Scott J. Weir

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.

Drug interactions at the renal level: Implications for drug development

The kidney plays a major role in the elimination of drugs. The purpose of this paper is to: (i) review the mechanisms of renal elimination; (ii) identify potential mechanisms for renal drug interactions; (iii) review in vitro and in vitro animal models for studying renal elimination mechanisms and identifying potential drug-drug interactions; (iv) review experimental designs used in identifying drug-drug interactions in humans with an emphasis on gaining information regarding the mechanism of the interaction; and (v) make recommendations regarding the potential for renal drug interactions in drug development.It is concluded that clinically significant drug interactions resulting in toxicity because of some mechanism at the renal level appear to be relatively rare and that in vitro screening should not be done on all drugs during drug development. Five potential mechanisms exist for drug interactions at the renal level: (i) a displacement of bound drug resulting in an increase in drug excretion via an increase in glomerular filtration; (ii) competition at a tubular secretion site resulting in a decrease in drug excretion; (iii) competition at the tubular reabsorption site resulting in an increase in drug excretion; (iv) a change in urinary pH and/or flow that may increase or decrease drug excretion depending on the pKa of the drug; and (v) inhibition of renal drug metabolism.The most well known renal drug interaction is competitive inhibition of tubular secretion, ultimately leading to an increase in plasma drug concentration. Only when renal clearance is a major contributor to the total clearance (>30%) and plasma concentrations are greater than the Michaelis-Menten transport constant does the potential exist for clinically significant renal drug-drug interactions because only then does nonlinear pharmacokinetics become evident. The potential for drug interactions is small when renal clearance is less than 20 to 30% of the total clearance and/or when plasma concentrations are less than the Michaelis-Menten transport constant, unless the drug has a narrow therapeutic window.

Percutaneous absorption of ketoprofen from different anatomical sites in man

AbstractPurpose. The purpose of this study was to investigate the percutaneous absorption of ketoprofen applied topically to different anatomical sites on the body. Methods. The study design was a randomized, four-way crossover in 24 healthy male subjects. One gram of ketoprofen 3% gel (30 mg dose) was applied every six hours for 25 doses over a 100 cm2 of the back, arm, and knee. A 0.5 ml of ketoprofen solution (60 mg/ml) was applied to the back as a reference treatment. Plasma and urine samples were obtained for the assay of racemic ketoprofen and ketoprofen enantiomers (S and R), respectively. Results. The relative bioavailabilities of ketoprofen gel were 0.90 ± 0.50, 1.08 ± 0.63, and 0.74 ± 0.38 when applied to the back, arm, and knee, respectively. The plasma ketoprofen Cmax for gel applied to the back and arm were similar (p > 0.05) but Cmax was lower when applied to the knee (p < 0.05). The time to Cmax ranged from 2.7 to 4.0 hours and was similar for gel treatments on the back and arm, but longer for the knee treatment. The fraction of dose excreted in urine as total S and R enantiomers ranged from 5.41 to 9.10%. Conclusions. The percutaneous absorption of ketoprofen was similar when applied to either the back or arm but was lower when applied to the knee.

Single-dose Pharmacokinetics of Rifapentine in Elderly Men

AbstractPurpose. This study was undertaken to characterize the pharmacokinetic profiles of rifapentine and its active metabolite, 25-desacetyl-rifapentine, in elderly men. Methods. Fourteen healthy, nonsmoking male volunteers between the ages of 65 and 82 years received a single oral 600 mg dose of rifapentine. Plasma samples were collected at frequent intervals for up to 72 hours postdose. The control group consisted of 20 healthy, young (18−45 years) male volunteers from a previous, single-dose (600 mg) rifapentine pharmacokinetic study. Results. Plasma rifapentine concentrations above the minimum inhibitory concentration for M. tuberculosiswere observed at 2 hours after dosing. Disposition of rifapentine was monophasic with a mean terminal half-life of 19.6 hours. The peak plasma concentration of 25-desacetyl-rifapentine was found 21.7 hours, on average, after the rifapentine dose; the mean 25-desacetyl-rifapentine t1/2was 22.9 hours. Compared to the younger subjects, apparent oral clearance of rifapentine (24%) was lower in the elderly male (p < 0.05), and Cmax (28%) was higher. The only adverse event reported in both the older and younger subjects in these single-dose studies was discoloration of the urine. Conclusions. Because the age-related changes in the pharmacokinetic profile of rifapentine observed in this study were modest and unlikely to be associated with toxicity, no dosage adjustments for this antibiotic are recommended in elderly patients.

Amiodarone pharmacokinetics. I. Acute dose-dependent disposition studies in rats

Single intravenous bolus doses of amiodarone hydrochloride of 30, 60, 90 and 120 mg/kg were administered to male Sprague-Dawley rats to determine the effects of dose on amiodarone pharmacokinetics. Serial blood samples and total urine were collected over 48 hr and assayed for amiodarone and desethylamiodarone by HPLC. The blood amiodarone concentration-time curves for the four doses were best described by a triexponential equation with terminal half-lives (t1/2γ) ranging from 17 to 20 hr. Over the dose range studied, no changes in γ, t1/2γ, or central compartment volume (Vc=1.2–1.4 L/kg) were observed. On the other hand, reductions in amiodarone clearance (CL and steady-state volume of distribution (Vss of 44% (17.7 to 10.0 ml/min per kg) and 50% (16.4 to 8.2 L/kg), respectively, were noted as the dose of amiodarone increased. The conversion of amiodarone to desethylamiodarone (fm was dose-independent and amounted to approximately 10% of each amiodarone dose. No amiodarone or desethylamiodarone was detected in the urine of any of the treated animals. The blood-to-plasma concentration ratio of amiodarone was concentration-independent and therefore did not account for the dose-dependent changes in Vssand CL observed. The data suggested that the dose-dependent changes noted were due to an alteration in the volume (s) of the peripheral tissue compartment(s).

Intravenous pharmacokinetics and absolute oral bioavailability of dolasetron in healthy volunteers: part 1.

In this first part of a two‐part investigation, the intravenous dose proportionality of dolasetron mesylate, a 5‐HT3 receptor antagonist, and the absolute bioavailability of oral dolasetron mesylate were investigated. In an open‐label, randomized, four‐way crossover design, 24 healthy men between the ages of 19 and 45 years received the following doses: 50, 100, or 200 mg dolasetron mesylate administered by 10‐min intravenous infusion or 200 mg dolasetron mesylate solution administered orally. Serial blood and urine samples were collected for 48 h after dosing. Following intravenous administration, dolasetron was rapidly eliminated from plasma, with a mean elimination half‐life (t1/2) of less than 10 min. Dolasetron was rarely detected in plasma after oral administration of the 200 mg dose. Hydrodolasetron, the active primary metabolite of dolasetron, appeared rapidly in plasma following both oral and intravenous administration of dolasetron mesylate, with a mean time to maximum concentration (tmax) of less than 1 h. The mean t1/2 of hydrodolasetron ranged from 6.6–8.8 h. The plasma area under the concentration–time curve (AUC(0→∞)) for both dolasetron and hydrodolasetron increased proportionally with dose over the intravenous dose range of 50–200 mg dolasetron mesylate. Approximately 29–33% and 22% of the dose was excreted in urine as hydrodolasetron following intravenous and oral administration of dolasetron, respectively. For dolasetron as well as hydrodolasetron, mean systemic clearance (Cl), volume of distribution (Vd), and t1/2 were similar at each dolasetron dose. The mean ‘apparent’ bioavailability of dolasetron calculated using plasma concentrations of hydrodolasetron was 76%. The R(+) enantiomer of hydrodolasetron represented the majority of drug in plasma (>75%) and urine (>86%). Dolasetron was well tolerated following both oral and intravenous administration. Copyright

Pharmacokinetics of Rifapentine in Patients with Varying Degrees of Hepatic Dysfunction

In this open‐label investigation, the pharmacokinetics of rifapentine and its active metabolite, 25‐desacetyl‐rifapentine, were characterized in patients with varying degrees of hepatic dysfunction. Eight patients with mild‐to‐moderate chronic, stable hepatic dysfunction and seven patients with moderate‐to‐severe hepatic dysfunction received single oral 600‐mg doses of rifapentine. Maximum plasma concentration of rifapentine was lower, time to maximum plasma concentration (tmax) was greater, and elimination half‐life (t1/2) was longer in the patients with moderate‐to‐severe hepatic dysfunction than in those with mild‐to‐moderate dysfunction. However, mean area under the concentration—time curve extrapolated to infinity (AUC0–∞) for the two groups was similar. AUC0–∞ values in patients with hepatic dysfunction were 19% to 25% higher than values previously reported for healthy volunteers. The 25‐desacetyl metabolite appeared in plasma slowly after the single oral dose of rifapentine. Similar to findings for the parent drug, comparable plasma exposures of 25‐desacetyl‐rifapentine based on AUC0–∞ were found in the two groups of patients with mild‐to‐moderate and moderate‐to‐severe hepatic dysfunction. Rifapentine was well tolerated in this patient population, irrespective of the etiology or severity of hepatic dysfunction. These safety and pharmacokinetic results suggest that no dosage adjustments for rifapentine are needed in patients with hepatic impairment.

Single-Dose Pharmacokinetics of Rifapentine in Women

Gender can be an important variable in the absorption and disposition of some drugs. In this open-label study, 15 healthy, nonsmoking women received a single 600-mg oral dose of rifapentine. Plasma samples were obtained at frequent intervals for up to 72 hr after the dose to determine the pharmacokinetic (PK) parameters of rifapentine and its active metabolite, 25-desacetyl-rifapentine. Peak plasma rifapentine concentrations (Cmax) were observed 5.9 hr after ingestion of the single dose. The mean area under the rifapentine plasma concentration–time curve [AUC(0 → ∞ )] was 325 μg · hr ml and the mean elimination half-life (t1/2) was 16.3 hr. Plasma concentrations for the 25-desacetyl metabolite peaked at 15.4 hr after the rifapentine dose and declined with a terminal half-life of 17.3 hr. These rifapentine and 25-desacetyl-rifapentine PK data in women were compared to data generated previously in healthy men. Striking similarities in the PK profiles of parent drug and metabolite were found in the two populations. Mean differences in rifapentine CL/F (12%) and t1/2(2%) were small. The only adverse event reported in the female subjects was discoloration of the urine. Based on these PK and safety data, no dosage adjustments for rifapentine based on gender are recommended.

Steady-state pharmacokinetics of diltiazem and hydrochlorothiazide administered alone and in combination

Diltiazem and hydrochlorothiazide are widely used to treat cardiovascular disease, often in combination. The purpose of this investigation was to determine whether a drug–drug pharmacokinetic interaction exists between diltiazem and hydrochlorothiazide. In a randomized, crossover, open study, multiple doses of diltiazem (60 mg four times daily for 21 doses) and hydrochlorothiazide (25 mg twice daily for 11 doses) were administered alone and in combination on three separate occasions to 20 healthy male volunteers. Trough and serial blood samples were collected and plasma was assayed for diltiazem, hydrochlorothiazide, and diltiazem metabolites (desacetyldiltiazem and N‐desmethyldiltiazem) using HPLC. Total urine was also collected and quantified for hydrochlorothiazide.

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.