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Etanercept pharmacokinetics in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriasis were assessed separately with distinct models using population pharmacokinetics methods of limited precision. The different model structures and associated significant covariates identified by these earlier methods made it difficult to compare etanercept pharmacokinetics among disease groups. This integrated analysis aimed to establish a framework to evaluate previously established population pharmacokinetic models of etanercept, and to identify consistent and important demographic and disease factors that affected etanercept pharmacokinetics in a diverse population of healthy subjects and patients with RA and AS. In this integrated analysis, cumulative rich and sparse etanercept concentration data from 53 healthy volunteers, 212 patients with RA, and 346 patients with AS were examined and compared using nonlinear mixed effect methodology implemented the in NONMEM VI software package. A more precise estimation method (FOCEi) was employed and compared with the first-order method in population pharmacokinetics model building and evaluation. The integrated analysis found that an optimal population pharmacokinetics model with a 2-compartment structure adequately characterized etanercept pharmacokinetics in all subject groups. Health status or disease type did not significantly affect etanercept pharmacokinetics. In adult patients with RA and AS, age and body weight do not significantly affect etanercept pharmacokinetics.

The time of peak concentration after administration of oral drug is an often quoted and used pharmacokinetic parameter. It is not well appreciated, however, that the peak times after a single dose and a dose at steady state during a multiple administration regimen can differ significantly. This article derives the mathematical relationships that determine how a peak time at steady state differs from that after a single or first dose. These relationships are then evaluated using three different approaches: 1) graphic simulations of time courses of drug concentration for three hypothetical drugs; 2) comparisons of predicted and observed peak times using examples from the literature; and 3) comparisons of predicted and simulated peak times based on different sampling schedules for three hypothetical drugs. The key finding is that peak times after a dose at steady state can occur considerably earlier after administration than after a single dose. However, the manner by which peak times are usually determined, that is, the sampling time corresponding to the highest measured drug concentration, imposes significant limitations on the usefulness of this parameter.

A matrix method has been developed for the evaluation of therapeutic agents based on six categories of therapeutic specificities and three levels of therapeutic effectiveness. The therapeutic specificity categories are based on the relationship between a drug’s therapeutic effect and the pathophysiologic process being treated or prevented. The therapeutic effectiveness levels are based on the drug’s degree of effectiveness with respect to the underlying disease or disease process. By providing a framework for comparisons across different therapeutic agents, this matrix evaluation method may have applications in assessing different therapeutic options, choosing clinical trials endpoints, and selecting drug discovery targets.

A famotidine wafer that rapidly disperses on the tongue without water is a novel alternative to other histamine2 (H2)-antagonist dosage forms. Benefits associated with such a dosage form include convenience and potentially improved compliance for patients who dislike or have difficulty taking tablets and capsules. This report describes the research of three studies on the famotidine wafer dosage form. In the first trial, the bioequivalence and tolerability of the new 40-mg famotidine wafer and the marketed 40-mg famotidine tablet were studied in a 2-period crossover study (n = 18). The two formulations were bioequivalent as assessed by area under the plasma concentration versus time curve and maximum plasma concentration of famotidine. The plasma concentration of famotidine associated with 50% inhibition of pentagastrin stimulated gastric acid secretion (EC50; 10 ng/mL) was attained on average within 0.5 hours post-dose for the wafer and tablet. In a second trial, the tolerability of the famotidine 20-mg and 40-mg wafers or placebo given twice daily (bid) for 14 days were evaluated (n = 192). Both wafer strengths were well and equally tolerated. In a third trial of 450 subjects, the 40-mg wafer was preferred over tablets by 75% of the subjects, when they were asked to consider the method of administration and flavor. When used as an alternative to tablets and other conventional dosage forms, the wafers have the potential therapeutic benefit of improved compliance. It is concluded that similar systemic exposure, excellent tolerability, palatability, and preference make the famotidine wafer a clinically acceptable and convenient dosage from for patients on H2-antagonist therapy.

Simulations of time courses of drug concentrations after oral administration are frequently hampered by the lack of pharmacokinetic parameters after oral dosing. This article presents methods by which to estimate such parameters from pharmacokinetic parameters after intravenous dosing and knowledge of time of peak concentration and bioavailability after oral dosing. The application of these approaches enables the generation of meaningful graphic simulations of time courses of drug concentrations after oral administration that can have educational and illustrative uses.

In 15 non-diabetic Type II hypercholesterolemic patients, the effect of 80 mg lovastatin daily on oral glucose tolerance was investigated. Using a randomized, double-blind, two-panel, parallel design, patients on a low cholesterol diet received lovastatin (n = 7) or placebo (n = 8) for 6 weeks. After 6 weeks of treatment, patients receiving lovastatin had a significant reduction in total cholesterol (30%), LDL-cholesterol (36%), and triglycerides (26%). Time courses of plasma glucose and serum insulin changes from baseline after the oral glucose tolerance test were evaluated by AUC. No statistically significant differences were observed in the AUC of changes from baseline between treatment groups or within either treatment group at prestudy, 6 weeks, and poststudy. No patient had a clinically important laboratory or clinical drug-related adverse effect during the study. This study demonstrated that short-term administration of 80 mg lovastatin daily effectively lowers cholesterol without having adverse effects on oral glucose tolerance.

Losartan is an orally active, nonpeptide angiotensin II (Ang II) (site-1) receptor antagonist. We conducted a multiple-dose study in healthy male volunteers to investigate the tolerability, blood pressure effects, and changes in plasma renin activity (PRA) and plasma Ang II concentration associated with once-daily administration of 100 mg losartan for a week. Subjects were studied on a standardized sodium diet (24-hour urinary sodium excretion, 98 +/- 37 [SD] mEq per 24 hours on the placebo run-in day). Measurements of blood pressure, heart rate, PRA, Ang II, and aldosterone were taken during a placebo run-in day and after single and multiple (7 days) daily doses of losartan (100 mg, n = 10) or placebo (n = 4). Ang II was measured specifically by high performance liquid chromatography coupled with radioimmunoassay. In subjects given losartan, respective decreases (systolic/diastolic) from run-in in supine blood pressure 6 hours after dosing were (mean +/- SD), compared with the placebo run-in day, first dose: -8.8 +/- 9.6/-6.8 +/- 5.0, last dose: -11.6 +/- 8.9/-7.0 +/- 4.8 mm Hg (p < 0.05 for all changes). At this 6-hour time point, corresponding increases from run-in in PRA were from 1.2 +/- 0.6 to 12.0 +/- 6.3 (first dose) and 9.6 +/- 4.9 (last dose) ng angiotensin I per milliliter per hour and in Ang II were from 4.3 +/- 1.7 to 72.4 +/- 33.3 and 45.7 +/- 14.1 pg/mL. All changes in PRA and Ang II were statistically significant within the losartan-treated group, and the biochemical changes were significantly greater than those in the placebo-treated group. The increment in Ang II was less after the last dose than after the first (p < 0.05). The drug was well tolerated by all subjects. These data indicate that, under the conditions of this study, losartan administration (100 mg/day for eight doses over 9 days) results in treatment-related decreases in blood pressure and increases in PRA and Ang II octapeptide.

The International Conference on Harmonization (ICH) E5 guidelines were developed to provide a general framework for evaluating the potential impact of ethnic factors on the acceptability of foreign clinical data, with the underlying objective to facilitate global drug development and registration. It is well recognized that all drugs exhibit significant inter-subject variability in pharmacokinetics and pharmacologic response and that such differences vary considerably among individual drugs and depend on a variety of factors. One such potential factor involves ethnicity. The objective of the present work was to perform an extensive review of the world literature on ethnic differences in drug disposition and responsiveness to determine their general significance in relation to drug development and registration. A few examples of suspected ethnic differences in pharmacokinetics or pharmacodynamics were identified. The available literature, however, was found to be heterologous, including a variety of study designs and research methodologies, and most of the publications were on drugs that were approved a long time ago.

Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches, to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (P450) probe substrates, inhibitors and inducers and for the development of classification systems to improve the communication of risk to health care providers and to patients. While existing guidances cover mainly P450-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently, and should also be addressed. This article was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.

A systematic classification system has been developed for the categorization of therapeutic effects of individual drugs based on their relationships to the underlying disease processes being treated or prevented, rather than on the pharmacologic or biochemical effects of the individual drugs. This system involves a total of six categories of different therapeutic specificities, involving four categories based on disease process-oriented mechanisms of drug action (Categories I through IV), and two additional ones (Categories 0 and V) to complete the classification system. Category 0 includes drugs or drug uses that prevent the development of a disease when none exists; Category I, those that affect etiologic factors of a disease; Category II, those that affect specific disease processes; Category III, those that affect specific disease manifestations; Category IV, those that affect non-specific disease manifestations or symptoms; and Category V includes drug uses or drugs used to diagnose or facilitate treatment of a disease. Examples are provided for each category as well as for applications of the classification system.

Losartan, on orally active, nonpeptide angiotensin II receptor antagonist is being developed as a therapeutic agent for the treatment of hypertension and heart failure. Many patients requiring anticoagulant therapy with warfarin also may have hypertension or heart failure, and thus, are potential candidates for losartan therapy. This study was designed to investigate whether losartan at likely dosage levels would alter the anticoagulant response to warfarin. In a two-period, placebo-controlled, randomized, crossover study, ten healthy male subjects received a single oral dose of 30 mg warfarin sodium on the seventh day of a 13-day treatment with losartan, 100 mg daily by mouth, or placebo. Multiple plasma samples were collected over a 6-day period after both warfarin doses for the measurements of R- and S-warfarin concentrations and prothrombin times. The pharmacokinetics of R- and S-warfarin were comparable in the absence and presence of losartan (no significant effects of losartan on area under the curve, Cmax, or tmax). Losartan also had no significant effect on the anticoagulant effect of warfarin, as assessed by the area under the prothrombin time versus time curve and the maximum response for prothrombin time. The lack of pharmacokinetic or pharmacodynamic interaction between warfarin and losartan observed in this investigation suggests that a clinically important interaction between these drugs is unlikely to occur in patients requiring concomitant administration of both drugs.

Abstract We investigated the effects of angiotensin II (Ang II) type 1 receptor blockade with losartan on the renin-angiotensin-aldosterone system in hypertensive patients (supine diastolic blood pressure, 95 to 110 mm Hg). Qualifying patients (n=51) were allocated to placebo, 25 or 100 mg losartan, or 20 mg enalapril. Blood pressure, plasma drug concentrations, and renin-angiotensin-aldosterone system mediators were measured on 4 inpatient days: end of placebo run-in, after first dose, and 2 and 6 weeks of treatment. Plasma drug concentrations were similar after the first and last doses of losartan. At 6 weeks, 100 mg losartan and 20 mg enalapril showed comparable antihypertensive activity. Four hours after dosing, compared with the run-in day, 100 mg losartan increased plasma renin activity 1.7-fold and Ang II 2.5-fold, whereas enalapril increased plasma renin activity 2.8-fold and decreased Ang II 77%. Both drugs decreased plasma aldosterone concentration. For losartan, plasma renin activity and Ang II increases were greater at 2 than at 6 weeks. Effects of losartan were dose related. After the last dose of losartan, plasma renin activity and Ang II changes were similar to placebo changes by 36 hours. These results indicate that long-term blockade of the feedback Ang II receptor in hypertensive patients produces modest increases of plasma renin activity and Ang II that do not appear to affect the antihypertensive response to the antagonist.

A simple method is presented for graphically illustrating time courses of relative drug concentrations and accumulation during multiple dosing. This method is based on the drug amount ratio and requires knowledge of only the elimination half-life and the dosing interval. It involves the use of relative drug concentrations, where a concentration of unity is assigned to the time-averaged concentration at steady state in a reference subject for the dosing regimen(s) being evaluated. Examples of application of the method of relative drug accumulation involve simulations of the effects of different multiple-dose regimens and variability in drug elimination on time courses of drug concentrations and drug accumulation.

The goal of this study was to assess fibrinolytic activity after vessel wall injury and to correlate changes in fibrinolytic activity with angiographic and histologic findings. Accordingly, in 18 atherosclerotic rabbits, vessel wall injury was produced by means of iliac artery balloon angioplasty (the injury group), whereas 8 atherosclerotic rabbits served as a control group. In all rabbits from the injury group, deep vessel wall injury was documented by either angiography or histologic study. Plasminogen activator inhibitor-1 activity in plasma increased significantly, from 21.79 +/- 1.29 arbitrary units/ml (AU/ml) at baseline study to 32.05 +/- 1.47 AU/ml at 6 h after vessel wall injury (p less than 0.01), whereas activity remained unchanged throughout the 24-h period in the control group. Plasma levels of tissue plasminogen activator activity were similar in both groups. Intravascular thrombus was found in five of six additional rabbits 6 h after vessel wall injury, that is, at the time of impaired fibrinolytic activity, whereas no thrombus was found in the control group (p less than 0.05). It is concluded that deep vessel wall injury is associated with reduced fibrinolytic activity. In addition to other procoagulant factors, elevated plasminogen activator inhibitor-1 activity may lead to intravascular thrombosis and impaired resolution of thrombus.

This study evaluated the efficacy of a prostacyclin analog, iloprost, and a thromboxane A2 receptor antagonist, daltroban, as inhibitors of experimental intimal hyperplasia. The vascular injury model used is based on an endothelial injury induced by a brief infusion of air into an isolated segment of the common carotid artery in the rat. Iloprost and daltroban were administered by continuous IV infusion for two weeks. The infusion rates were 0.1 micrograms/kg/min for iloprost and 0.1 mg/kg/hr for daltroban; these dosing rates are associated with significant alterations in eicosanoid-related pharmacologic effects. The animals were sacrificed at two weeks and the carotid arteries fixed in situ for light microscopy. The myointimal thickening was measured as the intima to media area (I/M) ratio. The control animals developed marked intimal thickening, with an I/M ratio of 0.76 +/- 0.12 (mean +/- SEM; N = 7). There was no inhibition of intimal hyperplasia (P greater than 0.05) after either iloprost (I/M ratio: 1.04 +/- 0.13; N = 8) or daltroban (I/M ratio: 0.70 +/- 0.04; N = 6). It is concluded that neither of these two modulators of eicosanoid activity, iloprost and daltroban, inhibit intimal hyperplasia following experimental endothelial injury.

Drug interactions related to inhibition of hepatic drug metabolism have been identified for some fluoroquinolone antibiotics. This study was designed to investigate whether the fluoroquinolone norfloxacin at the usual clinical dosage interacts with the anticoagulant agent warfarin. Ten healthy male subjects were administered a single oral dose of 30 mg warfarin sodium alone or during multiple-dose treatment with norfloxacin, 400 mg bid, in a randomized, crossover fashion. Plasma warfarin concentrations and prothrombin times were measured for 6 days after each of the two warfarin doses. The pharmacokinetic parameters of warfarin were comparable in the absence and presence of norfloxacin, including no significant differences in warfarin's elimination half-life, apparent total clearance, apparent volume of distribution, or peak plasma concentration. Norfloxacin also had no significant effect on the anticoagulant effect of warfarin, as assessed by the area under the prothrombin time versus time curve and the maximum response for prothrombin time. The lack of pharmacokinetic or pharmacodynamic interaction observed in this study suggests that a clinically important interaction of norfloxacin and warfarin is unlikely to occur in patients requiring both drugs.

To assess the safety, pharmacokinetics, and erythropoietic responses to human recombinant erythropoietin (epoetin beta), single intravenous doses (10, 50, 150, and 500 IU/kg) were administered at monthly intervals to 16 healthy subjects in a two-panel, placebo-controlled, double-blind ascending-dose trial. A 1000 IU/kg dose was subsequently administered in an open manner. Epoetin concentrations were determined in serum and urine by radioimmunoassay. Reticulocyte, hemoglobin, and hematocrit values were serially measured after each dose. Mean epoetin apparent half-lives ranged from 4.42 to 11.02 hours. The apparent volume of distribution was between 40 and 90 ml/kg, consistent with plasma water, and the apparent clearance values ranged from 4 to 15 ml/kg/hr, with both parameters having the highest values at the 10 IU/kg dose level. Clearance tended to decrease as a function of dose. Maximum reticulocyte counts were dose-dependent and occurred 3 to 4 days after the epoetin dose. Epoetin was well tolerated, and no antibodies were detected.

• A double-masked, randomized, placebo-controlled, rising-dose, single-dose study was undertaken to assess the effect of low concentrations of timolol maleate ophthalmic solution (0.008%, 0.025%, 0.08%, and 0.25%) on intraocular pressure and its diurnal variation in healthy, normal volunteers. A single dose of 0.008% timolol exhibits a definite but minimal-effect on intraocular pressure in this normal volunteer model, causing a significant peak mean decrease in intraocular pressure from its value immediately pre-dose. This decrease was 1.8 mm Hg (a peak mean percent decrease of 12.8%) at 2 hours postdose compared with an increase of 0.1 mm Hg (+2.5%) during a pre-study curve due to normal diurnal variation. One drop of 0.008% solution represents a single dose of approximately 2.5 μg of timolol. A slight contralateral ocular hypotensive effect appears to be present for 0.25% timolol at 2 hours postdose although it just failed to reach statistical significance.

Plasma adenosine levels in five healthy volunteers for 5 consecutive days showed far less intrasubject than intersubject variation (p less than 0.0001), indicating that plasma adenosine levels are relatively constant during this period. Plasma adenosine levels were then measured in a different group of five healthy subjects for a 5-day control period and during a 5-day course of oral dipyridamole at a dose of 100 mg every 6 hours. Intrasubject comparisons showed that plasma adenosine levels were significantly higher during the 5 days of dipyridamole administration than during the control period (p = 0.017) and that this increase was most significant after 48 hours of drug (p less than 0.001) administration. The average increase was 0.133 mumol/L (60%) with a range of 0.063 to 0.197 mumol/L (37% to 212%) during the last 3 days. A significant positive correlation was noted between plasma adenosine and dipyridamole levels (p = 0.001). We conclude that adenosine levels are relatively stable for an individual and are maximally increased after 2 days of oral dipyridamole.

Eight young women taking oral contraceptives and 10 young men each received three different doses of diazepam, 0.07, 0.14, and 0.28 mg/kg. The women also received each dose both on days 10 and 28 of an oral contraceptive cycle. Performance based on both a psychomotor and cognitive-encoding task was significantly impaired after a 0.28-mg/kg dose of diazepam in women taking oral contraceptives and in men. In general, however, impairment in performance was less on day 10 than on day 28 of the oral contraceptive cycle. The onset of behavioral impairment was also slower on cycle day 10 than on day 28; peak impairment was reached at 20 min after dosing for men and women on day 28, but at 60 min for women on day 10. The cycle phase effects are potentially dangerous because of their unexpected nature. Individuals may obtain an expectation of intoxication based on the 21-day OC period yet experience capriciously greater acute impairment during their 7-day menstrual pause.

Simulation of complex dosage regimens for drugs with multicompartmental kinetics is described using the method of separate exponentials. This approach requires that α- and β-phases are treated separately throughout and summed only at the end of the simulation. The method was used to devise a loading regimen for pirmenol, comprising a priming injection, and a rapid loading infusion, followed by a maintenance infusion. The regimen was tested in a patient with excellent agreement. The method of separate exponentials is mathematically simple and of informational value in that it demonstrates when the early distribution phase is important. Its use can avoid the potentially dangerous assumption of one-compartmental kinetics in the design of intravenous loading regimens. Clinical Pharmacology and Therapeutics (1981) 29, 542–547; doi:10.1038/clpt.1981.76

This study investigated the absorption of low molecular weight heparin (LMWH) after oral administration in man. Six healthy subjects received 5,000 anti-Xa units of LMWH (Kabi 2165) by both i.v. and oral administration. The oral formulations were prepared in pH 4.0 and pH 7.0 buffered solutions. Multiple blood samples were collected after each dose for measurements of anti-Xa, anti-IIa and APTT plasma heparin activities. Pharmacokinetic parameters based on the anti-Xa activity measurements after the i.v. dose were as follows (mean +/- s.d.): t1/2, 1.82 +/- 0.23 h; V, 4.34 +/- 0.651; and CL, 28.0 +/- 6.2 ml min-1. Half-life values based on the anti-IIa and APTT activities were 1.63 +/- 0.43 and 1.09 +/- 0.51 h, respectively. Considerable prolongations in APTT were observed, with APTT at 30 min averaging 55.7 +/- 4.1 s (1.84 +/- 0.27 times baseline values). After oral administration, no measurable plasma heparin activities were observed with either LMWH preparation. The results of this investigation indicate that LMWH does not have detectable plasma activity after oral administration, and that after i.v. administration it has significant anti-IIa and APTT activities in addition to its anti-Xa activity.

The pharmacodynamics of MK-912, a benzofuroquinolizine α2-adrenoceptor antagonist, were evaluated in healthy male volunteers. Eight subjects were treated with single oral doses of 0.1, 1.0, and 2.0 mg MK-912 and with a placebo in a four-period, double-blind, balanced, crossover study. Hemodynamic effects were observed with the 2.0 mg dose of MK-912 (peak increase from baseline in systolic and diastolic blood pressure ± SEM, 14.8/9.2 ± 2.9/2.1 mm Hg; peak increase in heart rate, 6.3 ± 2.1 beats/min; p < 0.05 versus placebo). Plasma concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG, a catecholamine metabolite) were increased 29% ± 7% and 40% ± 10% above baseline 2 hours after administration of 1.0 and 2.0 mg MK-912, respectively (p < 0.01 compared with placebo). A modest dose-dependent reduction (5% to 10%) in fasting plasma glucose concentration was observed ½ to 1 hour after administration of 1.0 and 2.0 mg MK-912 (p < 0.05 compared with placebo), without significant change in plasma insulin values. MK-912 was well tolerated, although it did have a mild anxiogenic effect. MK-912 is a potent, orally active agent with a pharmacologic profile consistent with α2-adrenoceptor antagonism. Clinical Pharmacology and Therapeutics (1989) 46, 566–575; doi:10.1038/clpt.1989.187

The oral absorption of digoxin in tablet form has been reported to be reduced after cancer chemotherapy and radiation therapy because of cancer treatment-induced damage to the intestinal epithelium. We investigated possible differences in the effects of high-dose cancer chemotherapy on the relative bioavailability of digoxin administered in tablet form (Lanoxin; Burroughs Wellcome Co.) and in solution-in-capsule form (Lanoxicaps; Burroughs Wellcome Co.). Each subject received a single oral dose of either 0.5 mg Lanoxin (six subjects) or 0.4 mg Lanoxicaps (seven subjects) both before and after chemotherapy. For Lanoxin, there was a significant reduction in the AUC after chemotherapy to 54.4% +/- 35.5% (mean +/- SD) of the value before chemotherapy (P = 0.02), whereas for Lanoxicaps there was an insignificant reduction in AUC to 85.1% +/- 42.7% of the value before chemotherapy. These findings show that changes in the oral dosage formulation of digoxin from a tablet to a solution-in-capsule form can overcome the adverse effects of high-dose cancer chemotherapy on drug absorption, and suggest a similar approach may be successful for other drugs.

Serum creatinine concentration is commonly used in conjunction with individual patient characteristics (e.g., age, sex, and body weight) in order to estimate creatinine clearance. Such estimates of creatinine clearance are widely used as a parameter for individualization of dosages of drugs excreted primarily via the kidneys in patients with diminished renal function. However, estimation of creatinine clearance in patients with concurrent hepatic disease tends to result in substantial overprediction of observed creatinine clearance in this patient population. This report suggests that a diminished rate of creatinine production in patients with hepatic disease is a likely explanation for this anomaly. This postulated mechanism is based on a presentation of the biology of creatinine formation.

Several methods have been published for estimating creatinine clearance from serum creatinine concentrations. Such estimates of creatinine clearance are widely used for dosage adjustments of drugs which are primarily eliminated through the kidneys in patients with reduced renal function. Most of these methods involve the use of equations, requiring a few steps of calculations. A simple and easy-to-use nomogram is presented for estimating creatinine clearance from serum creatinine concentration, plus the age, sex, and bodyweight of the individual patient. This nomogram is based on the linear relationship between creatinine clearance and the reciprocal value of the serum creatinine concentration, where the slope of this relationship is determined by the rate of creatinine production. The rate of creatinine production, however, is related to age, sex, and bodyweight. These physical characteristics are therefore used to scale the slopes of the relationships between creatinine clearance and serum creatinine concentration. The validity of the nomogram was tested in 50 consecutive hospitalised patients for which creatinine clearance was measured. There was an excellent correlation (r = 0.903) between predicted and observed creatinine clearance values.

A 3-stage infusion of diltiazem was tested in 8 subjects for up to 48 hours: a bolus injection (10 mg over 3 minutes), a rapid loading infusion (20 mg over 30 minutes) and a maintenance infusion (10 mg/hour to the end of the study). This regimen produced stable median plasma diltiazem concentrations of approximately 150 ng/ml. The median half-life of elimination for diltiazem was 206 minutes (range 144 to 452) and median total clearance was 980 ml/min (range 665 to 1,907). The PR interval lengthened 10 to 18% during the maintenance infusion in 7 subjects; in 1 subject atrioventricular nodal Wenckebach conduction was recorded during the rapid loading infusion. Systolic blood pressure decreased from 124 ± 7 mm Hg (mean ± standard deviation) during the control period to 121 ± 8 mm Hg during the rapid loading infusion (p = 0.03 compared with control) and to 117 ± 7 mm Hg (p = 0.04 compared with control) during the maintenance infusion. Heart rate did not change. PR interval and blood pressure returned to control levels within 4 hours after the infusion was stopped. Loading and maintenance infusion may be an attractive method of administering diltiazem when stable drug concentrations are required for prolonged periods.

Twenty patients received dipyridamole by two different dosage regimens yielding a total daily dose of 150 mg, either as 50 mg three times a day or 75 mg twice a day. The rationale for comparing these two regimens is that dipyridamole is usually given three times a day, but recent studies have revealed a final elimination half-life of the drug of about half a day. Based on drug cumulation during chronic dosing, the final half-life of dipyridamole observed in this study also averaged about half a day. The 75 mg b.i.d. regimen did not result in lower trough concentrations than the 50 mg t.i.d. regimen. There was wide interpatient variability in observed plasma dipyridamole concentrations for both regimens, averaging about 10-fold. These results suggest that dipyridamole could be administered twice a day and that dipyridamole levels should be monitored in clinical studies on the antithrombotic effect of the drug.

Three patients under treatment with phenacemide for uncontrollable psychomotor epilepsy were found to have greatly increased serum creatinine levels in the absence of elevated blood urea nitrogen (BUN) values or any other evidence of renal disease. Serum creatinine returned promptly to normal after omission of the phenacemide and rose quickly again on resumption. Experiments in rabbits and rats fully reproduced these clinical observations. In vivo and in vitro studies with the drug and its metabolites excluded these as a cause for a spurious analytical finding. Rabbits given phenacemide have a fall in serum and urine creatine, while the corresponding creatine values rise. With the use of a creatininase degradation procedure, it could be proved that the markedly elevated serum level and the increased excretion consist of the creatinine and not of any other substance. An effect of phenacemide on the conversion rate of creatinine to creatinine in the body is a speculative possibility.

The purpose of this study was to determine the pharmacokinetics of intravenous streptokinase in humans. Five patients with myocardial infarction, six patients with venous thromboembolism, and two normal volunteers were studied. The patients with myocardial infarction received 500,000 U over 30 minutes, the patients with venous thromboembolism received 250,000 U over 30 minutes followed by 100,000 U/hr over 16 to 78 hours, and the normal volunteers received 100,000 U over 15 minutes. Plasma streptokinase levels were measured based on the amidolytic activity of the streptokinase-plasminogen complex on the chromogenic substrate S-2251. Pharmacokinetic parameters were: biologic half-life 82 +/- 25 minutes, total clearance 10.8 +/- 8.8 ml/min, and apparent volume of distribution 1.10 +/- 0.71 l. Streptokinase levels declined progressively during the continuous, prolonged infusion in the patients with venous thromboembolism over 60 hours of treatment. We conclude that there are distinct time-dependent changes in the pharmacokinetics of streptokinase during continuous intravenous infusion and that this phenomenon is likely to be associated with progressively decreasing thrombolytic efficacy.

A nomogram is presented for the rapid determination of the dosage adjustment factor for drugs eliminated in part by the kidneys in patients with reduced renal function. This nomogram method is based on knowledge of the fraction of a dose of the drug of interest eliminated by the kidneys in subjects with normal renal function and an estimation of the renal function of the patient in question. It assumes that there is no reduction in the liver metabolism of the drug in patients with reduced renal function. The dosage adjustment factor thus derived can be used to change the dosage regimen of the drug in patients with reduced renal function.

The pharmacokinetics off dipyridamole were studied in six normal subjects and 20 patients. The normal subjects received 20 mg IV each and five also took a 50 mg oral dose. Concentrations after the intravenous dose showed a tri-exponential decline with a terminal half-life of 11.6 +/- 2.2 hr (mean +/- S.D.). Total plasma clearance was 138 +/- 30 ml/min and the apparent volume of distribution was 141 +/- 51 l. Peak concentrations after oral dipyridamole occurred 2--2.5 hr after the dose. Systemic availability of the oral dose was 52 +/- 23%. Plasma protein binding was 99.13 +/- 0.24%. Twenty patients, admitted for coronary artery bypass grafting, received total daily doses of 150 mg, either as 50 mg tid or 75 mg bid. Based on drug cumulation during chronic dosing, the terminal half-life averaged about half a day. There was wide interpatient variability, averaging about 10-fold, in observed plasma concentrations for both dosage regimens. The bid regimen was not associated with lower trough concentrations of the drug than the tid regimen. These results indicate that dipyridamole concentrations vary widely in patients receiving the drug, and suggest that it could be administered twice a day, and that dipyridamole levels should be monitored for the antithrombotic effect in clinical studies.