Richard J. Fruncillo

Quantitation of cytochrome P450 mRNA levels in human skin

There is considerable interindividual variation in mans ability to metabolize drugs and foreign compounds. These differences can partly be attributed to genetic polymorphisms that result in the generation of multiple phenotypes with different drug-metabolizing capabilities. Genetically derived differences can easily be assessed by genotyping assays in cases where the polymorphism has been identified. However, many of the polymorphisms that result in these are not known, secondly not all the differences can be attributed to genetic polymorphisms, hence genotyping methods cannot be employed. We have therefore, developed real-time (Taqman) PCR assays to quantitate levels of P450 mRNAs in human tissues. These assays are highly sensitive, reproducible, and specific and will allow quantitation of P450 mRNA levels in various human tissues. We have applied these assays to quantitate cytochrome P450 mRNA levels in human skin samples from 27 healthy volunteers. The expression of 13 P450s was assessed. The major enzymes detected were CYP1B1, CYP2B6, CYP2D6, and CYP3A4 with mean values of 2.5, 2.6, 2.7, and 1.1 fg/18S rRNA in 50ng total RNA, respectively. Lower levels of CYP2C18, CYP2C19, and CYP3A5 were also detected while CYP1A2, 2A6, and 2C8 were below limits of detection. There was interindividual variation in the levels of mRNA among the 27 subjects studied although Poisson analysis showed data to be normally distributed, except for CYP2B6, as some individuals completely lacked CYP2B6 mRNA.

Multiple‐Dose, Linear, Dose‐Proportional Pharmacokinetics of Retigabine in Healthy Volunteers

Retigabine, a first‐in‐class selective M‐current potassium channel opener, is a novel antiepileptic compound currently in clinical development. The purpose of this randomized placebo‐controlled study was to assess retigabine oral safety and pharmacokinetics in healthy male volunteers (N = 45). Subjects received one dose on day 1 and doses every 12 hours for the next 14 days. Fixed doses were given to the first four groups (200, 400, 500, and 600 mg per day). Titrated doses were given to group 5 in 100 mg increases every 4 days, achieving 700 mg per day on day 15. Serial blood samples were collected on days 1 and 15. Pharmacokinetic parameters were compared between days and among dose groups. After administration of a single dose, retigabine was rapidly absorbed, with maximum concentrations of 387 ng/ml (normalized to a 100 mg dose) occurring within 1.5 hours. Retigabine was eliminated with a mean terminal half‐life of 8.0 hours and an apparent oral clearance of 0.70 L/h/kg in white subjects. In black subjects, retigabine clearance and volume of distribution were 25% and 30% lower, respectively, after normalizing by body weight, leading to higher exposure in this population. Retigabines pharmacokinetics was linearly dose proportional. Steady‐state pharmacokinetics was in agreement with single‐dose pharmacokinetics, and the accumulation ratio was about 1.5. Retigabine and AWD21‐360 trough evening concentrations were significantly lower (about 30% to 35%) than morning values. The titration regimen allowed for higher doses to be tolerated compared to the fixed‐dose regimen. In conclusion, the pharmacokinetics of retigabine is linearly dose proportional for daily doses of 100 to 700 mg and is not modified on multiple administrations.

The Pharmacokinetics of Venlafaxine When Given in a Twice-Daily Regimen

The comparative bioavailability of the novel antidepressant venlafaxine and its pharmacologically active metabolite O‐desmethylvenlafaxine was assessed when venlafaxine was given orally twice daily (75 mg bid) or 3 times daily (50 mg tid). Eighteen healthy subjects participated in an open‐label, randomized, two‐period, crossover study lasting 12 days. Each subject was randomly assigned to take venlafaxine according to a bid or a tid regimen through day 8 and was crossed over to the other regimen on days 9 to 12. The daily dose was titrated up to 150 mg/d and was held constant on days 5 to 12. Plasma samples for quantitation of venlafaxine and O‐desmethylvenlafaxine were obtained during a 24‐hour steady‐state interval on days 8 and 12. Analysis of variance showed no significant differences between the two venlafaxine regimens for peak concentration (Cmax), area under the curve during 24 hours (AUC0–24), trough concentration, or fluctuation ratio for venlafaxine or O‐desmethylvenlafaxine in plasma. The bioequivalence ratios for Cmax and AUC0–24 of both compounds were calculated to compare the bid regimen and the tid regimen. The mean value for each of the 4 ratios was between 96 and 100%, and the 90% confidence limits around each ratio were within 90 to 110%. These results indicate that dividing a daily 150‐mg venlafaxine dose into 2 or 3 doses provides equivalent total exposure and peak plasma concentrations of venlafaxine and O‐desmethylvenlafaxine, its active metabolite. Therefore, based on pharmacokinetic considerations, it appears that the same daily dose of venlafaxine can be given in either two or three divided doses without compromising efficacy.

Effects of age and sex on single-dose pharmacokinetics of tigecycline in healthy subjects.

ABSTRACT The pharmacokinetics of tigecycline was evaluated in 46 healthy young and elderly men and women. Except for the volumes of distribution at steady state (approximately 350 liters in women versus 500 liters in men), there were no significant differences in tigecycline pharmacokinetic parameters. Based on pharmacokinetics, no dosage adjustment is warranted based on age or sex.

Lack of Pharmacokinetic Interaction between Oral Pantoprazole and Cisapride in Healthy Adults

Pantoprazole, an irreversible proton pump inhibitor, may be administered with cisapride, a prokinetic agent. As increased cisapride concentrations may result in longer electrocardiogram (ECG) QTc intervals, a crossover study was conducted in healthy subjects to evaluate the oral pharmacokinetic interaction between cisapride (20 mg) and pantoprazole (40 mg). After dosing, serial blood samples and 12‐lead ECGs were collected, and cisapride plasma concentrations were quantitated. For cisapride alone, mean parameter values were the following: peak concentration (Cmax), 56 ng/mL; time to Cmax (tmax), 1.7 hours; area under the concentration‐time curve (AUC), 426 ng•h/mL; and terminal half‐life (t1/2), 5.8 hours. Pantoprazole coadministration did not alter cisapride AUC or other pharmacokinetic parameters except for a slight 17% decrease in Cmax, resulting in 90% confidence limits of 79% to 88%, which were marginally outside strict bioequivalence limits. In addition, cisapride did not affect ECG QTc intervals, with or without pantoprazole. Therefore, no dosage adjustment is needed when pantoprazole and cisapride are coadministered.

Absence of an interaction between tigecycline and digoxin in healthy men.

Study Objective. To evaluate a potential interaction between tigecycline and digoxin using pharmacokinetic and pharmacodynamic assessments.

Pharmacokinetics and Pharmacodynamics of A Novel Vasopressin Receptor Antagonist, VPA‐985, in Healthy Subjects

Clinical Pharmacology & Therapeutics (1999) 65, 189–189; doi:

An ascending multiple‐dose study of the safety and pharmacokinetics of a sustained‐release formulation of desvenlafaxine succinate in healthy subjects

To assess the safety, tolerability, and pharmacokinetics (PK) of ascending multiple oral doses of a sustained‐release formulation of desvenlafaxine succinate (DVS‐SR) in healthy subjects.

The absolute bioavailability of an oral sustained‐release formulation of desvenlafaxine succinate in healthy subjects

To assess the absolute bioavailability of sustained‐release desvenlafaxine succinate (DVS‐SR) and pharmacokinetics of desvenlafaxine (DV) in healthy subjects.

Bromfenac disposition in patients with impaired kidney function

To compare the pharmacokinetics of bromfenac among normal subjects and renally compromised patients and patients with end‐stage renal disease.