8.2 hours, respectively. Breast milk concentrations of unchanged dilevalol as a function of time, paralleled those of plasma but were consistently lower. The milk Cmax, 149 ng/mL, occurred during the 0 to 2 hour collection interval; the AUC(42 hours) for unchanged dilevalol in milk was 663 hr × ng/mL. The mean milk to plasma concentration ratio was 0.46. The unchanged dilevalol plasma concentrations were 12 to 18% those of total drug suggesting that the drug is extensively conjugated. By contrast, the concentrations of unchanged dilevalol in breast milk, based on Cmax and AUC data were 63 to 94% those of total drug, indicating that very little conjugated drug is secreted into breast milk. Through 48 hours, a mean of only 27 μg dilevalol or 0.007% of the administered dose was secreted into breast milk, which is much less than that reported for other beta blockers.

Pharmacokinetics and Bioavailability of Dilevalol in Normotensive Volunteers

The bioavailability and pharmacokinetics of dilevalol following oral and intravenous administration were investigated in 12 healthy male volunteers. Dilevalol HCl was administered as a 200‐mg oral tablet and a 50‐mg intravenous infusion using a randomized cross‐over design. Blood and urine samples were collected over 60 hours and analyzed for unchanged and total (unchanged plus Glusulase‐released) dilevalol using an high performance liquid chromatography (HPLC) assay. After intravenous administration, total body clearance and volume of distribution of unchanged dilevalol were determined to be 23.2 mL/min/kg and 24.6 L/kg, respectively. After oral administration, a mean maximum concentration of 62 ng/mL was reached at an average peak time of 1.4 hours. Drug was eliminated with a half‐life of 8.3 hours after oral administration and 12 hours after intravenous administration. Based on plasma levels and urinary excretion of total dilevalol, the drug was completely absorbed; however, due to first‐pass metabolism, the absolute bioavailability of unchanged drug was 11 to 14%.

Pharmacokinetics of dilevalol in normotensive and hypertensive volunteers

Dilevalol is a novel antihypertensive agent combining vasodilation due to selective beta 2-adrenergic receptor agonism with nonspecific antagonism of beta 1- and beta 2-adrenergic receptors. Studies of dilevalols pharmacokinetics in normotensive and hypertensive volunteers have demonstrated that (1) it is rapidly and well absorbed; (2) because of extensive first-pass metabolism its absolute oral bioavailability is about 12%; (3) its mean elimination half-life is 8 to 12 hours after administration of single oral or intravenous doses to normal volunteers, a value consistent with once-daily dosing; and (4) food does not appear to alter its bioavailability or pharmacokinetics.