Wayne A. Colburn

The Clinical Pharmacokinetics of Quinapril

Quinapril (Q) and quinaprilat (QT) pharmacokinetics are dose pro portional following single oral 2.5- to 80-mg Q doses. Q absorption and hy drolysis 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 follow ing 40-mg Q). Dose-proportional QT area under the curve and dose-inde pendent percent of dose excreted in urine as QT demonstrate that the ex tent of Q conversion to QT is con stant 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 clear ances of 1,850 and 220 mL/min, re spectively, 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 radioactiv ity circulating in plasma and 56% of that excreted in urine. Metabolism to compounds other than QT is not extensive. Two diketo piperazine metabolites of Q have been identified in plasma and urine, with approximately 6% of an admin istered 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 ex cretion profiles indicate the presence of other minor metabolites. In summary, the absorption of Q and conversion to QT is rapid and dose-proportional, subsequent clear ance of both Q and QT is independ ent of dose, and metabolism to compounds other than QT is not ex tensive.

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] μg/ml) was virtually the same as the mean Css50 value for sedation (0.336 ± 0.205 [SD] μg/ml). Similarly, the mean γ (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.

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.

Determination of quinapril and its active metabolite in human plasma and urine by gas chromatography with electron-capture detection

Quinapril is a non-sulfhydryl angiotensin-converting enzyme (ACE ) inhibitor currently being studied in patients for treatment of hypertension and congestive heart failure. Quinapril is deesterified in vivo to the diacid (Fig. 1) ( [ 3S[ 2 [R* (It*)] ] ,3R*] -2[ 2[ (1-carboxy-3-phenylpropyl) amino] -1-oxopropyl] 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid) (CI-928, I) [ 11, which is the compound primarily responsible for drug efficacy. Quantitation of the ACE inhibitors enalapril and ramipril has been conducted by radioimmunoassay (RIA) or ACE inhibition assay [ 2-41. These techniques are not selective for the parent drugs. To evaluate clinical pharmacokinetic studies of quinapril, a quantitative gas chromatographic ( GC ) method with electron-capture detection (ECD ) was developed. The method allows simultaneous quantitation of both parent drug and active diacid metabolite concentrations in plasma and urine, and is sufficiently sensitive to measure concentrations in human plasma to 10 ng/ml and urine to 50 ng/ml.

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?

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.

Controversy IV: Population Pharmacokinetics, NONMEM and the Pharmacokinetic Screen; Academic, Industrial and Regulatory Perspectives

T he Second Annual Pittsburgh Pharmacodynamics Conference was held on May 13 and 14, 1986. The topic of the conference was NONMEM: applications to drug development and utilization. I was asked to pontificate on the past, present, and future of population pharmacokinetics with specific reference to NONMEM. While I supervise the investigation of potential applications of this methodology in drug development at Parke-Davis Pharmaceutical Research and am a proponent of this evaluation, I have been somewhat skeptical of some of the blind applications of the method to retrospective data analysis. For that reason, I was more than happy to give my perspectives on current use and potential for future evaluations and applications. Based on the response to my presentation, I was not the only person with concerns about the application of NONMEM to clinical data without first testing the method on data sets with a variety of real experimental error structures. During the course of the conference, I talked to some of the conference speakers and attendees about presenting their perspectives in the Pharmacokinetic and Biopharmaceutic Principles for Clinical Pharmacologists Section of The Journal of Clinical Pharmacology. One academic scientist, two industrial scientists and two scientists from the FDA agreed to participate and their views are contained in the following pages. Before we move on to their perspectives, it is important to set the tenor of the discussions by more clearly defining the topic and giving a definition of terms. In the following articles, the term pharmacokinetics will encompass both pharmacokinetics and pharmacodynamics. The terms population pharma-

Influence of Food on the Pharmacokinetics of Quinapril and Its Active Diacid Metabolite, CI‐928

A randomized two‐way crossover study was conducted in 12 healthy volunteers to assess the effect of food on the pharmacokinetics of quinapril (CI‐906) and its active metabolite, CI‐928, after quinapril dosing. Forty‐milligram oral quinapril doses were administered in a fasted or a fed state with a one‐week washout period between treatments. No significant treatment differences were observed in quinapril and CI‐928 values for maximum plasma concentration, area under the plasma concentration‐time curve, or percentage of dose excreted in the urine. Small but significant increases of less than 0.5 hour in quinapril and CI‐928 tmax values were observed after consumption of food. The pharmacokinetic profiles of quinapril and CI‐928 were not significantly altered by the administration of food.

Controversy V: Phase I, First Time in Man Studies

P hase I, first time in human studies, are an integral part and often fa t accompli, of the drug development process. Having worked in a few pharmaceutical companies during my career, I can attest that these studies are conducted in a variety of forms to achieve somewhat different objectives. Drs. Posvar and Sedman from Parke-Davis were asked to write the lead article1 to provide a focus for the authors in the current article; i.e., to provide a target for Controversy V. For the last article in the didactic segment of the Pharmacokinetic Principles for Clinical Pharmacologists Series, I felt compelled to provide a truly introspective topic and to successfully address the topic, I required authors from diverse backgrounds to provide their commentary. I feel that I have been successful in this endeavor and I would like to thank them for providing a fitting conclusion to this portion of the series. The authors come from academia: Roger Williams, University of California, San Francisco; industry: Richard Bergstrom and Louis Lemberger, Eli Lilly and Company; contract laboratory: Denis O’Donnell, Medical and Technical Research Associates, Inc.; and regulatory: Carl Peck and Jerry Collins, Food and Drug Administration. With these commentaries, certain things become apparent. First time in human studies are extremely important to the development process. Results from these studies provide the foundation for further development; they can streamline the development process, or they can be the final step in terminating the development of a new chemical entity. Therefore, a well designed, focused study with clear-cut objectives is central to this end. The approaches to first time in human studies are diverse yet similar

Clinical Pharmacokinetics and Relative Bioavailability of Oral Procaterol

The pharmacokinetics and relative oral bioavailability of procaterol, an orally active β2-adrenergic agonist bronchodilator were evaluated in healthy volunteers. Procaterol was rapidly absorbed after oral administration. Mean plasma procaterol concentration–time profiles and pharmacokinetic parameters for both formulations were essentially superimposable. Following tablet administration, the mean Cmax was 358 pg/mL and the corresponding mean tmax was 1.6 hr. Mean renal clearance was 163 mL/min and accounted for approximately one-sixth of the mean apparent oral plasma clearance (988 mL/min). The mean apparent elimination half-life of procaterol was 4.2 hr. Hepatic metabolism appears to be the primary mechanism for elimination of procaterol from the body, and first-pass metabolism may limit systemic bioavailability.