Curve fitting and unique parameter identification.
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Animals↗
Biomedical subjects
W A Colburn
Publications and source records attributed to W A Colburn.
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↗
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↗
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↗
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↗
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↗
Controversy I: Patients or healthy volunteers for pharmacokinetic studies?
Many factors should be considered when choosing an appropriate population for a pharmacokinetic trial. Although there are some generalities that apply to most studies, each investigation must be judged separately, since the relevant considerations will vary depending on the particular study, the nature of the drug, and the population that will receive it for therapeutic benefit. Some of the most important information that is generated from pharmacokinetic studies concerns the pharmacokinetic variability among patients and the factors that can influence this variability under the conditions that the drug will be used. This information can best be obtained from a combination of baseline studies to define the variability within the patient population(s) and comparative studies to determine the impact of specific variables on the disposition of the drug and its pharmacokinetic variability. These data can provide valuable information to the clinician that can be used to individualize drug dosage and optimize therapy as well as to identify populations who may be at high risk of therapeutic failure or drug toxicity. It is our feeling that baseline studies in patients are necessary for understanding the pharmacokinetics of a drug, whereas the objectives of most comparative studies can be achieved using healthy volunteers. For most comparative studies, the data obtained from healthy volunteers will reflect what will occur in patients, especially if the variable of interest is drug absorption. This is particularly important when practical and ethical considerations preclude the use of patients. When considering studies in the elderly, one must decide whether the variable of interest may be influenced by age.(ABSTRACT TRUNCATED AT 250 WORDS)
Biological Availability↗
Relative bioavailability: what reference?
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Biological Availability↗
Evaluation of drug absorption by nonlinear regression, statistical moments, and Loo-Riegelman methods.
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Absorption↗
Balanced incomplete-block design: its use and misuse.
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Aspirin↗
Intravenous and intramuscular pharmacokinetics of recombinant leukocyte A interferon.
Interferon is currently being evaluated for the treatment of disseminated cancer and viral diseases. Alpha interferons have shown to be effective in the treatment of a number of malignancies. Recombinant leukocyte A interferon (rIFN-alpha A) is an alpha interferon produced by recombinant DNA techniques. A kinetic evaluation of rIFN-alpha A following intravenous and intramuscular administration has not been adequately defined. The present study was designed to evaluate the kinetics of rIFN-alpha A following intravenous and intramuscular administration of 3, 9 or 18 X 10(6) units to patients with disseminated cancer. A preliminary report of this study was presented at the meeting of the American Society for Clinical Pharmacology and Therapeutics in San Diego, March 1983 (1).
Adult↗
Dose dependent pharmacokinetics of midazolam.
The pharmacokinetics of midazolam and 1-hydroxymethylmidazolam were investigated following oral administration of 7.5, 15 and 30 mg doses of midazolam in solution to 12 healthy subjects. Compared to the 7.5 mg dose, the Cmax and AUC parameters of both midazolam and 1-hydroxymethylmidazolam increased proportionally after the 15 mg dose and more than proportionally after the 30 mg dose. The t1/2 for midazolam remained relatively constant between the 7.5 and 15 mg doses whereas it increased slightly but significantly after the 30 mg dose. These data indicated that the pharmacokinetics of midazolam and 1-hydroxymethylmidazolam were linear between the 7.5 and 15 mg oral dose range. However, after the 30 mg dose, the systemic availability of midazolam and the AUC for 1-hydroxymethylmidazolam appeared to be greater than that anticipated from the lower doses, possibly due to saturation of midazolam first-pass metabolism. This is not expected to have any clinical significance under the conditions of therapeutic use.
Adult↗
D-Propoxyphene: accumulation or altered kinetics?
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Dextropropoxyphene↗
Trimoprostil plasma concentration--gastric acid inhibition relationships: potentiation by food.
A single, oral, 1.5-mg dose of trimoprostil was taken before a standard meal and a matching placebo was taken after a standard meal by 10 subjects (group A). A second group of 10 subjects took placebo before a meal and trimoprostil after the meal (group B), while a third group took placebo both before and after the standard meal (group C). Food-stimulated gastric acid production was measured by intragastric titration for 6.5 hr after dosing. Trimoprostil taken after the meal had a greater effect on gastric acid secretion than when taken before the meal: Duration of effect was 5 to 5.5 hr in group B and 2 to 2.5 hr in group A. Blood samples were drawn and assayed for trimoprostil by gas chromatography-mass spectrometry. Mean trimoprostil plasma concentration and mean inhibition of gastric acid secretion data were fit to two models by the Hill equation. The mean plasma concentration associated with 50% inhibition of gastric acid secretion was 1.25 ng/ml. Trimoprostil plasma concentrations between 3 and 4 ng/ml were associated with 70% to 80% gastric acid inhibition. Overall, there appears to be a pharmacokinetic-pharmacologic correlation between trimoprostil plasma concentrations and inhibition of gastric acid secretion. Trimoprostil (1.5 mg) in the presence of food appears to have a therapeutic advantage, in that it decreases acid secretion longer than when taken without food and suffers no loss of bioavailability.
Adult↗
Isotretinoin kinetics after 80 to 320 mg oral doses.
Twelve healthy male subjects received 80, 160, 240, and 320 mg doses of oral isotretinoin as multiples of 40 mg capsules separated by 2-week washout periods in a randomized, crossover design. Blood samples were drawn at specific times over a 72-hour period after dosing. Blood concentrations of isotretinoin as well as its major metabolite, 4-oxo-isotretinoin, were determined by a specific HPLC method. In addition to the normal laboratory battery of tests, serum triglyceride levels were determined before the first dose and again 72 hours after each of the four doses. Mean (+/- SD) maximum concentrations after 80 to 320 mg doses were 366 +/- 159, 820 +/- 474, 1056 +/- 547, and 981 +/- 381 ng/ml, whereas the respective AUC0-infinity values were 3690 +/- 1280, 7030 +/- 4140, 9780 +/- 6080, and 9040 +/- 2900 ng X hr/ml. The observed apparent elimination t1/2 remained approximately the same (14.7 hours) for each dose. The maximum concentration and AUC values for isotretinoin appear to be dose proportional from 80 to 240 mg but plateau at the 320 mg dose level. Therefore, because isotretinoin blood concentrations may not increase with higher doses in the fasting state, single, oral doses in excess of 240 mg should be used with caution. The data also suggest that elevated triglyceride levels are not a simple function of isotretinoin blood concentrations across the entire study population and dose range studied, but that in subjects with triglyceride levels in excess of the normal range triglyceride levels were positively related to isotretinoin blood concentrations.
Administration, Oral↗
Pharmacokinetic model to describe the disposition of lead in the rat.
A pharmacokinetic model was developed to describe the disposition of lead in the rat. The model can be used to predict the effect of acute high-dose as well as low-dose exposure to lead. These results suggest that the model should be able to predict the effect of chronic low-dose exposures as well. Plasma, bone, liver, and bile profiles were generated from this model using previously published data. The results obtained supported the existing theory that lead demonstrates a dose-dependent pharmacokinetic profile in the rat.
Animals↗
Pharmacokinetics of recombinant leukocyte A interferon following various routes and modes of administration to the dog.
The pharmacokinetics of recombinant leukocyte A interferon (rIFN-alpha A) were studied following intravenous (i.v.) bolus, 60 min (i.v. inf.) infusion, intramuscular (i.m.), subcutaneous (s.c.), and oral (p.o.) administrations to 15 male beagle dogs. Each animal received at least one 3 X 10(6) units/kg dose of rIFN-alpha A by one of the five routes and/or modes of administration. Blood samples were collected and the serum was separated and analyzed for rIFN-alpha A concentrations by an enzyme immunoassay, ELISA. There were no measurable rIFN-alpha A concentrations (less than 0.020 ng/ml) following oral administration. In general serum rIFN-alpha A concentrations exceeded 100 ng/ml following i.v. bolus and infusion doses then declined rapidly in a biphasic manner. The volume of distribution at steady state Vdss ranged from 0.14 to 0.21 liters/kg after i.v. infusion. Total body serum clearance (ClB) ranged from 14.6 to 23.9 ml/min, which is about 50% the estimated inulin clearance in dogs. The harmonic mean elimination half-lives ranged from 4.5 to 9.5 h. A prolonged absorption profile was seen following i.m. and s.c. administrations and the systemic bioavailability for both routes was 42% when compared with the i.v. infusion. These appear to be the first pharmacokinetic profiles of rIFN-alpha A reported in the dog.
Animals↗
Single-dose pharmacokinetics and dose proportionality of oral cibenzoline.
The pharmacokinetics of cibenzoline were evaluated in four young healthy volunteers who received ascending oral doses of 65, 97.5, 130, 162.5, 195, 227.5, and 260 mg separated by one week. Cibenzoline plasma concentrations exhibited an apparent biexponential decline following oral absorption. Maximum plasma concentrations and area under the plasma concentration-time curve increased in proportion to the dose. The mean elimination half-life among subjects was independent of dose and ranged from 7.3 to 8.7 hours. Oral clearance ranged from 380 to 575 ml/min and was also independent of dose. A single pharmacokinetic equation was used to adequately describe the plasma concentration data over the entire range of doses for each subject, indicating dose-proportional and linear pharmacokinetics.
Administration, Oral↗