Vijay O. Bhargava

Dose proportionality and comparison of single and multiple dose pharmacokinetics of fexofenadine (MDL 16 455) and its enantiomers in healthy male volunteers

The pharmacokinetics and dose proportionality of fexofenadine, a new non‐sedating antihistamine, and its enantiomers were characterized after single and multiple‐dose administration of its hydrochloride salt. A total of 24 healthy male volunteers (31±8 years) received oral doses of 20, 60, 120 and 240 mg fexofenadine HCl in a randomized, complete four‐period cross‐over design. Subjects received a single oral dose on day 1, and multiple oral doses every 12 h on day 3 through the morning on day 7. Treatments were separated by a 14‐day washout period. Serial blood and urine samples were collected for up to 48 h following the first and last doses of fexofenadine HCl. Fexofenadine and its R(+) and S(−) enantiomers were analysed in plasma and urine by validated HPLC methods. Fexofenadine pharmacokinetics were linear across the 20–120 mg dose range, but a small disproportionate increase in area under the plasma concentration–time curve (AUC) (<25%) was observed following the 240 mg dose. Single‐dose pharmacokinetics of fexofenadine were predictive of steady‐state pharmacokinetics. Urinary elimination of fexofenadine played a minor role (10%) in the disposition of this drug. A 63:37 steady‐state ratio of R(+) and S(−) fexofenadine was observed in plasma. This ratio was essentially constant across time and dose. R(+) and S(−) fexofenadine were eliminated into urine in equal rates and quantities. All doses of fexofenadine HCl were well tolerated after single and multiple‐dose administration.

Pharmacokinetics and Safety of the Ketolide Telithromycin in Patients with Renal Impairment

The pharmacokinetics and safety of the ketolide telithromycin were evaluated in two separate studies after single and repeat oral dosing in patients with varying degrees of renal impairment and in subjects with normal renal function. The single‐dose study was an open‐label, nonrandomized, parallel‐group design in which all 40 patients received a single oral dose of telithromycin 800 mg. The repeat‐dose study was an open‐label study with a randomized, balanced, incomplete three‐block treatment crossover design. In this study, each of the 36 patients received two of three telithromycin regimens (400, 600, or 800 mg once daily for 5 days), with a washout period of ≥ 7 days between treatments. Telithromycin was well tolerated. Adverse events were generally mild in severity, and no serious drug‐related adverse events were reported. Plasma exposure to telithromycin (Cmax, AUC) showed a tendency to increase with increasing severity of renal impairment in both studies. In patients with severe renal impairment (CLCR < 30 mL/min) receiving telithromycin 800 mg in the repeat‐dose study, Cmax,ss and AUC(0–24 h)ss increased 1.5‐fold (p < 0.05) to 2.0‐fold (p = 0.0005), respectively, compared with healthy subjects. The percentage of dose excreted in urine and renal clearance (CLR) of telithromycin was found to decrease significantly with increasing severity of renal impairment in both studies, and CLR was found to be independent of telithromycin dose in the repeat‐dose study. In conclusion, telithromycin dosage adjustment is not necessary in patients with mild to moderate renal impairment (CLCR ≥ 30 mL/min). In patients with severe renal impairment (CLCR < 30 mL/min), dosage adjustment could be considered.

PHARMACOKINETICS OF MDL 26 479, A NOVEL BENZODIAZEPINE INVERSE AGONIST, IN NORMAL VOLUNTEERS

MDL 26479 is a new drug undergoing clinical evaluation for the treatment of depression and for memory loss associated with Alzheimers disease. As part of a dose tolerance trial, the single- (SD) and multiple-dose (MD) pharmacokinetics of MDL 26479 were evaluated in healthy male volunteers. SDs ranging from 2 to 465 mg, and doses of 30, 60, and 120 mg administered twice daily for 28 d, were examined. Serial blood samples were collected for up to 48 h. Plasma MDL 26479 concentrations were determined by HPLC. Plasma MDL 26479 concentration versus time profiles increased rapidly, followed by multiexponential decline. Time to maximum plasma concentration increased over the 230-fold SD range from 0.5 to 3.8 h. Maximum concentrations and areas under the concentration versus time curves increased disproportionately with dose. Apparent oral clearance estimates decreased from 52.9 to 13.8 Lh-1. MD pharmacokinetic parameters for doses from 30 to 120 mg were consistent with those observed following SD, thus indicating that SD pharmacokinetics are predictive of MD. SD and MD terminal half-life estimates were similar and independent of dose.

AN INVESTIGATION OF THE DOSE PROPORTIONALITY OF DEFLAZACORT PHARMACOKINETICS

The dose proportionality of deflazacort was assessed following single-dose oral administration at doses of 3, 6, and 36 mg to 24 healthy young adult volunteers. The active metabolite of deflazacort (21-desacetyl deflazacort) was monitored in plasma using a sensitive, semi-microbore liquid chromatographic method. Cmax averaged 10.4 +/- 5.0, 19.8 +/- 7.5, and 132.6 +/- 52.5 ng mL-1 for the 3, 6, and 36 mg doses, respectively. AUC(0-infinity) averaged 38.5 +/- 37.1, 64.9 +/- 20.8, and 411.7 +/- 148.5 ng h mL-1 for the same three doses, respectively. Elimination half-life ranged from 1.9 +/- 0.5 h at the 6 mg dose to 2.4 +/- 1.5 h at the 36 mg dose. Regression analyses of dose versus Cmax and AUC(0-infinity) yielded intercepts which were not significantly different from zero (p > 0.05) and slopes which were significant (p < 0.05). Regression analysis of dose versus apparent oral clearance yielded a slope which was not significantly different from zero (p > 0.05). These data indicate that deflazacort exhibits dose-proportional pharmacokinetics.

Selection of Doses for Phase II Clinical Trials Based on Pharmacokinetic Variability Consideration

Pharmacokinetic variability is an important component of the total variability in drug response, but Phase II dose‐response trials frequently are designed without considering this important factor. Mixed‐effects model simulation was performed to examine overlap of patient area under the concentration‐time curve (AUC) values between doses for drugs with differing inter‐ and intrapatient pharmacokinetic variability. Based on the results of this simulation, a dose increment of at least threefold is needed to ensure that drug exposure does not overlap in at least 50% of the patient population for a drug that exhibits greater than 25% variability. In contrast, an increment factor of 2 is normally sufficient to produce the same degree of resolution when the variability is less than 25%. These results suggest that a more aggressive choice of administration increments could lead to a better separation in systemic drug exposure between doses. This needs to be balanced against the therapeutic window of an individual drug product.

First-Pass Metabolism of Acetoaminophen in Thyroxine Treated Rats

The study on the first-pass metabolism of acetaminophen was carried out in normal and thyroxine-treated rats, administered 30 mg/kg by three routes of intravenous, intraperitoneal, and oral one. Unconjugated acetaminophen and two major metabolites, glucuronide and sulfate in the plasma and urine were then measured 5 and 24 h after the administration, respectively. It was found that there was no difference in total percentage of excreted amount, independent of the routes for administration, between normal and thyroxine-treated rats. This fact shows that acetaminophen is absorbed completely from the gastrointestinal tract. However, it was also found that the extraction ratio of gastrointestinal tract in thyroxine-treated rats became smaller, and that the volume of distribution and total body clearance became larger than those in normal rats. The first-pass metabolism of acetaminophen was found to be influenced by the continuous administration of thyroxine.