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Biomedical subjects

W A Colburn

Publications and source records attributed to W A Colburn.

At least 19 recordsLinked to original sources
PubMed1992

Clinical pharmacokinetics of procaterol: dose proportionality after administration of single oral doses.

Procaterol is a potent, orally active beta 2-agonist bronchodilator useful in the treatment of reversible bronchospastic disease. It is effective when administered as single or multiple (Q8H) 50 and 75 micrograms doses. As part of the clinical development of procaterol, the pharmacokinetics and dose proportionality of single 25, 50, 75, and 100 micrograms doses were investigated in 14 healthy subjects. Serial blood samples were collected for 16 h and urine was quantitatively collected for 48 h following administration of each dose. Procaterol concentrations in plasma and urine were determined using sensitive and specific radioimmunoassay methods. Mean values for tmax, the apparent elimination rate constant, Cl/F, renal clearance, and per cent of dose excreted unchanged in urine were similar for all doses. Dose-normalized AUC, Cmax, and amount excreted unchanged in urine (Ae) were also similar across dosage levels. Thus, the pharmacokinetics of procaterol appear to be proportional to dose over the range of doses studied.

Administration, Oral↗
PubMed1990

Multiple-dose propranolol administration does not influence the single dose pharmacokinetics of quinapril and its active metabolite (quinaprilat).

To evaluate the influence of multiple dose propranolol administration on the single dose pharmacokinetics of quinapril and its active metabolite, quinaprilat, a drug-drug interaction study was performed in ten healthy volunteers. Each subject received a single 20 mg quinapril oral dose on Days 1 and 16 of the study. Oral propranolol doses of 40 mg BID were initiated on Day 3, titrated gradually to 80 mg TID by Day 10, and continued at 80 mg TID through Day 17. Comparable mean quinapril pharmacokinetic parameter values as well as comparable mean quinaprilat pharmacokinetic parameter values determined following quinapril administered alone and following quinapril administered with propranolol, indicate that propranolol does not alter the single dose pharmacokinetics of quinapril or quinaprilat.

Adult↗
PubMed1990

Pharmacokinetic-pharmacodynamic relationships of methadone infusions in patients with cancer pain.

To determine the relationship between changes in plasma methadone concentration and pharmacodynamic effects, plasma methadone profiles and pharmacodynamics (analgesia and sedation) were measured during and after the continuous infusion of methadone for 180 to 270 minutes in 15 patients with pain caused by cancer. An increase in plasma methadone concentration resulted in a rapid increase in pain relief or sedation. The estimates of values of 50% of maximum effect (Css50) for pain relief and sedation obtained with a pharmacokinetic-pharmacodynamic model varied tenfold to twentyfold among patients; the mean Css50 value for pain relief (0.359 +/- 0.158 [SD] micrograms/ml) was virtually the same as the mean Css50 value for sedation (0.336 +/- 0.205 [SD] micrograms/ml). Similarly, the mean gamma (slope function) for pain relief (4.4 +/- 3.8 [SD]) and sedation (5.8 +/- 5.4 [SD]) did not differ. Examination of hysteresis plots of data obtained during the infusion and for 4 to 5 hours after cessation of the infusion revealed a very rapid equilibration between plasma methadone values and the sites mediating pain relief. There was no indication of the development of tolerance to the pharmacodynamic effects of methadone during the study. This report describes a method for quantitating the pharmacokinetic-pharmacodynamic relationships of the desirable and undesirable effects of opioid analgesics.

Adult↗
PubMed1990

Theophylline dosage adjustment during enoxacin coadministration.

Based on the results of a previous study which demonstrated a 50% reduction in theophylline clearance during coadministration of 400 mg of enoxacin twice a day (b.i.d.), a sequential-design study was completed with seven nonsmoking, healthy adult female human volunteers. The subjects were given 200 mg of theophylline (Theo-Dur) orally every 12 h for 4 days. On day 5, the subjects began receiving 400 mg of enoxacin with each theophylline dose, and the dosage of theophylline was reduced to 100 mg b.i.d. This regimen was continued through day 8, after which enoxacin was discontinued. The theophylline dosage was increased to 200 mg b.i.d. on day 9, and theophylline monotherapy continued through day 12. The mean apparent theophylline clearance decreased by approximately 50% during enoxacin coadministration. No significant differences in mean theophylline maximum concentration in serum, time to maximum concentration in serum, lowest concentration observed, or area under the concentration-time curve during the steady-state dosing were observed before, during, or after enoxacin coadministration when the theophylline dosage was reduced to 100 mg b.i.d. Reduction of the theophylline dose by 50% at the onset of enoxacin dosing maintained constant theophylline concentrations in plasma. A return to the original theophylline dose immediately upon cessation of enoxacin therapy resulted in a transient 35% increase in theophylline concentrations in plasma which lasted 24 to 48 h before returning to preenoxacin values. Although a 50% reduction in the theophylline dose maintained constant mean theophylline concentrations when enoxacin was administered concomitantly, it appears that larger dose reductions (up to 75%) could be required in patients with high theophylline clearances. In addition, larger transient increases in the theophylline concentration in plasma may be observed in these patients upon cessation of enoxacin therapy if the theophylline dose is immediately returned to normal. Thus, it is recommended that theophylline concentrations in plasma be monitored when concurrent enoxacin therapy is required.

Adult↗
PubMed1989

Differences in oral verapamil absorption as a function of time of day.

As part of a multiple dose bioavailability study, 80-mg verapamil hydrochloride tablets were administered to healthy subjects every 8 hours for 15 doses. Statistically significant successive decreases in verapamil maximum plasma concentrations (Cmax) and area under the concentration-time curve (AUC) values were observed corresponding to dosing at 8 AM, 4 PM, and 12 AM. Mean Cmax and AUC values from the 12 AM dose were decreased 36% and 30%, respectively, relative to those from the 8 AM dose. Similar effects on norverapamil pharmacokinetics were observed. Decreased Cmax and AUC values show that verapamil absorption is influenced by the time of day when doses are administered. Pharmacokinetic simulation results suggest that the rate of absorption is reduced approximately by one half and two thirds during the 4 PM and 12 AM dosing intervals, respectively, relative to the 8 AM dosing interval. The reductions in verapamil absorption as a function of time of administration observed in this study may in part explain previous reports of reduced antihypertensive effect during evening and night hours as compared to daytime hours.

Administration, Oral↗
PubMed1989

The clinical pharmacokinetics of quinapril.

Quinapril (Q) and quinaprilat (QT) pharmacokinetics are dose proportional following single oral 2.5- to 80-mg Q doses. Q absorption and hydrolysis to QT is rapid with peak Q and QT concentrations occurring one and two hours postdose, respectively. Peak plasma QT concentrations were approximately fourfold higher than those of Q (923 vs 207 ng/mL following 40-mg Q). Dose-proportional QT area under the curve and dose-independent percent of dose excreted in urine as QT demonstrate that the extent of Q conversion to QT is constant over the dose range studied. Q and QT were eliminated from plasma with apparent half-lives of 0.8 and 1.9 hours and apparent plasma clearances of 1,850 and 220 mL/min, respectively, over the 2.5- to 80-mg dose range. Following oral 14C-Q, 61% and 37% of radiolabel was recovered in urine and feces, respectively. Q plus QT accounted for 46% of radioactivity circulating in plasma and 56% of that excreted in urine. Metabolism to compounds other than QT is not extensive. Two diketopiperazine metabolites of Q have been identified in plasma and urine, with approximately 6% of an administered dose excreted in urine as each of these metabolites. Peak plasma concentrations of these metabolites are similar to that of Q, and each is eliminated rapidly with a half-life of approximately one hour. Urinary excretion profiles indicate the presence of other minor metabolites. In summary, the absorption of Q and conversion to QT is rapid and dose-proportional, subsequent clearance of both Q and QT is independent of dose, and metabolism to compounds other than QT is not extensive.

Absorption↗
PubMed1988

Relative and absolute bioavailability of prednisone and prednisolone after separate oral and intravenous doses.

A randomized, four-way cross-over study was conducted in eight healthy male volunteers to determine the relative and absolute bioavailability of prednisone (PN) and prednisolone (PL). PN and PL were administered as single, oral 10-mg tablet doses and as 10-mg zero-order 0.5-hour intravenous infusions. Comparable mean PN and PL maximum plasma concentrations (Cmax), times for Cmax, areas under the plasma concentration-time curves (AUC), and apparent elimination rate constants between tablet treatments demonstrated that PN and PL tablets were bioequivalent. Absolute bioavailability (F) determinations based on plasma PL concentrations were independent of which IV treatment was used as reference and indicated complete systemic availability of PL from both PN and PL tablets. However, F based on plasma PN data was contradictory. Using IV PN as reference, approximately 70% systemic availability was observed from both tablets, whereas using IV PL as reference, systemic availability was greater than unity. PN and PL are model compounds that exemplify the difficulties involved in accurately determining the relative and absolute bioavailability of substances that undergo reversible metabolism.

Administration, Oral↗
PubMed1988

Physiologic pharmacokinetic modeling.

Although physiologic modeling has not gained the widespread acceptance that was originally projected, it may serve as the basis for future PK/PD modeling approaches. In addition, with more effort applied to developing in vitro and animal-to-human predictions, physiologic modeling may assume a higher position in the pharmacokinetic modeling hierarchy.

Animals↗
PubMed1988

Combined pharmacokinetic/pharmacodynamic (PK/PD) modeling.

Several compartmental and noncompartmental approaches have been successfully applied to PK/PD modeling. Although great opportunities exist to expand on these techniques, application of these methods to relate concentrations of all drugs to their effects is possible.

Humans↗
PubMed1987

Pharmacokinetic/pharmacodynamic modeling: what it is!

Although Pharmacokinetic/pharmacodynamic modeling has been around for decades, it is still in its infancy with respect to the future of its current manifestation. Due to the amount of time and other resources that must be committed for successful development and application of these methods, economic incentives must be made available to academic and industrial scientists through the NIH and FDA, respectively. The long-term returns should more than compensate for the investments in the form of scientific understanding of the concentration-effect relationships as well as more efficient and acceptable NDAs. Could this be the answer to the drug lag in the United States and other countries?

Forecasting↗
PubMed1987

Dose-proportional absorption of etretinate after doses of 25, 50, 75, and 100 mg.

Twelve healthy male subjects received single oral doses of etretinate, ranging from 25 to 100 mg (1 to 4 x 25-mg capsules) in an open-label, four-way randomized crossover design. Plasma concentrations of etretinate and two active metabolites were determined by a specific high-performance liquid chromatographic (HPLC) method. Analysis of variance and orthogonal contrasts were used to assess dose proportionality. Mean (+/- %CV) maximum concentrations after 25- to 100-mg doses were 133 (50), 195 (33), 261 (53), and 446 (65) ng/ml, whereas AUC0-12 values were 581 (46), 1090 (39), 1500 (52), and 2440 (63) ng.hr/ml, respectively. The test for proportionality indicated that Cmax and AUC0-12 increased proportionally with an increase in dose (P greater than 0.05).

Adult↗
PubMed1987

Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain.

Concentrations of methadone in plasma, estimates of pain relief, and pupillary size were determined after a single intravenous dose (10 to 30 mg) of methadone hydrochloride to eight patients with chronic pain, five of whom had cancer. The pharmacokinetic parameter estimates reveal rapid and extensive distribution (Varea) and a slow apparent elimination half-life (t1/2) (mean Varea = 3.59 L/kg and harmonic mean t1/2 = 23 hours). The harmonic mean blood clearance is 106 ml/min, the harmonic mean renal clearance is 3.9 ml/min, the mean hepatic extraction ratio is 0.089, and plasma protein binding is 86% to 89%. These results suggest that only the free (unbound) fraction of methadone present in blood is extracted by the liver and that methadone can be classified as a low (hepatic)-extraction drug. The data were fit to a pharmacokinetic-pharmacodynamic model to obtain estimates of the steady-state plasma methadone concentration required to produce 50% of the maximum pain relief. This value varied from 0.04 to 1.13 micrograms/ml (mean = 0.29 micrograms/ml). These results indicate substantial interindividual variation in the relationship between changes in plasma methadone concentration and analgesia in patients with chronic pain receiving opioids. A pharmacokinetic-pharmacodynamic model may be useful for the individualization of analgesic dosage and therefore the optimization of pain management in patients with chronic pain.

Adult↗
PubMed1987

Relationships between CSF drug concentrations, receptor binding characteristics, and pharmacokinetic and pharmacodynamic properties of selected 1,4-substituted benzodiazepines.

Pharmacokinetic profiles of the 1,4-substituted benzodiazepines are defined by their absorption, distribution, metabolism, and excretion characteristics. An ability to cross the blood-brain barrier and the onset of pharmacological activity have been associated with the physiochemical properties of the benzodiazepines. In addition, drug concentrations in the CSF correlate with the unbound drug concentrations in blood or plasma. Duration of pharmacological activity of the benzodiazepines in humans is associated with the affinity of these compounds for the benzodiazepine receptors in human brain. Therefore, benzodiazepines with high affinity for the benzodiazepine receptor sites in human brain tend to exhibit prolonged half-lives of elimination from the CSF which correlate with the prolonged duration of clinical and pharmacological effects and lower therapeutic doses of these drugs in vivo.

Benzodiazepines↗
PubMed1986

Verapamil pharmacodynamics after intravenous and oral dosing: theoretic consideration.

Differences in the potency of intravenous (IV) and oral verapamil have recently been reported with the concentration-response curve for PR-interval prolongation being shifted further to the right following oral administration relative to IV administration. Using well-established pharmacokinetic models, a theoretic basis for these observations is presented. Simultaneous curve fitting of the IV and oral verapamil plasma concentration and PR-interval data to a single pharmacokinetic-pharmacodynamic model allowed prediction of differences in the pharmacodynamic potency of verapamil as a function of the rate of drug administration. These data indicate that the rate of input of drug into the systemic circulation can influence the rate and extent of entry of drug into an effect compartment, which in turn can result in different plasma concentration-response relationships.

Administration, Oral↗