Apparent tolerance to the acute effect of nicotine results in part from distribution kinetics.

Persons exposed to nicotine develop tolerance to many of its effects. When heart rate and forearm venous blood concentration are plotted against time after intravenous administration of nicotine, a greater increase in heart rate is seen for a given nicotine concentration during the rising phase of nicotine concentrations than during the decreasing phase. This could be due to acute tolerance or to more rapid distribution of drug to effect site (brain) than to venous blood. To distinguish between these possibilities, six rabbits were given nicotine intravenously. Blood samples were taken from the internal jugular vein (reflecting brain concentration), and the femoral vein and artery. Brain concentrations peaked before femoral venous concentrations. Seven men received intravenous infusions of nicotine. Peripheral venous blood concentrations and cardiovascular responses were measured. Heart rate peaked before venous concentrations. A physiological kinetic model, fit to the rabbit data, was scaled to humans and used to predict "brain" concentrations in them. Heart rate and predicted brain concentrations peaked simultaneously. We conclude that the rapid development of tolerance to the cardioaccelerating effect of nicotine can be attributed, at least in part, to its distribution kinetics.

Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer.

PURPOSE: The population pharmacokinetic/pharmacodynamic (PK/PD) approach was prospectively integrated in the clinical development of docetaxel to assess the PK profile in a large population of patients and investigate systemic exposure as a prognostic factor for clinical outcome. PATIENTS AND METHODS: PK analysis was performed at first course in 24 phase II studies of docetaxel monotherapy using four randomized limited-sampling schedules. Bayesian estimates of clearance (CL), area under the concentration-time curve (AUC), and peak and duration of plasma levels greater than threshold levels were used as measures of exposure. PD data included for efficacy, response rate, time to first response, and time to progression (TTP) in breast cancer and non-small-cell lung cancer (NSCLC), and for toxicity, grade 4 neutropenia, and febrile neutropenia at first course and time to onset of fluid retention. PK/PD analysis was conducted using logistic and Cox multivariate regression models. RESULTS: PK protocol implementation was successful. Most of the patients registered (721 of 936, 77%) were sampled and 68% were assessable for PK (640 patients). First-course docetaxel AUC was a significant predictor (P = .0232) of TTP in NSCLC (n = 151). Docetaxel CL was a strong independent predictor (P < .0001) of both grade 4 neutropenia and febrile neutropenia (n = 582). Cumulative dose was the strongest predictor (P < .0001) of the time to onset of fluid retention (n = 631). However, the duration of exposure over 0.20 micromol/L (0.16 microg/mL) at first course was an independent predictor (P = .0029). Few patients (n = 25, 4%) received the recommended dexamethasone premedication. CONCLUSION: First-course docetaxel PK is a predictor of first-course hematologic toxicity, but also of fluid retention, which is cumulative in nature. Patients with elevated hepatic enzymes have a 27% reduction in docetaxel CL and are at a higher risk of toxicity. A starting dose of 75 mg/m2 is currently being evaluated in this population. Prospective implementation of large-scale population PK/PD evaluation is feasible in early drug development and this approach generates clinically relevant findings.

Saliva lithium concentrations in the management of lithium therapy.

To define conditions under which saliva lithium carbonate concentrations can be used as a guide in lithium therapy, serum (Cp) and saliva (Cs) concentrations were determined simultaneously under different circumstances in 12 patients receiving lithium, and the effect of seven variables for example, (sex, saliva flow rate) on the Cp:Cs ratio was examined. The average ratio was 0.57 if saliva was collected in the morning before breakfast and 0.45 otherwise. The Cp:Cs ratio was found to vary much more between individuals than within an individual. We propose a method that minimizes the effect of the interindividual variation on the error in the prediction of Cp from Cs by using one or two measured Cp:Cs ratios to adjust the individual ratio. Using this technique the Cs may be useful as a predictor of the Cp in monitoring lithium therapy.

Clearance of serum creatine kinase activity.

There is confusion regarding the calculation of serum creatine kinase (CK) activity clearance from an elimination rate constant and a distribution volume derived from one- and two-compartment serum enzyme elimination models. We measured serum CK activity clearance from hepatic enzyme extraction and compared this direct measurement with clearance calculated assuming one- and two-compartment elimination models after bolus and constant infusions of a purified preparation of the MM isoenzyme of CK (MM-CK) activity. Although serum CK activity appears to confer on the body the characteristics of first-order disposition from two compartments, clearance is estimated equally well by one-, two-, and noncompartmental models of disposition and is essentially identical to the hepatic clearance of CK activity. As long as the rate constant and distribution volume are compatible and appropriate for a given elimination model, clearance, the product of the two, will be properly estimated regardless of the model chosen.

Characterizing patterns of drug-taking behavior with a multiple drug regimen in an AIDS clinical trial.

OBJECTIVE: To characterize drug-taking behavior using continuous electronic monitoring in an AIDS clinical trial. SETTING: This was a substudy of AIDS Clinical Trials Group (ACTG) protocol 175, a phase II/III study of dideoxynucleoside monotherapy versus combination therapy in asymptomatic HIV-positive subjects. Participants were required to comply with regimens containing zidovudine, zalcitabine and didanosine, or matching placebos; the total daily pill count was 16. DESIGN: For participants at two ACTG 175 sites, electronic devices were used to monitor drug-taking behavior of all study medications over a period of approximately 90 days. MEASUREMENTS: Four indices of drug-taking behavior were calculated and their distributions and relationship to the prescribed regimen were examined. RESULTS: Data from 41 subjects were analyzed. Of the prescribed doses of zidovudine, zalcitabine and didanosine, 88, 84 and 82%, respectively, were taken. Of these, 55, 66 and 79%, respectively, were taken at the prescribed dosing frequency. The median percentage of days on which participants failed to take any of the doses was 2-5%. There was a trend towards lower adherence in the combination therapy arms compared with those assigned to receive monotherapy. In this analysis, older patients demonstrated better adherence, although patient characteristics, in general, were poorly predictive of adherence. CONCLUSION: Drug-taking behavior for all three active study medications differed from that prescribed. One result of this erratic adherence was that study participants sustained little antiretroviral effect during more than 25% of the monitoring period.

A new approach to the analysis of analgesic drug trials, illustrated with bromfenac data.

A clinical trial of an analgesic agent compares pain relief scores (ordered categorical responses) over time among groups of patients, each subject to a painful procedure and given various doses of active agent (including zero, i.e., placebo) on demand. Patients may elect to remedicate with an active agent if their pain relief is insufficient, so the sample of patients at any given time is biased toward those with better relief. Standard analyses usually (1) fill in the missing data but make no correction for so doing and (2) treat the ordered categorical variable as continuous. Both of these create problems in interpretation and inference, but the former is more serious than the latter. An alternative analysis has been recently proposed that deals with these problems. This article presents that method for a nonstatistical audience and illustrates its use on some data from the analgesic bromfenac.

Estimating bioavailability when clearance varies with time.

The influence of interoccasion variability in clearance on bioavailability estimates from a traditional two-period crossover design is reported for five methods of analysis: (1) the standard crossover analysis, (2) a groupwise, parallel, analysis, (3) and (4) two correction procedures suggested by J.G. Wagner and by P.S. Collier and S. Riegelman, and (5) a pharmacokinetic nonlinear mixed-effects model analysis. Three bioavailability parameters are considered the population mean bioavailability (F), the interindividual variance of bioavailability (omega 2F) and the correlation of bioavailability with clearance [cor (CL,F)]. Data are simulated with different degrees of interoccasion variability and/or non-zero cor(CL,F). With the standard crossover analysis of these data, estimates of F, omega F, and cor(CL,F) are all biased in the presence of interoccasion variability in clearance. Estimates of F and omega 2F obtained from the parallel-group analysis are not reliable because the approach relies on the assumption that cor(CL,F) is zero. The two correction procedures are very sensitive to random error in the estimates of terminal half-life. The mixed-effect model approach produces unbiased estimates of all three bioavailability parameters. These results from simulations are supported by a real data example.

Population dose versus response of betaxolol and atenolol: a comparison of potency and variability.

The dose-response curves of betaxolol and atenolol were compared in 140 patients with mild to moderate essential hypertension. Patients with a supine diastolic blood pressure of 95 to 115 mm Hg at the end of a 4-week single-blind placebo washout phase were randomized (double-blind) to receive either betaxolol or atenolol in a dose-escalation manner. The dose (5 mg, 10 mg, and 20 mg betaxolol; 25 mg, 50 mg, and 100 mg atenolol) was increased if the supine diastolic blood pressure remained greater than 90 mm Hg after 4 weeks at each level. The final dose in the escalation phase was continued for an additional 12 weeks and then followed by a 2-week placebo phase. The data were analyzed with a population model using the program NONMEM (nonlinear mixed effects model). Atenolol exhibited a graded dose-response curve, whereas the lowest dose of betaxolol produced maximum or near-maximum effect. The estimated maximum effect (drug plus possibly unmeasured placebo effect) was similar for both treatments, about 13 mm Hg (95% confidence interval, 10 to 15 mm Hg). A trend toward less interindividual variability (coefficient of variation) was apparent for betaxolol compared to atenolol, 19% (95% confidence interval, 0% to 29%) versus 31% (95% confidence interval, 0% to 47%). The intraindividual variability (standard deviation) in supine diastolic blood pressure, 5.9 mm Hg (95% confidence interval, 5.2 to 6.5 mm Hg), did not differ significantly between drugs despite significantly greater intraindividual variability (coefficient of variation) in atenolol concentrations, 62% (95% confidence interval, 48% to 73%) versus 26% (95% confidence interval, 22% to 29%) for betaxolol.

Simultaneous modeling of pharmacokinetics and pharmacodynamics with a nonparametric pharmacodynamic model.

We describe a variation on an approach to simultaneous modeling of pharmacokinetics (PK) and pharmacodynamics (PD). Both approaches model the often-observed time lag between plasma drug concentration (Cp) and drug effect (E) in non-steady-state experiments by postulating an E site whose concentration (Ce) is kinetically linked to Cp by a first-order process. With the linking model, the time lag can be removed from the data and the underlying concentration-response (Ce-E) relationship can be estimated. The original method requires the analyst to postulate a particular parametric form for the Ce-E model, whereas ours does not. It estimates the rate constant of the linking model as the value that causes the hysteresis curve (Ce vs E points connected in time order) to collapse to a single curve that represents the (empirical) Ce-E relationship. The method is presented as an algorithm and is tested by means of simulation and a real-world example. The results suggest that the method can faithfully estimate the Ce-E curve for a variety of PD models and degrees of experimental error when its basic assumption of time-invariant PD holds.

Simultaneous modeling of pharmacokinetics and pharmacodynamics with nonparametric kinetic and dynamic models.

Three models, linked in series, can be used to analyze combined pharmacokinetic (PK) and pharmacodynamic (PD) data arising from non--steady-state experiments. A PK model relates dose to plasma drug concentration (Cp); a link model relates Cp to drug concentration at the effect site (Ce); and a PD model relates Ce to drug effect (E). All three submodels can be stated parametrically. Recently the use of a nonparametric PD submodel has been proposed (CLIN PHARMACOL THER 1984;35:733-41). In this article we use an extended nonparametric approach that represents both the PK and PD models nonparametrically, but retains a parametric link model. Cp data from several PK models and E data from several PD models were simulated. After the addition of noise to both the Cp and E data, they were analyzed by both the parametric and extended nonparametric methods. The methods were compared by how well they estimated the PD model. To assess robustness, the effect of misspecification of the PK submodel on the goodness of estimation of both methods was also compared. In the absence of model misspecification, the parametric method usually estimates the PD model better than the nonparametric method. However, this difference in the performances diminishes and even reverses when the PK model is misspecified. Because one can rarely be certain that model misspecification is absent, the nonparametric approach may offer a distinct advantage for routine analysis of PK/PD data.

Zidovudine response relationships in early human immunodeficiency virus infection.

OBJECTIVE: To examine predictors of magnitude of CD4+ response to treatment of human immunodeficiency virus (HIV) infection with zidovudine. METHODS: This was a post hoc analysis of randomized placebo-controlled clinical trial in a multicenter trial, 1423 asymptomatic HIV-positive subjects with CD4+ cell counts less than 500 mm-3 were given 500 mg/day zidovudine, 1500 mg/day zidovudine, or placebo. The main outcome measure was change in the CD4+ cell counts over time. RESULTS: This study suggests that earlier treatment with zidovudine results in a larger increment in the CD4+ cell count. In addition, the increment in CD4+ cell count is very long lived. However, drug exposure was not found to be a predictor of response to treatment in the dose range studied. CONCLUSIONS: A parametric model of disease progression can be estimated with use of data collected in a conventionally designed study. These parametric models may provide insight into the optimal use of drugs. This model suggests that zidovudine does not change the underlying course of HIV infection but simply delays the time course. The model also suggests that the magnitude of this delay is larger when treatment is begun earlier in the course of the disease.

Pharmacokinetic-pharmacodynamic modeling of caffeine: tolerance to pressor effects.

We propose a parametric pharmacokinetic-pharmacodynamic model for caffeine that quantifies the development of tolerance to the pressor effect of the drug and characterizes the mean behavior and inter-individual variation of both pharmacokinetics and pressor effect. Our study in a small group of subjects indicates that acute tolerance develops to the pressor effect of caffeine and that both the pressor effect and tolerance occur after some time delay relative to changes in plasma caffeine concentration. The half-life of equilibration of effect with plasma caffeine concentration is about 20 minutes. The half-life of development and regression of tolerance is estimated to be about 1 hour, and the model suggests that tolerance, at its fullest, causes more than a 90% reduction of initial (nontolerant) effect. Whereas tolerance to the pressor effect of caffeine develops in habitual coffee drinkers, the pressor response is regained after relatively brief periods of abstinence. Because of the rapid development and regression of tolerance, the pressor response to caffeine depends on how much caffeine is consumed, the schedule of consumption, and the elimination half-life of caffeine.

A pharmacodynamic model of erythropoietin therapy for uremic anemia.

Fifty-seven patients receiving chronic high-flux hemodialysis began receiving recombinant alpha-human erythropoietin (rHuEPO). The mean initial rHuEPO dose used in 54 evaluable patients was 9963 +/- 4364 U/week; the final dose was 8972 +/- 4058 U/week. Treatment over a mean period of 154 +/- 40 days (84 to 224 days) resulted in an average increase in hematocrit from 24.7% +/- 3.7% to 32.5% +/- 4.4%. We present a model for these data that describes changes in hematocrit during rHuEPO therapy and that allows simultaneous estimation of red blood cell lifespan and rHuEPO-induced increases in red blood cell production rate. Analysis of the hematocrit values of the patients with the model, by use of NONMEM, a computer program for analysis of population data, reveals a nonlinear dose-response relationship with large interindividual variability (coefficient of variation) of about 50%. The estimated mean red blood cell lifespan is 64 days, with interindividual variability of about 30% (coefficient of variation). The intraindividual random variability in hematocrit about its prediction is +/- 5% of the prediction. For clinical dose adjustment, we present a method that uses only simple calculations.

Study designs for dose-ranging.

Premarketing dose-ranging studies of a drug are done to establish a reasonable initial dose. According to the current procedure sanctioned by the Food and Drug Administration, each patient is given one of several possible doses, including placebo, after an initial placebo run-in period. Data analysis is based on a model in which the mean response at each dose is independent of the magnitude of the dose. The initial dose is the lowest dose tested that has a response that is statistically significantly greater than the response after placebo administration. We suggest that the present conceptual approach to, and standard study design and analysis for, dose-ranging studies be changed. We believe one must begin with a parametric model for patient-specific dose-response curves. Knowledge of the distribution of these curves in a population provides a basis for choice of an initial dose (e.g., the dose that achieves a given response in a given fraction of patients) and, after observation of response to an initial dose, for choice of an incremental dose for a specific patient (by use of Bayes rule). The current parallel-dose design can provide only poor information about the distribution of dose-response curves, biased estimates of the typical curve, and little information on interpatient variability. Crossover studies provide better information. In studies in which a parametric patient-specific dose-response model is used, a dose-escalation design provides no less information than a crossover design, and it has ethical advantages that allow a more representative patient group and clinical setting to be studied.

Pyridostigmine kinetics with and without renal function.

Pyridostigmine kinetics were examined under conditions of clinical use as an antagonist of nondepolarizing neuromuscular blockade in anesthetized patients with and without renal function. Pyridostigmine serum levels were assayed by gas-liquid chromatography, and data were fitted to a 2-compartment kinetic model. Pyridostigmine kinetics following renal transplantation (n = 5) were not different from those in patients with normal renal function. Renal function (n = 5) elimination half-life increased from 112 +/- 12 min (mean +/- SD) to 379 +/- 162 min, and serum clearance decreased from 9 +/- 2 ml/kg/min to 2 +/- 0.6 ml/kg/min in anephric patients (n = 4). We conclude that renal function accounts for 75% of pyridostigmine clearance.

Forecasting individual pharmacokinetics.

Often drug dosage may be chosen rationally by use of plasma concentration (CP) as the "therapeutic" end point. The ability to accurately forecast the CP resulting from a dosage regimen is central to choosing that regimen. Tradionally forecasting has been attempted only by accounting for known influences on pharmacokinetics, such as sex, age, and renal disease. One must also adjust for previously observed CPs. Herein, we discuss and explain an approach to both of these tasks, mainly focusing on the latter. The approach balances observed outcomes against prior expectations taking account of observation CP error. For digoxin, use of 1 measured CP, as opposed to none, improves forecast precision for future CPs by 40% (decrement in variance of forecast error), and 2 CPs improve it by 67%. There is also an increase in forecast accuracy (decrement in mean of forecast error) as the number of CPs used increases. After only 2, forecast accuracy and precision are as good as theoretically possible. Moreover, information from CPs is far more valuable for forecasting than that from observable patient features-sex, age, and the like; use of all the latter information does not improve accuracy and precision as much as only 1 CP.

The renal elimination of procainamide.

The question of pH or flow dependence for the renal elimination of procainamide (PCA) was studied under 4 conditions in each of 4 subjects. Each subject received 500 mg of PCA intravenously at weekly intervals while in a state of (1) acid load (NH4Cl) and water deprivation, (2) acid load and water excess, (3) alkali load (NaHCO3) and water deprivation, and (4) alkali load and water excess. Plasma and urine were collected at frequent intervals for PCA and N-acetyl PCA (NAPA) analysis. Urine flow rates varied markedly between the water deprivation and water excess states (approximately 1.2 vs 5 ml/min, respectively), and urine pH varied markedly between the acid and alkali load states (pH = ca 5 vs 8, respectively). Despite this marked variation, there were no significant changes in PCA renal clearance or 24-hr PCA or NAPA excretion. If passive diffusion of PCA were taking place, such flow and pH changes would have caused marked changes in PCA clearance were the pH partition hypothesis true. We therefore conclude that passive diffusion is not an important mechanism in the renal elimination of PCA in man and that there must be tubular secretion. The implication for the clinical use of the drug is that dose adjustments need not be made in response to variations in urine flow and pH.

Determinants of the renal clearance of digoxin.

The renal clearances of digoxin, creatinine, and urea nitrogen were determined simultaneously in each of 41 patients receiving digoxin, in most of whom there was prerenal azotemia. Mean plus or minus SD values were: blood urea nitrogen (BUN), 26.1 plus or minus 12.8 mg per 100 ml; creatine, 1.1 + 0.41 mg per 100 ml; creatinine clearance, 78 plus or minus 42 ml/min/1.73 m2; digoxin clearance, 66.6 plus or minus 42.1 ml/min/1.73 m2; urea nitrogen clearance, 27.8 plus or minus 19.2 ml/min/1.73 m2. Correlation analysis revealed that urea clearance is superior to creatinine clearance, and BUN is superior to serum creatinine concentration in the degree of relationship to renal digoxin clearance. Moreover, using partial correlation techniques, it is apparent that in these patinets digoxin clearance was significantly related to urine flow rate. These findings are compatible with the hypothesis that digoxin undergoes some degree of tubular reabsorption as well as filtration and secretion.

Passive versus electrotransport-facilitated transdermal absorption of ketorolac.

OBJECTIVE: To investigate the bioavailability (extent and rate of absorption) of ketorolac from two cutaneous absorption sources, active electrotransport and passive transdermal, and to examine the enantiomeric selectivity of bioavailability for each source. METHODS: Based on a crossover study in 12 healthy volunteers, the extent and rate of absorption of ketorolac, delivered by a patch, were found by estimating the input rate function of the drug. For that purpose, deconvolution was used in two steps. First, intravenous data were analyzed to estimate the ketorolac disposition function, and second, postpatch data were deconvolved to estimate the unknown patch input profile given the disposition function estimated in the first step. Because the input rate function curves to be estimated for the patches may be of arbitrary shape, a spline was used to model the patch input function, whereas intravenous data were modeled with use of a sum of exponentials. Differences in the extent of absorption (F) for the four treatment-enantiomer combinations were further examined with a mixed-effect regression model, based on the sets of four individual estimates of bioavailability. RESULTS: On average, the F value for the active electrotransport treatment, which exhibited the faster absorption rate, was four times greater than the F for the passive transdermal treatment. Further, during the passive treatment, R-ketorolac yielded an average F that is 42% greater than that for S-ketorolac and also exhibited a smaller absorption lag-time. During the active treatment, there was no important enantiomeric difference in either extent or rate of absorption.

Relationship between the pharmacokinetics and pharmacodynamics of procainamide.

The kinetics of a measure of pharmcologic effect (prolongation of the QT interval) of procainamide, as well as the kinetics of the plasma concentration, urine excretion, and saliva concentration of the drug were investigated in 14 trials in 4 subjects. A single 500-mg dose was given by rapid intravenous infusion, and frequent subsequent determinations of the above variables were made. A 2-compartment pharmacokinetic model with a third compartment for the saliva was used to fit the plasma, urine, and saliva data simultaneously. Analysis of the data reveals that the kinetics of the drug concentrations in saliva and of the pharmacologic effect are indistinguishable. They both must be considered to be different from those of the drug concentrations in plasma. Thus, in normal individuals under the conditions of this study, saliva concentrations more precisely indicate the time-course of drug at a cardiac site of action, although they do not parallel plasma drug concentrations until 6 hr or more after a rapid intravenous infusion. The following average pharmacokinetic parameters for plasma were found: terminal half-life, 2.9 hr; total clearance, 828 ml/min; renal clearance, 334 ml/min; and steady-state volume of distribution, 180 L. Average distribution pseudoequilbrium half-time (t1/2 alpha) was 5.2 min from an initial volume of distribution of 36.6 L.