Arthur J. Atkinson

Amphotericin B Pharmacokinetics in Humans

The pharmacokinetics of amphotericin B were studied in two patients at the conclusion of long-term therapy for disseminated histoplasmosis. The distribution kinetics of this drug were adequately described by a three-compartment mamillary model with a total distribution volume averaging 4 liters/kg. The elimination phase half-life of amphotericin B was approximately 15 days, reflecting slow release of amphotericin B from a peripheral compartment. In accordance with previous reports, renal excretion accounted for only 3% of total amphotericin B elimination. The pharmacokinetic model for one of the patients also was used to compare the simulated amphotericin B serum levels that would be expected if initial therapy followed two recommended regimens.

Drug dosing consideration in patients with acute and chronic kidney disease—a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO)

Drug dosage adjustment for patients with acute or chronic kidney disease is an accepted standard of practice. The challenge is how to accurately estimate a patients kidney function in both acute and chronic kidney disease and determine the influence of renal replacement therapies on drug disposition. Kidney Disease: Improving Global Outcomes (KDIGO) held a conference to investigate these issues and propose recommendations for practitioners, researchers, and those involved in the drug development and regulatory arenas. The conference attendees discussed the major challenges facing drug dosage adjustment for patients with kidney disease. In particular, although glomerular filtration rate is the metric used to guide dose adjustment, kidney disease does affect nonrenal clearances, and this is not adequately considered in most pharmacokinetic studies. There are also inadequate studies in patients receiving all forms of renal replacement therapy and in the pediatric population. The conference generated 37 recommendations for clinical practice, 32 recommendations for future research directions, and 24 recommendations for regulatory agencies (US Food and Drug Administration and European Medicines Agency) to enhance the quality of pharmacokinetic and pharmacodynamic information available to clinicians. The KDIGO Conference highlighted the gaps and focused on crafting paths to the future that will stimulate research and improve the global outcomes of patients with acute and chronic kidney disease.

Kinetics of cocaine distribution, elimination, and chronotropic effects

The pharmacokinetics of cocaine were studied in five subjects with histories of drug abuse who were otherwise healthy. A two‐compartment system was used to model the distribution kinetics of the drug. The steady‐state volume of distribution averaged 131.8 L or 1.96 L/kg, elimination clearance was 2.10 L/min, and the t½ was 48 minutes. Cocaine concentrations in a hypothetic biophase were estimated to correlate the chronotropic effects of this drug with its pharmacokinetics. The experimentally determined kinetic parameters indicate that the peak chronotropic effect would occur 7.3 minutes after intravenous bolus injection of cocaine, and that biophase cocaine concentrations would initially accelerate the heart rate by 0.3 bpm for each 1 ng/ml. The kinetic analysis also demonstrated that the chronotropic effects of cocaine decline more rapidly than either plasma levels or biophase concentrations. This progressive attenuation in intensity of the chronotropic effect of a given biophase cocaine concentration could be modeled as a first‐order process and is compatible with either the intervention of homeostatic reflex mechanisms or the phenomenon of acute tolerance.

Antiarrhythmic potency of N‐acetylprocainamide

Compared to procainamide in an animal arrhythmia model, the antiarrhythmic potency of the N‐acetylated metabolite of procainamide (NAPA) was 92% with respect to dose and 70% with respect to plasma level. The antiarrhythmic effects of combinations of the drugs were additive. Measurements of procainamide and NAPA plasma levels needed to suppress ventricular extrasystoles suggested that both compounds are nearly equipotent in patients as well. The average plasma level required for arrhythmia control in these patients was equivalent to 5.1 mcg/ml procainamide. Since patients on long‐term procainamide therapy have plasma concentrations of NAPA that are usually comparable to, and occasionally greater than, their procainamide levels, dose regimens based on procainamide levels alone need revision to include consideration of the levels of this metabolite.

d-Xylose testing: A review

The efficacy of D-xylose testing in clinical situations has been reviewed in the light of recent kinetic studies. The standard 25-g D-xylose test in adults, based on analysis of 5-h urine collection and a 1-h serum sample, discriminates between normal subjects and patients with proximal small intestinal malabsorption with greater than 95% specificity and sensitivity. The 1-h serum level measured after administering this dose is also useful in evaluating malabsorption in patients with intermediate degrees of renal insufficiency and in the elderly. The 1-h serum test after administration of 5 g of D-xylose should be used in pediatrics and is greater than 91% sensitive and close to 100% specific. The [14C]D-xylose breath test with 1 g of D-xylose has been useful in identifying malabsorption caused by bacterial overgrowth in the small intestine.

Acute tolerance to cocaine in humans

There is controversy as to whether acute tolerance develops to the principal effects of cocaine in humans. The studies described here demonstrate the phenomenon of acute tolerance to cocaine chronotropic and subjective effects and the rate and extent of tolerance development. Stable plasma cocaine concentrations were produced and then maintained in volunteer cocaine users by administering an intravenous cocaine injection followed by a cocaine infusion designed to compensate for the plasma clearance of cocaine. The euphoric effect (high) intensified to a peak at about 1 hour and then declined toward baseline at 4 hours despite the presence of constant plasma cocaine levels. The chronotropic effect reached a peak within 10 minutes and then declined, with a half‐life of 31 ± 13 (mean ± SD) minutes toward a plateau at 33% ± 21% of its peak intensity. Tolerance development was quantified as an exponential process, with a rate constant (tolerance factor) accounting for the progressive alteration of the cocaine concentration‐effect relationship.

Absolute bioavailability in man of N‐acetylprocainamide determined by a novel stable isotope method

Absorption of a single oral dose of N‐acetylprocainamide (NAPA) was studied in 3 normal subjects. Approximately 85% of the oral dose was absorbed and peak plasma NAPA concentrations were reached in 45 to 90 min. In 2 subjects, NAPA was absorbed at a fast initial rate, then more slowly, prolonging the apparent elimination phase half‐life. Absolute bioavailability was determined by a new stable isotope method that entailed intravenous injection of NAPA− 13C at the same time that an unlabeled NAPA capsule was given orally. Plasma levels and urine excretion of both compounds were determined by mass fragmentography. Bioavailability was assessed by deconvoluting the plasma level vs time curves resulting from intravenous and oral drug administration, and also by comparing the relative percentage of NAPA and NAPA− 13C excreted unchanged in the 24 hr after simultaneous administration.

Use of biomarkers from drug discovery through clinical practice: report of the Ninth European Federation of Pharmaceutical Sciences Conference on Optimizing Drug Development.

The Ninth European Federation for Pharmaceutical Sciences (EUFEPS) Conference on Optimizing Drug Development was held in Basel, Switzerland, December 10-12, 2001. The overall objective of the conference was to find new ways of advancing the integration of biomarkers into drug development and clinical practice to make drug development more efficient and the clinical use of drugs more effective. The aim of this conference report is to summarize the key ideas and recommendations that were identified at the meeting, both by formal presentation and from the breakout sessions, which all participants were encouraged to join. Rather than providing a synopsis of each individual presentation, the report is organized along the key themes that emerged during the meeting.

Pharmacokinetics of furosemide in advanced renal failure

The pharmacokinetics of furosemide were studied in 12 patients with advanced renal failure. The elimination half‐life of furosemide averaged 9.7 hours. Renal furosemide clearance was reduced, but furosemide elimination by non renal mechanisms was unimpaired in uremic patients without liver disease and accounted for 86% to 98% of total elimination. Nonrenal furosemide clearance also was reduced in 3 uremic patients with liver cirrhosis, and elimination half‐life was prolonged to 20 hours in 1 of these patients. The diuretic response to intravenous furosemide appeared to be adversely affected by poor renal function and dehydration. Diuretic response was always less after oral than after intravenous furosemide, and the slow, intravenous infusion of this drug is recommended for maximal efficacy in uremic patients.

Dose‐ranging trial of N‐acetylprocainamide in patients with premature ventricular contractions

Ten patients with chronic premature ventricular contractions (PVCs) received short‐term oral therapy with N‐acetylprocainamide (NAPA) to determine its antiarrhythmic efficacy and side effects under the conditions of a placebo‐controlled, dose‐ranging trial. NAPA was effective in suppressing PVCs in 8 patients but caused a paradoxical increase in PVC frequency in one. Results were equivocal in the remaining patient because PVCs did not recur when NAPA therapy was withdrawn. Mean NAPA plasma levels as high as 41.1 µg/ml did not have untoward hypotensive or myocardial depressant effects, as judged by electrocardiographic and systolic time intervals. There was, infact, a consistent reduction in PEP/LVET ratio, indicating that NAPA increases the force of myocardial contraction. The mean NAPA elimination half‐life of 10.9 hr was longer than the 6.2 hr half‐life reported for normal subjects, but its prolongation was predictably correlated with reductions in creatinine clearance. Gastrointestinal side effects experienced by 3 patients and insomnia noted by 2 patients are similar to known adverse reactions to procainamide.