Carl C. Peck

Computer-Assisted Digoxin Therapy

Abstract In 42 patients requiring digitalis, and randomly divided into two groups, the performance of a computer program using patient size and renal function to compute digoxin dosage was compared to that of unaided physician judgment. Serum digoxin concentrations were measured repeatedly. Efficacy was measured by changes in the manifestations of heart failure, and toxicity by electrocardiographic criteria. For each patient, physicians specified a desired serum digoxin concentration and predicted this concentration at each visit. For one group, the computer program suggested the dosage needed to achieve the desired digoxin concentration. Efficacy was the same in both groups, and there was no toxicity. Although the computer slightly outperformed the physicians, prediction and achievement errors were unacceptably large. Hence, much between-patient variability in serum digoxin concentrations remains unexplained after adjustments for dose, body size and renal function. This argues for measurement of digoxin ...

The randomized concentration-controlled trial: An evaluation of its sample size efficiency

A randomized concentration-controlled trial (RCCT) is one in which subjects are randomly assigned to predetermined levels of average plasma drug concentration. These target concentrations can be achieved (within reasonable ranges) by an individualized pharmacokinetically controlled dosing scheme. The RCCT is designed to minimize the interindividual pharmacokinetic (PK) variability within comparison groups and consequently decrease the variability in clinical response within these groups. In this paper, we investigate the extent of improvement in sample size efficiency that can be gained from the RCCT design in comparison to the traditional randomized dose-controlled trial (RDCT) design. Our investigations involve both theoretical arguments and simulation studies, illustrated with data on PK and pharmacodynamic (PD) characteristics of the antiasthma drug theophylline. Aside from safety concerns that strongly suggest the use of RCCT for drugs with narrow therapeutic windows, sample size considerations favor the choice of RCCT in many situations, as shown in this paper.

Opportunities for Integration of Pharmacokinetics, Pharmacodynamics, and Toxicokinetics in Rational Drug Development

Carl C. Peck, MD, William H. Barr, PharmD, PhD, Leslie Z. Benet, PhD, Jerry Collins, PhD, Robert E. Desjardins, MD, Daniel E. Furst, MD, John G. Harter, MD, Gerhard Levy, PharmD, Thomas Ludden, PhD, John H. Rodman, PharmD, Lilly Sanathanan, PhD, Jerome J. Schentag, Pharmfl, Vinod P. Shah, PhD, Lewis B. Sheiner, MD, Jerome P. Skelly, PhD, Donald R. Stanski, MD, Robert J. Temple, MD, C. T. Viswanathan, PhD, Judi Weissinger, PhD, and Avraham Yacobi, PhD

A pharmacodynamic Markov mixed‐effect model for the effect of temazepam on sleep

A hypnogram shows how sleep travels through its various stages in the course of a night. The sleep stage changes can be quantified to study sedative drug effects.

Principles and criteria in the development and optimization of topical therapeutic products : Sponsored by the American Association of Pharmaceutical Scientists (AAPS) and U.S. Food and Drug Administration (FDA)

Abstract This report derived from the dermatological workshop discusses the problems and issues in the development and optimization of topical therapeutic drug products. It provides a clear understanding and differentiation between transdermal and dermal products. The report also discusses the bioavailability/bioequivalence issues for topical therapeutic products.

Integration of pharmacokinetic and pharmacodynamic studies in the discovery, development, and review of protein therapeutic agents: A conference report

Clinical Pharmacology & Therapeutics (2001) 69, 387–399; doi: 10.1067/mcp.2001.115455

Randomized concentration-controlled trials: motivations, use, and limitations.

BACKGROUND The effectiveness of a drug is usually described by some type of relationship between dose and effect. However, instead of dose being the treatment factor of primary interest, investigators may in some cases be interested in characterizing how the concentration of drug in body fluids (eg, in plasma or serum) is related to the pharmacologic effect. Adherence to the biasminimizing principle, that experimental units should be randomized to the treatment factor whose effect on outcomes is addressed, to estimate the dose-response relationship requires a randomized dose-controlled trial (RDCT), in which drug effects in subjects randomized to different drug dosages are measured. If, in contrast to the dose-effect relationship, the goal of the investigation is minimum biased estimation of the concentrationeffect relationship, randomization to different drug concentrations may be used. The latter approach is the main characteristic of a randomized concentrationcontrolled trial (RCCT). Terminology. Customarily, an RDCT is defined as a trial in which subjects are randomized to two or more doses of the investigational drug (or to one or more doses of two or more drugs in comparative studies). For the purpose of this discussion, we define an RCCT as a trial in which (1) subjects are randomly allocated to two or more predefined concentration ranges of the same drug (or to one or more concentration ranges of two or more drugs for comparative studies), which are achieved in subjects, if necessary, via adaptively individualized doses, and (2) the relationship between the prespecified or achieved concentrations and the observed effect(s) is analyzed. Thus we distinguish the RCCT from trials in which concentrations are observed retrospectively, achieved passively as a result of assigned dosage, rather than prespecified and controlled by the investigator via individualized dosage regimens. An RCCT will ordinarily require a procedure for adaptive feedback control, via individualization of dosage regimen, to ensure that the concentration actually achieved in a given subject will, with high probability, lie in the prespecified concentration range. The RCCT can be related to the recently described randomized biomarker-controlled trial, in which patients are randomized to different levels of a biomarker; this design is the preferred method by which to obtain inferences if estimation of the biomarker-response relationship is the objective of the investigation. Formally, concentration and biomarker may be considered analogous in concentrationand biomarker-controlled trials, respectively. However, concentration can usually be interpreted as a causative factor for the drug response, whereas this is not necessarily true for biomarkers. Motivation for use of RCCTs. The current discussion about the value of the RCCT in drug development was initiated by the introduction of the term about a decade ago. At that time, the primary motivation for shifting the focus from the dose-response relationship to the concentration-response relationship, and from the RDCT to the RCCT in methodologic terms, was the theoretic gain in power of showing the pharmacologic effectiveness of an investigational drug by the use of an RCCT. The basis of this idea was the recognition that the overall variability in response to a given treatment comprises a combination of pharmacokinetic and pharmacodynamic variability. As a consequence, the reduction of pharmacokinetic variability by investigation of From the Department of Clinical Pharmacology, Gothenburg University, Gothenburg; Center for Drug Development Science, Georgetown University, Washington; Department of Pharmacology and Clinical Pharmacology Unit, Seoul National University College of Medicine and Hospital, Seoul; and Globomax LLC, Hanover. Supported by The Foundation for Strategic Research (Dr Kraiczi) and Center for Drug Development Science, Georgetown University Medical Center, Washington, DC. Received for publication March 5, 2003; accepted May 29, 2003. Reprint requests: Carl Peck, Georgetown University Medical Center, Center for Drug Development Science, Med-Dent NE 405, 3900 Reservoir Rd, Washington, DC 20057-1441. E-mail: carl_peck@compuserve.com Clin Pharmacol Ther 2003;74:203-14. Copyright

In vivo percutaneous penetration/absorption: Sponsored by the American Association of Pharmaceutical Scientist, U.S. Food and Drug Administration, American Academy of Dermatology, Skin Pharmacology Society and the U.S. Army Environmental Hygiene Agency May 1–3, 1989, Washington, DC

Abstract This workshop, ‘In Vivo Percutaneous Penetration/Absorption’ was held in Washington, DC, on May 1–3, 1989. The first workshop in this series, ‘In Vitro Percutaneous Penetration’, took place in November 1986 (the report of this earlier meeting was published in Pharmaceutical Research , 4 (1987) 265–267). The objectives of the workshop were to review the relevant literature and to address in detail: (1) In vivo percutaneous penetration/absorption methodology; (2) The characteristics of dosage forms designed for application to the skin; (3) Critical factors controlling in vivo drug transport into and across the skin; (4) The use of models in the assessment and evaluation of in vivo percutaneous penetration/absorption; and (5) Bioavailability/bioequivalence considerations for topical drug products. Scientific knowledge and technology are rapidly evolving in the topical and transdermal drug products area. This report focuses on the methodologies available for the measurement of percutaneous penetration in vivo; each scientific approach is discussed briefly followed by advantages and disadvantages of the methodology.

Randomization, Pk-Controlled Dosing, and Titration: An Integrated Approach for Designing Clinical Trials

In a separate paper we have pointed out that in addition to safety concerns which strongly suggest the use of concentration-controlled trials (CCTs) for drugs with narrow therapeutic windows, sample size considerations favor the choice of CCTs in many situations. In this paper, we consider ways in which CCTs can be utilized to streamline the drug development process. In particular, a randomized concentration-controlled titration design is proposed for Phase II of drug development. Such a design would facilitate an assessment of efficacy early in drug development, while providing information on concentration-response for a rational choice of dose or concentration in Phase III-Alternative schemes are considered for comparison. Data analysis and dose selection based on CCTs are also discussed.

An evaluation of Bayesian microcomputer predictions of theophylline concentrations in newborn infants.

Determination of appropriate theophylline maintenance doses in preterm infants is confounded by interpatient variability. This study evaluated the performance of an IBM PC computer program applying Bayesian regression before and during steady state in 37 preterm infants. Prior population estimates of clearance and distribution volume in preterm infants and Bayesian estimates of clearance and distribution volume based on one to three theophylline plasma concentrations were used to predict subsequent concentrations (drawn 1–17 days later). We assessed the accuracy and precision of the predictive performance of the Bayesian program with the mean prediction error and the mean absolute prediction error. The absolute prediction error (mean absolute error ± SEM) significantly decreased with increasing feedback concentrations from 3.54 ± 0.45 μg/ml (population estimates) to 2.74 ± 0.42 (one feedback) and 2.02 ± 0.35 μg/ml (two feedback concentrations). Mean prediction errors (±SEM) based on one to three feedbacks (-1.5 ± 0.40 μ/ml) were significant improvements over population predictions (- 2.63 ± 0.72 μ/ml, p < 0.05), although a small but significant average overprediction remained. Absolute prediction error was correlated with postconceptional and postnatal age when zero or one but not two feedback concentrations were available. Computer program predictions based on one measured feedback concentration were more accurate and precise than population-based predictions. Refinement of population parameters or two feedback concentrations further improved performance.