William H. Barr

Novel in vivo procedure for rapid pharmacokinetic screening of discovery compounds in rats

In therapeutic areas aimed at developing an orally administered drug, the pharmacokinetic profile of a drug candidate after oral administration in vivo is pivotal in evaluating its success. This can be done by monitoring the plasma concentration versus time after dosing and calculating the area under the curve (AUC). The authors describe a novel screening protocol in which an estimated AUC can be determined, allowing the rapid evaluation of large numbers of compounds and providing a rank order of estimated AUC values to prioritize compounds for further investigation.

A pharmacokinetic evaluation of 14C-labeled afovirsen sodium in patients with genital warts.

Afovirsen sodium is a 20‐mer phosphorothioate oligonucleotide designed to be complementary to the messenger ribonucleic acid sequence for the translation initiation codon of the E2 protein vital to replication of human papillomaviruses types 6 and 11. 14C‐Labeled afovirsen was given as a single‐dose intradermal injection in each of four warts of five patients to determine the time‐dependent changes in concentration of intact afovirsen in genital warts and to determine the systemic absorption and elimination of radiolabeled compound. Intact afovirsen in genital warts was determined by high pressure liquid chromatography analysis of protease K digested extracts. Intact afovirsen was present in wart tissue for at least 72 hours at concentrations several times in excess of the estimated minimal inhibitory concentration of 1 µmol/L. Absorption of radiolabeled afovirsen from the injection site was rapid, with a peak plasma concentration achieved within 1 hour. Clearance of afovirsen was primarily attributable to slow metabolism, with about 30% of the radiolabel eliminated as 14C‐CO2 in expired air over a 6‐day period after dosing. Radioactivity eliminated in urine represented metabolites of afovirsen. From the clinical pharmacokinetic data presented here and from previously published pharmacokinetic data in rats, the disposition of afovirsen in humans appears to be relatively similar to that in rats. These data suggest that once or twice weekly dosing regimen in the clinic may be appropriate.

Differential absorption of amoxicillin from the human small and large intestine

Differences in extent of amoxicillin absorption from various regions of the gastrointestinal tract were determined and compared with the same dose administered orally. Nine healthy men were intubated at a proximal (duodenum or jejunum) or distal (ileum or colon) site with use of a 15‐foot double lumen nasointestinal tube. Amoxicillin solutions (375 mg in 120 ml water) were delivered on 2 successive days as a bolus or a 4‐hour infusion. Subjects were reintubated at another site and amoxicillin administration was repeated. Subjects with colonie intubation received only infusions. Finally, all subjects received an oral dose of amoxicillin solution. Plasma samples were obtained at 16 time points over a 10‐hour period and assayed for amoxicillin by use of an HPLC method. Area under the concentration‐time curve and the maximum plasma concentration were computed to evaluate amoxicillin absorption. Amoxicillin absorption was rate and site dependent in the gastrointestinal tract. The drug was well absorbed in the duodenum and jejunum, with no significant differences in absorption when administered as a bolus or 4‐hour infusion, but absorption was decreased and rate dependent in the ileum, where more drug was absorbed as an infusion compared with a bolus. Amoxicillin was unabsorbed when infused in all colonie regions.

Risedronate Pharmacokinetics and Intra- and Inter-Subject Variability upon Single-Dose Intravenous and Oral Administration

AbstractPurpose. To determine the pharmacokinetics and absolute bioavailability of risedronate after single-dose oral administration of 30 mg risedronate as a tablet and an aqueous solution, and 0.3 mg risedronate as an intravenous infusion. Methods. This study was a randomized, three-treatment, four-period, partial replicate crossover study involving 33 healthy volunteers. Treatments were administered 7 weeks apart, and the third treatment was repeated during the fourth period. Serum and urine were collected over 72 hours and 672 hours, respectively. Results. Following intravenous administration, renal clearance accounted for 87% of total clearance, with 65% of the dose excreted within 24 hours and 85% of the dose excreted within four weeks. The absolute bioavailability was approximately 0.62% after both oral formulations, and the relative bioavailability of the tablet compared with the oral solution was 104%. The rate and extent of absorption from the two formulations were bioequivalent based on the range proposed for highly variable drugs. Intrasubject variability following oral administration was 50-80%, and was primarily associated with absorption. Conclusion. The majority of the total clearance after intravenous administration of risedronate was renal clearance, indicating that only a small percentage of a systemic dose is potentially incorporated, or “cleared,” into bone. The absolute bioavailability of orally administered risedronate is ∼0.6%, and is independent of formulation. Variability in the pharmacokinetics following oral administration is primarily associated with intrasubject variability in absorption.

Opportunities for Integration of Pharmacokinetics, Pharmacodynamics, and Toxicokinetics in Rational Drug Development

Carl C. Peck, MD, William H. Barr, PharmD, PhD, Leslie Z. Benet, PhD, Jerry Collins, PhD, Robert E. Desjardins, MD, Daniel E. Furst, MD, John G. Harter, MD, Gerhard Levy, PharmD, Thomas Ludden, PhD, John H. Rodman, PharmD, Lilly Sanathanan, PhD, Jerome J. Schentag, Pharmfl, Vinod P. Shah, PhD, Lewis B. Sheiner, MD, Jerome P. Skelly, PhD, Donald R. Stanski, MD, Robert J. Temple, MD, C. T. Viswanathan, PhD, Judi Weissinger, PhD, and Avraham Yacobi, PhD

Absorption of danazol after administration to different sites of the gastrointestinal tract and the relationship to single- and double-peak phenomena in the plasma profiles

The absorption of danazol (100 mg) after oral or intraintestinal administration to the proximal jejunum or proximal ileum has been studied in healthy female subjects. The extent of danazol absorption after administration as a solubilized glycerol mono‐oleate emulsion formulation was approximately twofold and fourfold greater after oral dosing when compared with jejunal or ileal administration, respectively. Although not statistically significant in this study, the extent of absorption after jejunal administration was generally greater than after ileal administration. After oral dosing, qualitative assessment identified the presence of double peaks or major shouldering characteristics in 14 of the 16 individual danazol plasma concentration‐time profiles, whereas only single peaks were present after intraintestinal administration. These data are consistent with the double peaking phenomena after oral administration of the emulsion formulation being stomach‐related. The double peaking effect may be explained in terms of a probable combination of gastric emptying regulated absorption (due to the presence of the lipid in the emulsion formulation) and the dependence of danazol solubility on bile salt solubilization within the upper small intestine.

Pharmacokinetics, safety, and tolerability of gadoversetamide injection (OptiMARK) in subjects with central nervous system or liver pathology and varying degrees of renal function

The pharmacokinetic parameters, safety, and tolerability of OptiMARK (gadoversetamide injection), a gadolinium‐based magnetic resonance imaging (MRI) contrast agent, were evaluated in 163 subjects with either central nervous system (CNS) or liver pathology with and without renal insufficiency, for which a contrast‐enhanced MRI was indicated. A multicenter, double‐blind, randomized, placebo‐controlled, parallel‐group design was used in which subjects received 0.1, 0.3, or 0.5 mmol/kg of OptiMARK or placebo intravenously. Samples were analyzed for total gadolinium by inductively coupled plasma/mass spectrometry. Gadolinium pharmacokinetics were affected by renal impairment: area under the curve, half‐life, and steady‐state distribution volume significantly increased with declining renal function, while total body clearance decreased. In subjects with normal renal function, neither age, gender, nor liver versus CNS pathology altered gadolinium pharmacokinetics. No clinically significant changes from baseline were noted in vital signs, laboratory measures, electrocardiograms, or physical examinations. OptiMARK is safe and well‐tolerated following a single intravenous injection in subjects with either liver or CNS pathology despite a prolonged elimination half‐life in subjects with renal impairment. J. Magn. Reson. Imaging 1999; 9:317–321.

Comparison of the Pharmacokinetics of an Ondansetron Solution (8 mg) When Administered Intravenously, Orally, to the Colon, and to the Rectum

Ondansetron, an antagonist of the serotonin type 3 (5-HT3) receptor, is indicated for the treatment of chemotherapy-induced emesis. This study compares the pharmacokinetics, especially the bioavailability, of an Ondansetron 8-mg solution when administered intravenously, orally, to the colon via nasogastric intubation, and to the rectum using a retention enema. Six healthy, male volunteers received ondansetron infused into the colon during the first treatment period. These subjects then received the remaining three treatments in random order, with a minimum 1-week washout period between treatments. Serial plasma samples were obtained for up to 24 hr after dosing in each treatment period. Absolute bioavailability after the oral dosing, colonic infusion, and rectal administration averaged 71 ± 14, 74 ± 26, and 58 ± 18%, respectively. These values were not significantly different (P > 0.05). Values of Tmax and Cmax were also not significantly different among the nonparenteral routes. Mean absorption half-lives were 0.66, 1.1, and 0.75 hr after the oral, colonic, and rectal administrations, respectively. These results indicate that ondansetron is well absorbed in the intestinal segments studied including the upper small intestine, the colon, and the rectum and that sustained-release and suppository formulations of ondansetron are feasible.

Comparison of methods for the assessment of central nervous system stimulant response after dextroamphetamine administration to healthy male volunteers

The objective of this investigation was to evaluate a series of potential pharmacodynamic measures of central nervous system stimulation, including quantitative electroencephalography (EEG) and neuroendocrine, mood, and psychomotor performance measures. The reproducibility and sensitivity of the measures were compared. The study was conducted in two parts. The first part investigated the interindividual and intraindividual variability associated with a series of potential pharmacologic response measures under baseline (i.e., drug‐free) conditions. It was an open‐label, three‐period pilot study in which healthy male volunteers underwent a series of tests (EEG, a visual continuous performance task, a finger tapping task, and self‐rated mood scales) repeatedly during each study period. The second part evaluated the sensitivity of a series of potential response measures to detect the effects of dextroamphetamine, and was a double‐blind, placebo‐controlled, four‐period crossover study in nine healthy male volunteers. Subjects received 5 mg, 10 mg, or 20 mg of dextroamphetamine or placebo orally and underwent the same series of tests as in Part I in addition to blood collection for determination of serum prolactin and dextroamphetamine levels. Peripheral response to dextroamphetamine was assessed by heart rate and blood pressure measurement. The greatest variability among days, within days, and among participants was associated with the quantitative electroencephalographic parameters studied. First‐session effects were apparent for several of the tests, including EEG. Consistent response on EEG (increased alpha power) to dextroamphetamine was observed only in the three subjects who had a baseline alpha activity greater than 35%. Serum prolactin levels were inversely associated with the amount of dextroamphetamine administered, with the largest decrease in serum prolactin levels observed after the 5‐mg dose, and this finding was statistically significant. Mood scales showed that three of nine participants experienced dysphoria after at least one dose level of dextroamphetamine. The effect on mood was generally greater as the dose increased. Doses could not be distinguished based on the results of the performance tests. Serum prolactin concentration was the most sensitive measure of central nervous system stimulation on EEG produced by dextroamphetamine under these study conditions. Cardiovascular measures were more sensitive measures of dextroamphetamine effects than the central nervous system measures.

Site-Differential Gastrointestinal Absorption of Benazepril Hydrochloride in Healthy Volunteers

The absorption of benazepril-HCl (BZPH), an orally active angiotensin-converting enzyme (ACE) inhibitor, in various regions of the gastrointestinal (GI) tract was investigated using an intestinal intubation technique. Thirteen subjects completed this single-dose, three-phase sequential crossover study. The drug (20 mg) was administered either as a 4-hr colonic infusion (COLON) or as a small intestinal infusion (SI) in the first two phases and as an oral bolus solution (ORAL) in the third phase, with a 2-week washout between each treatment. Serial plasma and urine samples were collected for up to 4 days after dosing. BZPH and its active metabolite benazeprilat (BZPL) were determined using a gas chromatography/mass spectrometry method. BZPH was absorbed rapidly into the bloodstream (Tmax = 0.5 hr after ORAL). Absorption was also rapid for SI, with a postinfusion half-life (0.57 hr) nearly identical to that for ORAL (0.59 hr). The absorption rate after COLON was much slower (lower Cmax and longer Tmax) compared to that after SI, and the apparent half-life (1.7 hr) was prolonged. SI delivered 90%, whereas COLON delivered 23%, of the drug into the systematic circulation as compared to ORAL. BZPL was rapidly formed upon drug absorption. The metabolite-to-drug AUC ratios were comparable for SI and ORAL (8.9 vs 9.7), indicating that first-pass metabolism of BZPH was neither saturable nor input rate dependent. The metabolite-to-drug AUC ratio was reduced for COLON (5.0), indicating that the mechanism of absorption of BZPH in the colon may be different than that after SI and ORAL. Urinary recovery data were consistent with plasma data. It can be concluded that COLON delivered a smaller amount of drug at a slower absorption rate to the body than either SI or ORAL.